Rochester, MN, United States
Rochester, MN, United States

Mayo Medical School is a research institution and medical school which is a part of the Mayo Clinic in Rochester, Minnesota, United States. It grants degrees in medicine, and is accredited by the North Central Association of Colleges and Schools. Currently, it is considered the most selective school in terms of acceptance rates. It had an acceptance rate of 2.1% in the year 2012. It is also considered one of the least expensive private medical schools in the country in the 2012-2013 academic school year. Wikipedia.

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Murad M.H.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2017

Trustworthy clinical practice guidelines should be based on a systematic review of the literature, provide ratings of the quality of evidence and the strength of recommendations, consider patient values, and be developed by a multidisciplinary panel of experts. The quality of evidence reflects our certainty that the evidence warrants a particular action. Transforming evidence into a decision requires consideration of the quality of evidence, balance of benefits and harms, patients’ values, available resources, feasibility of the intervention, acceptability by stakeholders, and effect on health equity. Empirical evidence shows that adherence to guidelines improves patient outcomes; however, adherence to guidelines is variable. Therefore, guidelines require active dissemination and innovative implementation strategies. © 2017 Mayo Foundation for Medical Education and Research

In selected centers, colonic manometry with non-high-resolution catheters is used to document colonic motor dysfunction in chronic constipation. Recently, high-resolution manometry (HRM) catheters, with more closely spaced sensors have been used for this purpose. Corestti et al. assessed colonic pressures with HRM in 17 healthy people and 10 constipated patients. The main finding was pan-colonic pressurizations, which occurred frequently, increased after eating and cholinergic stimulation, were associated with the desire to pass flatus, and were less frequent in slow-transit constipation. These events resemble esophageal common cavity pressure waves. Further studies are necessary to understand the pathogenesis, functional consequences, and clinical utility of pan-colonic pressurizations. © 2017 by the American College of Gastroenterology.

Viozzi C.F.,Mayo Medical School
Clinics in Sports Medicine | Year: 2017

Sports account for 3% to 29% of facial injuries and 10% to 42% of facial fractures. Fractures of the facial skeleton most commonly occur owing to interpersonal violence or motor vehicle crashes. Facial fractures from sporting activities has clearly decreased over time owing to better preventive measures. However, this decreasing trend is offset by the emergence of more dangerous sports activities, or “pushing the envelope” of traditional sports activities. Fractures can occur from contact between athletes, and between athletes and their surroundings. Football, soccer, hockey, and baseball most frequently are involved in sports-related cases of facial bone fracture. © 2016 Elsevier Inc.

Neuroendocrine tumors (NETs) are rare neoplasms that can arise from any tissue. They are classified based on embryonic gut derivative (i.e. foregut, midgut and hindgut) with midgut tumors being the most common (e.g. gastrointestinal NET). The second most common category of NETs is that which arises from the lung. In fact, 25% of primary lung cancers are NETs, including small cell lung cancer (SCLC), which comprises 20% of all lung cancers. The remaining 5% are large cell neuroendocrine cancer (LCNEC, 3%), typical carcinoids (TCs, 1.8%), and atypical carcinoids (ACs, 0.2%). The less common TCs/ACs are well differentiated lung NETs. Their incidence has been increasing in more recent years and although these tumors are slow growing, advanced disease is associated with poor survival. There have been advances in classification of lung NETs that have allowed for more appropriate management upfront. They are cured by surgical resection when disease is limited. However, advanced and metastatic disease requires medical therapy that is ever changing and expanding. In this review, the aim is to summarize the current understanding and classification of well differentiated lung NETs (i.e. TCs and ACs), and focus on recent updates in medical management of advanced disease, along with a brief discussion on potential future discoveries. © SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses.

Katzka D.A.,Mayo Medical School
Current Gastroenterology Reports | Year: 2017

Purpose of Review: The costs to society and accuracy of screening for esophageal cancer and other esophageal diseases with standard endoscopy are formidable. As a result, the applicability of endoscopy as a general screening tool has been challenged. Recent Findings: To maintain accuracy but reduce the price of endoscopy on society, multiple adjunct or replacement technologies are being developed that are less expensive and more easily applied. These devices include image-enhancing techniques that more reliably identify dysplasia and cancer reducing the need for extensive biopsy sampling during standard endoscopy. They also include ambulatory forms for procuring esophageal imaging including smaller endoscopes and capsule endoscopy. Finally, some of the newer methods either obtain samples of esophageal tissue through bedside maneuvers not requiring endoscopy or retrieve information about mucosal inflammation and function without the need to procure esophageal tissue. Summary: There is an exciting future for esophageal diagnosis with tools that will save cost and/or provide greater accuracy and safety for some of the most common esophageal disorders. © 2017, Springer Science+Business Media New York.

Colbenson K.,Mayo Medical School
Clinics in Sports Medicine | Year: 2017

On-the-field evaluation of facial trauma requires a focused initial assessment of the patient's airway and breathing with a knowledge of the critical associated injuries. The initial triage in facial trauma involves assessing and protecting the athlete's airway, breathing, and cervical spine. The algorithm then requires a repeat evaluation for subtle causes of airway obstruction and aspiration risks. Final steps include control of hemorrhage, recognition of neurologic and ophthalmologic disability, and complete exposure of the athlete to examine for other associated injury. The ABC repeat ABCDE mnemonic allows providers to avoid missing critical injuries that require immediate intervention. © 2016 Elsevier Inc.

Chascsa D.,Mayo Medical School | Carey E.J.,Mayo Medical School | Lindor K.D.,Mayo Medical School | Lindor K.D.,Arizona State University
Liver International | Year: 2017

Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Peters S.A.,Mayo Medical School
American Journal of Gastroenterology | Year: 2017

OBJECTIVES:The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function.METHODS:A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g 13C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression.RESULTS:There were no differences in the in vivo measurements of barrier function between IBS-C patients and healthy controls: cumulative excretion of 13C mannitol (0–2 h mean (s.e.m.); IBS-C: 12.1 (0.9) mg vs. healthy: 13.2 (0.8) mg) and lactulose (8–24 h; IBS-C: 0.9 (0.5) mg vs. healthy: 0.5 (0.2) mg); duodenal impedance IBS-C: 729 (65) Ω vs. healthy: 706 (43) Ω; plasma mean endotoxin activity level IBS-C: 0.36 (0.03) vs. healthy: 0.35 (0.02); and in colonic mRNA expression of occludin, zonula occludens (ZO) 1–3, and claudins 1–12 and 14–19. The ex vivo findings were consistent, with no group differences: duodenal TMR (IBS-C: 28.2 (1.9) Ω cm2 vs. healthy: 29.8 (1.9) Ω cm2) and colonic TMR (IBS-C: 19.1 (1.1) Ω cm2 vs. healthy: 17.6 (1.7) Ω cm2); fluorescein isothiocyanate (FITC)–dextran (4 kDa) and E. coli Bio-Particle flux. Colonic basal Isc was similar, but duodenal basal Isc was lower in IBS-C (43.5 (4.5) μA cm2) vs. healthy (56.9 (4.9) μA cm2), P=0.05. Ach-evoked ΔIsc was similar.CONCLUSIONS:Females with IBS-C have normal colonic barrier and secretory function. Basal duodenal secretion is decreased in IBS-C.Am J Gastroenterol advance online publication, 21 March 2017; doi:10.1038/ajg.2017.48. © 2017 American College of Gastroenterology

Mukewar S.S.,Mayo Medical School
American Journal of Gastroenterology | Year: 2017

Objectives:Refractory celiac disease (RCD) is a rare condition often associated with poor prognosis. Various immunosuppressive medications (IMs) have been used with modest success. We describe outcomes in patients treated with open-capsule budesonide (OB), including those for whom IM treatment failed.Methods:We identified RCD patients treated with OB at Mayo Clinic, Rochester, Minnesota from 2003 to 2015. Demographic, serologic, and clinical variables were analyzed.Results:We identified 57 patients who received OB for suspected RCD. Based on clonal T-cell receptor gamma gene rearrangement or aberrant phenotype of intraepithelial lymphocytes (IELs), 13 patients (23%) were classified as having RCD-2 and 43 (75%) as RCD-1. In one patient (2%) TCR gene rearrangement status was unknown. Most patients were women (69%), mean (s.d.) age was 60.5 (3.5) years and body mass index was 28.4 (4.5) kg/m2. The majority had diarrhea (72%), with median of 6 bowel movements per day (range, 4–25). IM treatment (azathioprine, systemic corticosteroids, or regular budesonide) had failed in nearly half. Twenty-four patients (42%) had anemia and 12 (21%) had hypoalbuminemia. All had Marsh 3 lesions on biopsy: 3a (19%), 3b (46%), and 3c (35%). After OB therapy, the majority had clinical (92%) and histologic (89%) improvement. Follow-up biopsy in 7 out of 13 patients with RCD-2 (53%) showed an absence of clonal TCR gamma gene rearrangement/aberrant IEL phenotype previously seen. On follow-up, 2 patients (4%) died of enteropathy-associated T-cell lymphoma.Conclusions:Most patients with RCD show clinical and histopathologic improvement with OB therapy, including those with failure of IMs. OB is a promising therapeutic option for management of RCD.Am J Gastroenterol advance online publication, 21 March 2017; doi:10.1038/ajg.2017.71. © 2017 American College of Gastroenterology

OBJECTIVES:: Scleral lenses settle on the eye with time, and the depth of the postlens fluid reservoir decreases. We measured changes in central, superior, inferior, temporal, and nasal clearance beneath a small-diameter scleral lens after 2 hr of lens wear in healthy eyes. METHODS:: Thirty-one participants (age, mean±SD, 29±7 years) with no history of eye disease or scleral lens wear were fitted with a 15-mm scleral lens in 1 eye. Scheimpflug images were acquired by a camera system within 5 min of lens placement and again after 2 hr of continuous lens wear. The central cornea was located in both horizontal and vertical meridians, and lens clearance was measured at that point. Lens clearance was also measured 2 mm superior, inferior, nasal, and temporal to the center of the cornea. RESULTS:: After 2 hr of lens wear, central clearance was reduced 46% (mean [SD], from 227 [77] to 122 [61] μm; P<0.001). Superior clearance was reduced 48% (from 168 [62] to 87 [61] μm); inferior clearance, 54% (from 241 [82] to 111 [55] μm); temporal clearance, 45% (from 224 [79] to 124 [74] μm); and nasal clearance, 52% (from 166 [73] to 80 [49] μm) (P<0.001 for all). Statistically significant decreases in clearance were noted at all points assessed after 2 hr of lens wear. CONCLUSIONS:: Fluid reservoir depth beneath small-diameter scleral lenses decreased nearly 50% after 2 hr of lens wear in normal eyes. © 2017 Contact Lens Association of Ophthalmologists, Inc.

Renfro L.A.,Mayo Medical School | Sargent D.J.,Mayo Medical School
Annals of Oncology | Year: 2017

In recent years, cancers once viewed as relatively homogeneous in terms of organ location and treatment strategy are now better understood to be increasingly heterogeneous across biomarker and genetically defined patient subgroups. This has produced a shift toward development of biomarker-targeted agents during a time when funding for cancer research has been limited; as a result, the need for improved operational efficiency in studying many agent-and-target combinations in parallel has emerged. Platform trials, basket trials, and umbrella trials are new approaches to clinical research driven by this need for enhanced efficiency in the modern era of increasingly specific cancer subpopulations and decreased resources to study treatments for individual cancer subtypes in a traditional way. In this review, we provide an overview of these new types of clinical trial designs, including discussions ofmotivation for their use, recommended terminology, examples, and challenges encountered in their application. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Murashita T.,Mayo Medical School
Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery | Year: 2017

ABSTRACT: Redo aortic valve replacement (AVR) performed simultaneously with left ventricular assist device (LVAD) implantation carries potential for increased mortality rates. Although transcatheter AVR has been used for patients with previous LVAD placement, no literature reports concomitant valve-in-valve transcatheter AVR and LVAD implantation. Our patient had severe aortic prosthetic valve deterioration and advanced heart failure. Given the risks associated with reoperative aortic valve surgery, we chose transcatheter AVR at the time of LVAD implantation. Transthoracic echocardiography results showed severe aortic prosthetic valve deterioration with moderate aortic regurgitation as well as severe left ventricular dysfunction (ejection fraction, 11%). After redosternotomy, we performed transcatheter AVR via the ascending aorta and subsequent LVAD implantation. The postoperative course was uneventful. Generally, patients with structural deterioration of a bioprosthetic valve who report for LVAD therapy present considerable challenges to the surgeon. Concomitant transcatheter AVR offers a less-invasive alternative to surgical AVR that minimizes ischemic injury to myocardium. ©2017 by the International Society for Minimally Invasive Cardiothoracic Surgery

Objectives:The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNβ3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNβ3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy.Methods:Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNβ3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods.Results:GNβ3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy–Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNβ3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43).Conclusions:GNβ3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.Am J Gastroenterol advance online publication, 14 March 2017; doi:10.1038/ajg.2017.52. © 2017 American College of Gastroenterology

Shannon S.F.,Mayo Medical School
Journal of Pediatric Orthopaedics | Year: 2017

OBJECTIVES:: The purpose of this study was to evaluate pediatric scapula fractures occurring in high-energy motorized vehicle accidents and their associated injury patterns in a pediatric patient population. METHODS:: One thousand nine hundred sixty-eight pediatric patients who presented after either on-road or off-road motorized vehicle accidents between 1996 and 2015 were retrospectively reviewed. Thirty-eight patients were found to have scapula fractures and the remaining 1930 were identified as controls. RESULTS:: A total of 39 scapula fractures occurred in 38 patients. The most common pattern was the AO/OTA 14-A3 (n=32), followed by 14-A2 (n=5), 14-B1 (n=1), and 14-C2 (n=1). Scapula fracture patients experienced higher rate of spine fractures (42% vs. 18%, P=0.001), skull fractures (26% vs. 12%, P=0.02), rib fractures (40% vs. 7.6%, P<0.0001), clavicle fractures (34% vs. 6%, P<0.0001), and upper extremity fractures (58% vs. 21%, P<0.0001) compared with controls. Scapula fracture patients had higher Injury Severity Scores (22.1 vs. 10.8, P<0.0001), thoracic injury (79% vs. 31%, P<0.0001), intracranial hemorrhage (32% vs. 15%, P=0.012), pneumothorax (55% vs. 8%, P<0.0001), and lung contusion (63% vs. 12%, P<0.0001). No difference in mortality was observed for scapula and control patients (5% vs. 2%, P=0.302). CONCLUSIONS:: Pediatric scapula fractures were not associated with higher mortality rates in this series but were associated with significant morbidity as demonstrated by high rates of associated intracranial hemorrhage, skull fractures, thoracic injury, upper extremity fractures, and spine fractures compared with control patients. Surgeons who care for pediatric trauma patients should view scapula fractures as an indicator for more significant injuries. LEVEL OF EVIDENCE:: Level III. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Vyas K.S.,Mayo Medical School
Annals of Plastic Surgery | Year: 2017

BACKGROUND: Telemedicine, the use of information technology and telecommunication to provide healthcare at a distance, is a burgeoning field with applications throughout medicine. Given the visual nature of plastic surgery and dermatology, telemedicine has a myriad of potential applications within the field. METHODS: A comprehensive literature review of articles published on telemedicine since January 2010 was performed. Articles were selected for their relevance to plastic and reconstructive surgery and dermatology, and then reviewed for their discussion of the applications, benefits, and limitations of telemedicine in practice. RESULTS: A total of 3119 articles were identified in the initial query. Twenty-three articles met the inclusion criteria in plastic surgery (7 wound management, 5 burn management, 5 trauma, 4 free flap care, 2 in cleft lip/palate repair). Twenty-three (100%) reported a benefit of telemedicine often related to improved postoperative monitoring, increased access to expertise in rural settings, and cost savings, either predicted or actualized. Eight (35%) reported limitations and barriers to the application of telemedicine, including overdiagnosis and dependence on functional telecommunication systems. Sixty-six articles focused on telemedicine in dermatology and also demonstrated significant promise. CONCLUSIONS: Telemedicine holds special promise in increasing the efficiency of postoperative care for microsurgical procedures, improving care coordination and management of burn wounds, facilitating interprofessional collaboration across time and space, eliminating a significant number of unnecessary referrals, and connecting patients located far from major medical centers with professional expertise without impinging on—and in some cases improving—the quality or accuracy of care provided. Teledermatology consultation was found to be safe and has a comparable or superior efficacy to the traditional in-patient consultation. The system was consistently rated as convenient and easy to use by patients, referring physicians, and consulting dermatologists. Teledermatology has also been used as an educational tool for patients. A significant number of studies detailed strategies to improve the current state of teledermatology, either by implementing new programs or improving technologies. Telemedicine use is widespread among plastic surgeons and is enabling the spread of expertise beyond major medical centers. Further research is needed to conclusively demonstrate benefit in routine clinical care. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Mahipal A.,Mayo Medical School | Grothey A.,Mayo Medical School
Journal of Oncology Practice | Year: 2016

In the past decade, significant advances have been made in the treatment of advanced colorectal cancer. Multiple cytotoxic agents and targeted therapies have been approved formanagement of metastatic colorectal cancer, leading to improvement of median overall survival in clinical trials to more than 30 months. Of note, before the introduction of biologics into treatment algorithms for metastatic colorectal cancer, median survival in phase III trials never exceeded 24 months. In 2016, the most common treatment approach in first line is a combination of chemotherapy with a biologic agent. The choice of therapy is influenced by patient factors (eg, age, comorbidities), tumor characteristics (eg, overall tumor burden, pattern of metastatic spread, mutation signature), potential adverse effects of therapy, and goals of treatment. The choice between irinotecan- or oxaliplatin-based cytotoxic chemotherapy regimen is primarily based on differential toxicity profile because they have similar efficacy. Currently, three biologic agents-bevacizumab, cetuximab, and panitumumab-are approved for first-line treatment of metastatic colorectal cancer. For patients with mutant RAS and likely mutant BRAF V600E tumors, bevacizumab is the only biologic agent that can be used in conjunction with cytotoxic chemotherapy. The choice of anti-epidermal growth factor antibody or anti-vascular endothelial growth factor antibody in RAS wild-type tumors is based on the specific clinical scenario. Recently, some clinical and molecular biomarkers have emerged that may help in decision making. In this review, we discuss the role of biologics in the management of first-line treatment of metastatic colorectal cancer. Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

Ussavarungsi K.,Mayo Medical School | Kern R.M.,Mayo Medical School | Roden A.C.,Mayo Medical School | Ryu J.H.,Mayo Medical School | Edell E.S.,Mayo Medical School
Chest | Year: 2017

Background Diagnostic evaluation of patients with diffuse parenchymal lung disease (DPLD) is best achieved by a multidisciplinary team correlating clinical, radiological, and pathologic features. Surgical lung biopsy remains the gold standard for histopathologic diagnosis of idiopathic interstitial pneumonias. Emerging data suggest an increasing role for transbronchial cryobiopsy (TBC) in DPLD evaluation. We describe our experience with TBC in patients with DPLD. Methods We retrospectively reviewed medical records of patients with radiographic features of DPLD who underwent TBC at Mayo Clinic in Rochester, Minnesota from June 2013 to September 2015. Results Seventy-four patients (33 women [45%]) with a mean age of 63 years (SD, 13.8) were included. The mean maximal diameter of the samples was 9.2 mm (range, 2-20 mm [SD, 3.9]). The median number of samples per procedure was three (range, one to seven). Diagnostic yield was 51% (38 of 74 specimens). The most frequent histopathologic patterns were granulomatous inflammation (12 patients) and organizing pneumonia (OP) (11 patients), resulting in the final diagnoses of hypersensitivity pneumonitis (six patients), cryptogenic OP (six patients), connective tissue disease-associated OP (three patients), drug toxicity (three patients), infection-related OP (two patients), sarcoidosis (two patients), and aspiration (one patient). Other histopathologic patterns included respiratory bronchiolitis (three patients), acute fibrinous and organizing pneumonia (two patients), desquamative interstitial pneumonia (1 patient), diffuse alveolar damage (one patient), pulmonary alveolar proteinosis (one patient), amyloidosis (one patient), eosinophilic pneumonia (one patient), necrotizing vasculitis (one patient), bronchiolitis with food particles (one patient), and malignancy (three patients). Pneumothorax developed in one patient (1.4%), and bleeding occurred in 16 patients (22%). Conclusions Our single-center cohort demonstrated a 51% diagnostic yield from TBC; the rates of pneumothorax and bleeding were 1.4% and 22%, respectively. The optimal use of TBC needs to be determined. © 2016 American College of Chest Physicians

Holst K.A.,Mayo Medical School | Said S.M.,Mayo Medical School | Nelson T.J.,Molecular Therapeutics | Cannon B.C.,Molecular Therapeutics | Dearani J.A.,Mayo Medical School
Circulation Research | Year: 2017

Successful outcome in the care of patients with congenital heart disease depends on a comprehensive multidisciplinary team. Surgery is offered for almost every heart defect, despite complexity. Early mortality for cardiac surgery in the neonatal period is ≈10% and beyond infancy is <5%, with 90% to 95% of patients surviving with a good quality of life into the adult years. Advances in imaging have facilitated accurate diagnosis and planning of interventions and surgical procedures. Similarly, advances in the perioperative medical management of patients, particularly with intensive care, has also contributed to improving outcomes. Arrhythmias and heart failure are the most common late complications for the majority of defects, and reoperation for valvar problems is common. Lifelong surveillance for monitoring of recurrent or residual structural heart defects, as well as periodic assessment of cardiac function and arrhythmia monitoring, is essential for all patients. The field of congenital heart surgery is poised to incorporate new innovations such as bioengineered cells and scaffolds that will iteratively move toward bioengineered patches, conduits, valves, and even whole organs. © 2017 American Heart Association, Inc.

Leung N.,Mayo Medical School
Blood | Year: 2017

In this issue of Blood, Chauvet et al reported the largest study to date of the treatment outcomes in patients with monoclonal gammopathy-associated C3 glomerulopathy (C3G). Renal outcomes were found to be dependent on hematological response for the first time in this disease. The data presented here could be used to help design future studies and trials. © 2017 by The American Society of Hematology.

Rosales A.,Mayo Medical School
The American surgeon | Year: 2016

Spontaneous hemorrhage from hepatic tumors is an uncommon but serious complication. Recently, interventional radiologic (IR) techniques are being used increasingly in the management of these patients. We report our 16-year experience in managing spontaneous hemorrhage from liver tumors. Twenty-six consecutive patients were diagnosed with spontaneous liver hemorrhage between 1995 and 2011. Initial management was operative in eight, IR in six, and supportive in 12 patients. Of those managed operatively, five were segmentectomies; one hemihepatectomy; one wedge resection; and one packing who later died from coagulopathy. In the IR patients, seven had an angiographic embolization; two required reembolization; one underwent resection of a hepatic adenoma 21 days after angiographic embolization. The malignant lesions included hepatocellular carcinoma (n = 6), angiosarcoma (n = 1), metastatic squamous cell carcinoma (n = 1), metastatic leiomyosarcoma (n = 1), nonsquamous cell carcinoma (n = 1), or metastatic angiosarcoma (n = 1). Benign diseases included hepatic adenoma (n = 5), end-stage liver disease (n = 1), and polycystic liver (n = 1). Spontaneous hemorrhage from the liver occurs evenly from benign or malignant causes, one-third of which are primary liver disease. If the patients presents emergently, angiographic embolization may control the bleeding and allow for elective resection once the sequelae of bleeding have resolved.

Alvarez-Dominguez J.R.,Harvard Stem Cell Institute | Zhang X.,Mayo Medical School | Hu W.,Mayo Medical School
Blood | Year: 2017

Cell development requires tight yet dynamic control of protein production. Here, we use parallel RNA and ribosome profiling to study translational regulatory dynamics during murine terminal erythropoiesis. Our results uncover pervasive translational control of protein synthesis, with widespread alternative translation initiation and termination, robust discrimination of long noncoding from micropeptide-encoding RNAs, and dynamic use of upstream open reading frames. Further, we identify hundreds of messenger RNAs (mRNAs) whose translation efficiency is dynamically controlled during erythropoiesis and that enrich for target sites of RNA-binding proteins that are specific to hematopoietic cells, thus unraveling potential regulators of erythroid translational programs. A major such program involves enhanced decoding of specific mRNAs that are depleted in terminally differentiating/enucleating cells with decreasing transcriptional capacity. We find that RBM38, an erythroid-specific RNA-binding protein previously implicated in splicing, interacts with the general translation initiation factor eIF4G and promotes translation of a subset of these irreplaceable mRNAs. Inhibition of RBM38 compromises translation in erythroblasts and impairs their maturation, highlighting a key function for this protein during erythropoiesis. These findings thus reveal critical roles for dynamic translational control in supporting specialized mammalian cell formation. © 2017 by The American Society of Hematology.

Crepeau A.Z.,Mayo Medical School | Sirven J.I.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2017

Epilepsy is a common yet heterogeneous disease. As a result, management often requires complex decision making. The ultimate goal of seizure management is for the patient to have no seizures and no considerable adverse effects from the treatment. Antiepileptic drugs are the mainstay of therapy, with more than 20 medications currently approved in the United States. Antiepileptic drug selection requires an understanding of the patient's epilepsy, along with consideration of comorbidities and potential for adverse events. After a patient has failed at least 2 appropriate antiepileptic drugs, they are determined to be medically refractory. At this time, additional therapy, including dietary, device, or surgical treatments, need to be considered, typically at a certified epilepsy center. All these treatments require consideration of the potential for seizure freedom, balanced against potential adverse effects, and can have a positive effect on seizure control and quality of life. This review article discussed the treatment options available for adults with epilepsy, including medical, surgical, dietary, and device therapies. © 2016 Mayo Foundation for Medical Education and Research

Hruska C.B.,Mayo Medical School
American Journal of Roentgenology | Year: 2017

OBJECTIVE. The purposes of this review are to discuss the motivation for supplemental screening, to address molecular breast imaging (MBI) radiation dose concerns, and to provide an updated guide to current MBI technology, clinical protocols, and screening performance. Future directions of MBI are also discussed. CONCLUSION. MBI offers detection of mammographically occult cancers in women with dense breasts. Although MBI has been under investigation for nearly 15 years, it has yet to gain widespread adoption in breast screening. © American Roentgen Ray Society.

Rabinstein A.A.,Mayo Medical School
CONTINUUM Lifelong Learning in Neurology | Year: 2017

Purpose of Review: This article provides an update on the state of the art of the emergency treatment of acute ischemic stroke with particular emphasis on the alternatives for reperfusion therapy. Recent Findings: The results of several randomized controlled trials consistently and conclusively demonstrating that previously functional patients with disabling strokes from a proximal intracranial artery occlusion benefit from prompt recanalization with mechanical thrombectomy using a retrievable stent have changed the landscape of acute stroke therapy. Mechanical thrombectomy within 6 hours of symptom onset should now be considered the preferred treatment for these patients along with IV thrombolysis with recombinant tissue plasminogen activator (rtPA) within the first 4.5 hours for all patients who do not have contraindications for systemic thrombolysis. Patients who are ineligible for IV rtPA can also benefit from mechanical thrombectomy. Collateral status and time to reperfusion are the main determinants of outcome. Summary: Timely successful reperfusion is the most effective treatment for patients with acute ischemic stroke. Systems of care should be optimized to maximize the number of patients with acute ischemic stroke able to receive reperfusion therapy. © 2017 American Academy of Neurology.

Cutsforth-Gregory J.K.,Mayo Medical School | Benarroch E.E.,Mayo Medical School
Neurology | Year: 2017

The nucleus of the solitary tract (solitary nucleus, nucleus tractus solitarii [NTS]), located in the dorsomedial medulla, is the first relay station for general visceral and taste afferents carried by the cranial nerves and has a critical role in the initiation and integration of a wide variety of reflexes controlling cardiovascular function, respiration, and gastrointestinal motility. Though isolated bilateral involvement of the NTS in neurologic disorders is infrequent, its intimate anatomical relationship with the fourth ventricle and the area postrema may underlie its major role in clinical manifestations such as those described in this representative case. © 2017 American Academy of Neurology.

Bryce A.H.,Mayo Medical School
Prostate Cancer and Prostatic Diseases | Year: 2017

Background:Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested.Methods:Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups.Results:Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26–2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar.Conclusions:Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.Prostate Cancer and Prostatic Diseases advance online publication, 24 January 2017; doi:10.1038/pcan.2016.71. © 2017 The Author(s)

Knowledge of variant pathogenicity is key to implementing genomic medicine. We describe variability between expert reviewers in assigning pathogenicity to sequence variants in LDLR, the causal gene in the majority of cases of familial hypercholesterolemia. LDLR was sequenced on the Illumina HiSeq platform (average read depth >200 × ) in 1013 Mayo Biobank participants recruited from 2012 to 2013. Variants with a minor allele frequency (MAF) <5% predicted to be functional or referenced in HGMD (Human Gene Mutation Database) or NCBI-ClinVar databases were reviewed. To assign pathogenicity, variant frequency in population data sets, computational predictions, reported observations and patient-level data including electronic health record-based post hoc phenotyping were leveraged. Of 178 LDLR variants passing quality control, 25 were selected for independent review using either an in-house protocol or a disease/gene-specific semi-quantitative framework based on the American College of Medical Genetics and Genomics-recommended lines of evidence. NCBI-ClinVar included interpretations for all queried variants with 74% (14/19) of variants with >1 submitter showing inconsistency in classification and 26% (5/19) appearing with conflicting clinical actionability. The discordance rate (one-step level of disagreement out of five classes in variant interpretation) between the reviewers was 40% (10/25). Two LDLR variants were independently deemed clinically actionable and returnable. Interpretation of LDLR variants was often discordant among ClinVar submitters and between expert reviewers. A quantitative approach based on strength of each predefined criterion in the context of specific genes and phenotypes may yield greater consistency between different reviewers.European Journal of Human Genetics advance online publication, 1 February 2017; doi:10.1038/ejhg.2016.193. © 2017 Macmillan Publishers Limited, part of Springer Nature.

Study Design:Retrospective chart review.Objectives:To identify factors predictive of survival after spinal cord injury (SCI).Setting:Tertiary care institution.Methods:Multiple-variable Cox proportional hazards regression analysis for 759 patients with SCI (535 nontraumatic and 221 traumatic) included age, sex, completeness of injury, level of injury, functional independence measure (FIM) scores, rehabilitation length of stay and SCI cause. Estimated years of life lost in the decade after injury was calculated for patients vs uninjured controls.Results:Median follow-up was 11.4 years. Population characteristics included paraplegia, 58%; complete injury, 11%; male sex, 64%; and median rehabilitation length of stay, 16 days. Factors independently predictive of decreased survival were increased age (+10 years; hazard ratio (HR (95% CI)), 1.6 (1.4–1.7)), male sex (1.3 (1.0–1.6)), lower dismissal FIM score (−10 points; 1.3 (1.2–1.3)) and all nontraumatic causes. Metastatic cancer had the largest decrease in survival (HR (95% CI), 13.3 (8.7–20.2)). Primary tumors (HR (95% CI), 2.5 (1.7–3.8)), vascular (2.5 (1.6–3.8)), musculoskeletal/stenosis (1.7 (1.2–2.5)) and other nontraumatic SCI (2.3 (1.5–3.6)) were associated with decreased survival. Ten-year survival was decreased in nontraumatic SCI (mean (s.d.), 1.8 (0.3) years lost), with largest decreases in survival for metastatic cancer and spinal cord ischemia.Conclusions:Age, male sex and lower dismissal FIM score were associated with decreased survival, but neither injury severity nor level was associated with it. Survival after SCI varies depending on SCI cause, with survival better after traumatic SCI than after nontraumatic SCI. Metastatic cancer and vascular ischemia were associated with the greatest survival reduction.Spinal Cord advance online publication, 7 February 2017; doi:10.1038/sc.2016.182. © 2017 International Spinal Cord Society

Rustagi T.,Mayo Medical School
Journal of Clinical Gastroenterology | Year: 2017

BACKGROUND AND STUDY AIMS:: Percutaneous and intraoperative radiofrequency ablation (RFA) has become a valued tool in the management of primary and secondary hepatic lesions. A recent FDA-approved endoscopic ultrasound (EUS)-guided RFA probe now offers promise to help manage such lesions. However, there are no data to determine the ideal power setting and duration of ablation needed to effectively treat hepatic masses. The aim of the study was to evaluate the macroscopic zone of hepatic injury for EUS-RFA using a variety of settings within a fresh porcine hepatic specimen. METHODS:: RFA was performed using the Habib EUS-RFA needle (EMcision Ltd, London, UK) which is a 1-Fr wire (0.33 mm, 0.013 inch) with a working length of 190 cm. A step by step approach to deliver radiofrequency energy at 5, 10, 15, 20, and 50 W of power and 10, 30, 60, 90, 120, and 300 seconds, respectively, was followed. Macroscopic and microscopic findings of the ablation zone were evaluated at each setting. RESULTS:: The maximal zone (diameter, 8.2±0.14 mm; length, 20.85±0.21 mm) of coagulative necrosis was achieved using an ablation power of 10 W for duration of 90 seconds. Notably, increased power settings resulted in an unexpected and diminished effect on tissue destruction. CONCLUSIONS:: Our findings support the use of 10 W power for 90 seconds for maximum ablation in the liver. Our data also provide initial guidance and alternate settings to be considered when performing EUS-RFA to adjust the ablation power and duration to match the lesion size, shape, and risk of injury to adjacent structures. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Although clinical signs and symptoms of giant cell arteritis improve promptly after starting glucocorticoid therapy, reports have suggested that the vascular inflammation may persist. To assess the duration and quality of histopathologic changes in treated patients, we prospectively obtained second temporal artery biopsies in patients treated for 3 to 12 months after their first diagnostic biopsy. Forty patients (28 women, 12 men, median age 77 years) agreed to have a second temporal artery biopsy randomly assigned to 3, 6, 9, or 12 months subsequent to the first. Clinical and laboratory evaluation of the patient cohort revealed a typical rapid response and continued suppression of clinical manifestations as a result of glucocorticoid treatment. Histopathologic findings, evaluated in a blinded manner by a cardiovascular pathologist, showed unequivocal findings of vasculitis in 7/10 patients with second temporal artery biopsy at 3 months, 9/12 at 6 months, 4/9 at 9 months, and 4/9 at 12 months. Lymphocytes were present in all positive initial biopsies and remained the dominant cell population in chronically treated patients. Granulomatous inflammation decreased in a time-dependent manner from 78 to 100% at initial biopsy to 50% at 9 months and 25% at 12 months. The increased medial fibrosis noted in the second biopsies (60 vs 33% in primary temporal artery biopsies) suggested that the finding may represent a chronic finding in arteritis. In summary, the response to glucocorticoids in giant cell arteritis was frequently discordant. Clinical manifestations were readily suppressed, but vascular changes were gradual and often incomplete.Modern Pathology advance online publication, 3 March 2017; doi:10.1038/modpathol.2017.10. © 2017 United States & Canadian Academy of Pathology USCAP, Inc

Graham R.P.,Mayo Medical School
Modern Pathology | Year: 2017

Fibrolamellar carcinoma was first described in 1956. Subsequent large studies failed to identify cases before 1939 (the start of the World War II). This finding, combined with the presence of aryl hydrocarbon receptors on the tumor cells, have suggested that fibrolamellar carcinomas may be caused by environmental exposures that are new since World War II. To investigate this possibility, the surgical pathology files before 1939 were reviewed for hepatocellular carcinomas resected in young individuals. Two cases of fibrolamellar carcinoma were identified, from 1915 to 1924. The diagnosis of fibrolamellar carcinoma was confirmed at the histologic, ultrastructural and proteomic levels. These two fibrolamellar carcinoma cases clarify a key aspect of fibrolamellar carcinoma biology, reducing the likelihood that these tumors result exclusively from post World War II environmental exposures.Modern Pathology advance online publication, 3 March 2017; doi:10.1038/modpathol.2017.7. © 2017 United States & Canadian Academy of Pathology USCAP, Inc

Cheung A.C.,Mayo Medical School
Current Opinion in Gastroenterology | Year: 2017

PURPOSE OF REVIEW: The only currently approved treatment for primary sclerosing cholangitis (PSC) is liver transplantation, with a median time to transplant of 12–18 years after diagnosis. There are a number of emerging drugs that have the potential to meet this critically unmet need that will be summarized and discussed herein. RECENT FINDINGS: Although the cause of PSC is unknown, there are a number of novel therapeutics under development. These drugs target presumed pathogenic mechanisms largely extrapolated from ex-vivo and in-vivo preclinical models, as well as translational observations. SUMMARY: Future therapeutic strategies for PSC may include a multitude of complex pathogenic mechanisms encompassing pathways of immunomodulation, the microbiome and inflammation-related fibrosis. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

The optimal surveillance for patients with resected high-risk melanoma is controversial. Select locoregional or oligometastatic recurrences can be cured with salvage resection. Data on the ability of PET/CT to detect such recurrences are sparse. We evaluated whether surveillance PET/CT in patients with resected stage III–IV melanoma led to detection of clinically occult recurrences amenable to curative-intent salvage treatment. We retrospectively identified 1429 melanoma patients who underwent PET/CT between January 2008 and October 2012 at Mayo Clinic (Rochester, Minnesota). A total of 1130 were excluded because of stage I–II, ocular or mucosal melanoma, incomplete resection, PET/CT not performed for surveillance or performed at a different institution, and records not available. A total of 299 patients were eligible. Overall, 162 (52%) patients developed recurrence [locoregional: 77 (48%), distant: 85 (52%)]. The first recurrence was clinically occult in 98 (60%) and clinically evident in 64 (40%). Clinically evident recurrences were more often superficial (skin, subcutaneous, or nodal) or in the brain, whereas clinically occult recurrences more often visceral. Overall, 90% of all recurrences were detected by 2.8 years. In all, 70% of patients with recurrence underwent curative-intent salvage treatment (locoregional: 94%, distant: 48%), with similar rates for clinically occult versus clinically evident recurrences (66 vs. 75%, P=0.240). Overall survival was superior among those who underwent curative-intent salvage treatment [5.9 vs. 1.2 years; hazard ratio=4.27, 95% confidence interval (CI)=2.68–6.80; P<0.001], despite 79% developing recurrence again. PET/CT had high sensitivity (88%, 95% CI=79.94–93.31%), specificity (90%, 95% CI=88.56–91.56%), and negative predictive value (99%, 95% CI=98.46–99.52%). However, the positive predictive value was only 37% (95% CI=31.32–43.68%). In patients with resected stage III–IV melanoma, surveillance PET/CT detected a large proportion of clinically occult recurrences amenable to curative-intent salvage treatment. Despite a high rate of second relapse, curative-intent salvage treatment was associated with superior overall survival. Even though PET/CT had high sensitivity, specificity, and negative predictive value, positive predictive value was poor, highlighting the need for histologic confirmation of PET/CT-detected abnormalities. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

PURPOSE: To identify approaches to operationalizing the development of competence in Accreditation Council for Graduate Medical Education (ACGME) milestones. METHOD: The authors reviewed all 25 “Milestone Project” documents available on the ACGME Web site on September 11, 2013, using an iterative process to identify approaches to operationalizing the development of competence in the milestones associated with each of 601 subcompetencies. RESULTS: Fifteen approaches were identified. Ten focused on attributes and activities of the learner, such as their ability to perform different, increasingly difficult tasks (304/601; 51%), perform a task better and faster (171/601; 45%), or perform a task more consistently (123/601; 20%). Two approaches focused on context, inferring competence from performing a task in increasingly difficult situations (236/601; 29%) or an expanding scope of engagement (169/601; 28%). Two used socially defined indicators of competence such as progression from “learning” to “teaching,” “leading,” or “role modeling” (271/601; 45%). One approach focused on the supervisor’s role, inferring competence from a decreasing need for supervision or assistance (151/601; 25%). Multiple approaches were often combined within a single set of milestones (mean 3.9, SD 1.6). CONCLUSIONS: Initial ACGME milestones operationalize the development of competence in many ways. These findings offer insights into how physicians understand and assess the developmental progression of competence and an opportunity to consider how different approaches may affect the validity of milestone-based assessments. The results of this analysis can inform the work of educators developing or revising milestones, interpreting milestone data, or creating assessment tools to inform milestone-based performance measures. © 2017 by the Association of American Medical Colleges

Bursiek A.A.,Mayo Medical School
Journal of Patient Safety | Year: 2017

OBJECTIVES: This pilot study aimed to determine the effect of nurse/physician interdisciplinary team training on patient falls. Specifically, we evaluated team training in a simulation center as a method for targeting and minimizing breakdowns in perceptions of respect, collaboration, communication, and role misunderstanding behaviors between care disciplines. METHODS: Registered nurses (RNs) were randomly assigned to participate. Residents were divided into groups and assigned based on their availability and clinical responsibility. All participants completed a demographic form, the Professional Practice Environment Assessment Scale (PPEAS), and the Mayo High Performance Teamwork Scale (MHPTS) after consenting and before participation in simulation training. The PPEAS and the MHPTS were readministered at 2 and 6 months after the simulation experience. Differences in MHPTS and PPEAS scores between the baseline and 2- and 6-month assessments were analyzed; fall rates over time were evaluated using Cochran-Armitage trend tests. RESULTS: After the team training exercises, teamwork as measured by the MHPTS improved significantly at both 2 and 6 months (P = 0.01; P < 0.001) compared with baseline measurement. Practice environment subscores, with the exception of positive organizational characteristics, also increased when measured 6 months after training. The primary outcome, reduction in anticipated patient falls, improved significantly (P = 0.02) over the course of the study. CONCLUSIONS: Results of this pilot study show that team training exercises result in improvement in both patient safety (anticipated patient falls) and team member perception of their work environment. If validated by other studies, improvement in this patient safety metric would represent an important benefit of simulation and team training. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved

BACKGROUND AND PURPOSE—: Some have argued that it may be beneficial to expand the availability of endovascular revascularization services to lower-volume hospitals to minimize the morbidity associated with transfer to larger endovascular centers. We compared the outcomes after revascularization of patients directly admitted to a low-volume center and those transferred to a high-volume center. METHODS—: We searched a national database of hospital-reported outcomes for patients who underwent endovascular revascularization for acute ischemic stroke. Hospitals were categorized as low, medium, or high procedural volume hospitals. Outcomes of inpatient admissions were collected and compared on the basis of admission source and hospital procedural volume. RESULTS—: A total of 118 institutions with 8533 patients were included. Mortality rate (14.9% versus 18.6%; P=0.049) and mortality index (1.1 versus 1.6; P=0.048) were significantly lower among directly admitted relative to transferred patients. For all patients, there were significant differences in institutional mortality rate (low: 19.7%, medium: 14.9%, high: 9.8%; P=0.003) and mortality index (low: 1.5, medium: 1.1, high: 0.8; P=0.004) between low-, medium-, and high-volume hospitals. For transferred patients to high-volume centers, both mortality rate (high: 10.0% versus low: 20.4%; P=0.005) and mortality index (high: 0.8 versus low: 1.5; P=0.034) were significantly lower than that observed for directly admitted patients to low-volume hospitals. CONCLUSIONS—: We report a beneficial effect of treatment at high-volume hospitals in spite of the detrimental effects of transfer. These findings argue for the centralization of care. © 2017 American Heart Association, Inc.

Anzalone C.L.,Mayo Medical School
Otology and Neurotology | Year: 2017

OBJECTIVE:: To describe a unique case of an asymptomatic arteriovenous lesion of the internal auditory canal (IAC) and present the associated imaging findings. METHODS:: Retrospective case report and review of the literature. RESULTS:: A 55-year-old man presented for further evaluation of a left-sided sudden sensorineural hearing loss that occurred 8 years earlier. Careful review of outside serial magnetic resonance (MR) imaging revealed a contralateral, ill-defined right-sided IAC mass with low T2 signal and subtle peripheral enhancement on postcontrast T1-weighted sequencing. The patient had no history of right-sided otologic symptoms.Subsequent dedicated IAC MR imaging confirmed the presence of a space-occupying lesion adjacent to a complexity of vasculature. The presence of prominent flow voids, paucity of avid enhancement on previous studies, and marked signal within the lesion on time-of-flight MR angiography and MR venography was consistent with the diagnosis of a solitary arteriovenous lesion of the IAC. There was no radiological evidence of recent or remote parenchymal or subarachnoid hemorrhage or stroke. CONCLUSION:: We report a novel case of an occult asymptomatic IAC arteriovenous lesion. Vascular anomalies confined to the IAC are rare. To date, there have been only four reports in the literature of IAC arteriovenous lesions and our case is the first to present asymptomatically. A high index of suspicion and dedicated imaging is required to identify and accurately diagnose these lesions to guide appropriate counseling and potential intervention. Copyright © 2017 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

OBJECTIVE:: To describe a novel case of congenital profound bilateral sensorineural hearing loss in a patient with bilateral nodular internal auditory canal and labyrinthine enhancement and temporal bone dysplasia. PATIENTS:: A 76-day-old female was referred to the authors’ center for evaluation of congenital deafness. Behavioral observations and objective audiometric evaluation demonstrated bilateral profound sensorineural hearing loss and a comprehensive multidisciplinary evaluation identified compound heterozygous pathogenic variants in MYO7A, a gene associated with Usher Syndrome Type 1B or DFNB2. Computed tomography and contrast-enhanced magnetic resonance imaging studies demonstrated bilateral temporal bone anomalies with unique middle and inner ear malformations, as well as unique contrast enhancement in the membranous labyrinth, internal auditory canals, and cranial nerves, which have not been previously described with MYO7A variants. INTERVENTIONS:: Given the potential risk for progressive bilateral labyrinthitis ossificans, bilateral simultaneous cochlear implantation was performed at 4 months of age. MAIN OUTCOME MEASURES:: Subsequent audiologic follow up after implantation shows significantly improved access to auditory information and increased vocalizations. At last testing, speech and language skills for both receptive and expressive language abilities were found to be commensurate with her chronological age. CONCLUSION:: We report a novel presentation and imaging findings of congenital bilateral profound sensorineural hearing loss in a patient with nodular internal auditory canal and labyrinthine enhancement and coexisting inner ear dysplasia. Despite the multiple radiologic abnormalities, the patient has demonstrated good benefit from cochlear implantation. Future study of rare variants of congenital deafness, such as this, is critical toward defining new disease processes and determining optimal treatment. Copyright © 2017 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

Broski S.M.,Mayo Medical School
Clinical nuclear medicine | Year: 2017

Neuromuscular choristoma (NMC) is a rare benign peripheral nerve lesion consisting of mature skeletal muscle fibers admixed with nerve fascicles. Aggressive fibromatosis frequently develops in association with NMC, often after surgery or biopsy, but the exact pathogenesis is not known. We present a case of NMC complicated by aggressive fibromatosis evaluated by F-FDG PET/CT and examine the relationship of metabolic activity and MRI signal characteristics.

AUSTIN, Texas--(BUSINESS WIRE)--Daniel L. Hurley, MD, FACE, was installed today as President-Elect of the American Association of Clinical Endocrinologists (AACE) at its 26th Annual Scientific & Clinical Congress in Austin, Texas. “I am honored to serve as President Elect of AACE,” said Dr. Hurley. “This is a pivotal time in health care, and I’m looking forward to helping further advance AACE’s mission and goals in the future.” Dr. Hurley joined AACE in 1992, serving on numerous AACE committees and task forces as a member, Chair or Co-chair, and most recently as Vice President of AACE and Vice President and President of the Minnesota/Midwest AACE Chapter. Dr. Hurley completed his Internal Medicine Residency and Endocrinology Fellowship at the Mayo Graduate School of Medicine in Rochester, Minn., and joined the Mayo staff in 1986, following endocrine research training in bone and mineral metabolism. Currently, Dr. Hurley is a consultant in the Division of Endocrinology, Diabetes, Metabolism and Nutrition and Assistant Professor of Medicine Mayo Medical School. About the American Association of Clinical Endocrinologists (AACE) The American Association of Clinical Endocrinologists (AACE) represents more than 7,500 endocrinologists in the United States and abroad. AACE is the largest association of clinical endocrinologists in the world. The majority of AACE members are certified in endocrinology, diabetes and metabolism and concentrate on the treatment of patients with endocrine and metabolic disorders including diabetes, thyroid disorders, osteoporosis, growth hormone deficiency, cholesterol disorders, hypertension and obesity. Visit our site at About the American College of Endocrinology (ACE) The American College of Endocrinology (ACE) is the educational and scientific arm of the American Association of Clinical Endocrinologists (AACE). ACE is the leader in advancing the care and prevention of endocrine and metabolic disorders by: providing professional education and reliable public health information; recognizing excellence in education, research and service; promoting clinical research and defining the future of Clinical Endocrinology. For more information, visit

Gores G.J.,Mayo Medical School | Kaufmann S.H.,Molecular Therapeutics
Genes and Development | Year: 2012

Bcl-2, Bcl-x L, Mcl-1, and A1 are the predominant anti-apoptotic members of the Bcl-2 family in somatic cells. Malignant B lymphocytes are critically dependent on Bcl-2 or Bcl-x L for survival. In contrast, a new study by Glaser and colleagues in the January 15, 2012, issue of Genes & Development (pp. 120-125) demonstrates that Mcl-1 is essential for development and survival of acute myelogenous leukemia cells. These results provide new impetus for the generation of selective Mcl-1 inhibitors. © 2012 by Cold Spring Harbor Laboratory Press.

Tenner S.,New York University | Baillie J.,Carteret MedicalGroup | Dewitt J.,Indiana University | Vege S.S.,Mayo Medical School
American Journal of Gastroenterology | Year: 2013

This guideline presents recommendations for the management of patients with acute pancreatitis (AP). During the past decade, there have been new understandings and developments in the diagnosis, etiology, and early and late management of the disease. As the diagnosis of AP is most often established by clinical symptoms and laboratory testing, contrast-enhanced computed tomography (CECT) and/or magnetic resonance imaging (MRI) of the pancreas should be reserved for patients in whom the diagnosis is unclear or who fail to improve clinically. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed. Patients with organ failure and/or the systemic inflammatory response syndrome (SIRS) should be admitted to an intensive care unit or intermediary care setting whenever possible. Aggressive hydration should be provided to all patients, unless cardiovascular and/or renal comorbidites preclude it. Early aggressive intravenous hydration is most beneficial within the first 12-24 h, and may have little benefit beyond. Patients with AP and concurrent acute cholangitis should undergo endoscopic retrograde cholangiopancreatography (ERCP) within 24 h of admission. Pancreatic duct stents and/or postprocedure rectal nonsteroidal anti-inflammatory drug (NSAID) suppositories should be utilized to lower the risk of severe post-ERCP pancreatitis in high-risk patients. Routine use of prophylactic antibiotics in patients with severe AP and/or sterile necrosis is not recommended. In patients with infected necrosis, antibiotics known to penetrate pancreatic necrosis may be useful in delaying intervention, thus decreasing morbidity and mortality. In mild AP, oral feedings can be started immediately if there is no nausea and vomiting. In severe AP, enteral nutrition is recommended to prevent infectious complications, whereas parenteral nutrition should be avoided. Asymptomatic pancreatic and/or extrapancreatic necrosis and/or pseudocysts do not warrant intervention regardless of size, location, and/or extension. In stable patients with infected necrosis, surgical, radiologic, and/or endoscopic drainage should be delayed, preferably for 4 weeks, to allow the development of a wall around the necrosis. © 2013 by the American College of Gastroenterology.

Maron B.J.,Minneapolis Heart Institute Foundation | Ommen S.R.,Mayo Medical School | Semsarian C.,University of Sydney | Spirito P.,Ente Ospedaliero Ospedali Galliera | Olivotto I.,University of Florence
Journal of the American College of Cardiology | Year: 2014

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with diverse phenotypic and genetic expression, clinical presentation, and natural history. HCM has been recognized for 55 years, but recently substantial advances in diagnosis and treatment options have evolved, as well as increased recognition of the disease in clinical practice. Nevertheless, most genetically and clinically affected individuals probably remain undiagnosed, largely free from disease-related complications, although HCM may progress along 1 or more of its major disease pathways (i.e., arrhythmic sudden death risk; progressive heart failure [HF] due to dynamic left ventricular [LV] outflow obstruction or due to systolic dysfunction in the absence of obstruction; or atrial fibrillation with risk of stroke). Effective treatments are available for each adverse HCM complication, including implantable cardioverter-defibrillators (ICDs) for sudden death prevention, heart transplantation for end-stage failure, surgical myectomy (or selectively, alcohol septal ablation) to alleviate HF symptoms by abolishing outflow obstruction, and catheter-based procedures to control atrial fibrillation. These and other strategies have now resulted in a low disease-related mortality rate of <1%/year. Therefore, HCM has emerged from an era of misunderstanding, stigma, and pessimism, experiencing vast changes in its clinical profile, and acquiring an effective and diverse management armamentarium. These advances have changed its natural history, with prevention of sudden death and reversal of HF, thereby restoring quality of life with extended (if not normal) longevity for most patients, and transforming HCM into a contemporary treatable cardiovascular disease. © 2014 by the American College of Cardiology Foundation.

Kearns A.E.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2011

Patients rely on their primary care physician to manage multiple, often chronic medical conditions that require prescription medications. Balancing the risk to benefit of treatments can be challenging and requires that the primary care physician stay abreast of new information regarding risks and benefits. The number of medications with reported adverse effects on skeletal health is expanding. This review focuses on medications recently added to the list of "bad to the bone" drugs and on recent advances in management of glucocorticoid-induced osteoporosis. A practical approach to assessing and managing the skeletal risks is outlined. © 2011 Mayo Foundation for Medical Education and Research.

Borlaug B.A.,Mayo Medical School | Paulus W.J.,VU University Amsterdam
European Heart Journal | Year: 2011

Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future. © 2010 The Author.

Bergsagel P.L.,Mayo Clinic in Arizona | Mateos M.-V.,University of Salamanca | Gutierrez N.C.,University of Salamanca | Rajkumar S.V.,Mayo Medical School | San Miguel J.F.,University of Salamanca
Blood | Year: 2013

Multiple myeloma (MM) is a heterogeneous disease with certain genetic features [eg, t(4;14), del17p] associated with worse outcome. The introduction of thalidomide, lenalidomide, and bortezomib has dramatically improved the outlook for patients with MM, but their relative benefit (or harm) for different genetic patient subgroups remains unclear. Unfortunately, the small number of patients in each subgroup frequently limits the analysis of high-risk patients enrolled in clinical trials. Strategies that result in survival of high-risk genetic subgroups approximating that of patients lacking high-risk features are said to overcome the poor prognostic impact of these high-risk features. This outcome has been difficult to achieve, and studies in this regard have so far been limited by inadequate sample size. In contrast, strategies that compare the survival of high-risk genetic subgroups randomized to different treatment arms can identify approaches that improve survival. This type of analysis is clinically useful, even if the absolute gains do not improve outcomes to levels seen in patients without high-risk cytogenetics. Reviewing available data in high-risk MM from this perspective, it appears that bortezomib has frequently been associated with improved survival, whereas thalidomide maintenance has sometimes been associated with a shorter survival. © 2013 by The American Society of Hematology.

Hwang S.-J.,Mayo Medical School | Hwang S.-J.,Gyeongsang National University | Melenovsky V.,Mayo Medical School | Melenovsky V.,Institute of Clinical and Experimental Medicine IKEM | Borlaug B.A.,Mayo Medical School
Journal of the American College of Cardiology | Year: 2014

Objectives This study investigated the characteristics, evaluation, prognostic impact, and treatment of coronary artery disease (CAD) in patients with heart failure and preserved ejection fraction (HFpEF). Background CAD is common in patients with HFpEF, but it remains unclear how CAD should be categorized, evaluated for, and treated in HFpEF. Methods Clinical, hemodynamic, echocardiographic, treatment, and outcome characteristics were examined in consecutive patients with previous HFpEF hospitalizations who underwent coronary angiography. Results Of the 376 HFpEF patients examined, 255 (68%) had angiographically-proven CAD. Compared with HFpEF patients without CAD, patients with CAD were more likely to be men, to have CAD risk factors, and to be treated with anti-ischemic medications. However, symptoms of angina and heart failure were similar in patients with and without CAD, as were measures of cardiovascular structure, function, and hemodynamics. Compared with patients without CAD, HFpEF patients with CAD displayed greater deterioration in ejection fraction and increased mortality, independent of other predictors (hazard ratio: 1.71, 95% confidence interval: 1.03 to 2.98; p = 0.04). Complete revascularization was associated with less deterioration in ejection fraction and lower mortality compared with patients who were not completely revascularized, independent of other predictors (hazard ratio: 0.56, 95% confidence interval: 0.33 to 0.93; p = 0.03). Conclusions CAD is common in patients with HFpEF and is associated with increased mortality and greater deterioration in ventricular function. Revascularization may be associated with preservation of cardiac function and improved outcomes in patients with CAD. Given the paucity of effective treatments for HFpEF, prospective trials are urgently needed to determine the optimal evaluation and management of CAD in HFpEF. © 2014 by the American College of Cardiology Foundation. Published by Elsevier Inc.

Reiman J.M.,Mayo Medical School | Knutson K.L.,Mayo Medical School
Cancer Research | Year: 2010

Elements of the immune system act as intimate regulators of cancer progression, inhibiting early stages of tumor growth, through immunosurveillance while facilitating later stages of tumor progression. Recent findings have revealed that activated CD8 T cells can stimulate mammary epithelial tumor cells to undergo epithelial-mesenchymal transition (EMT) and to acquire the greatly increased tumorigenic capability and chemotherapeutic resistance of breast cancer stem cells (BCSC). These studies provide a window to understanding how BCSC arise and are maintained within tumors, and how to best target these processes for therapeutic benefit. ©2010 AACR.

Sargent D.J.,Sunnybrook Research Institute | Grothey A.,Mayo Medical School | Kerbel R.S.,Biological science Platform
Nature Reviews Clinical Oncology | Year: 2013

The established dogma in oncology for managing recurrent or refractory disease dictates that therapy is changed at disease progression, because the cancer is assumed to have become drug-resistant. Drug resistance, whether pre-existing or acquired, is largely thought to be a stable and heritable process; thus, reuse of therapeutic agents that have failed is generally contraindicated. Over the past few decades, clinical evidence has suggested a role for unstable, non-heritable mechanisms of acquired drug resistance pertaining to chemotherapy and targeted agents. There are many examples of circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) after a drug holiday following disease relapse or progression during therapy. Additional, albeit limited, evidence suggests that, in certain circumstances, continuing a therapy beyond disease progression can also have antitumour activity. In this Review, we describe the anticancer agents used in these treatment strategies and discuss the potential mechanisms explaining the apparent tumour re-sensitization with reintroduced or continued therapy. The extensive number of malignancies and drugs that challenge the custom of permanently switching to different drugs at each line of therapy warrants a more in-depth examination of the definitions of disease progression and drug resistance and the resulting implications for patient care. © 2013 Macmillan Publishers Limited.

Mohammed S.F.,Gonda 5 South | Hussain S.,Gonda 5 South | Mirzoyev S.A.,Mayo Medical School | Maleszewski J.J.,Mayo Medical School | Redfield M.M.,Gonda 5 South
Circulation | Year: 2015

BACKGROUND - : Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology. METHODS AND RESULTS - : We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with ≥1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD. CONCLUSIONS - : In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF.

Vemuri P.,Mayo Medical School
Clinical Epidemiology | Year: 2014

With the aging of the population, the burden of Alzheimer's disease (AD) is rapidly expanding. More than 5 million people in the US alone are affected with AD and this number is expected to triple by 2050. While men may have a higher risk of mild cognitive impairment (MCI), an intermediate stage between normal aging and dementia, women are disproportionally affected with AD. One explanation is that men may die of competing causes of death earlier in life, so that only the most resilient men may survive to older ages. However, many other factors should also be considered to explain the sex differences. In this review, we discuss the differences observed in men versus women in the incidence and prevalence of MCI and AD, in the structure and function of the brain, and in the sex-specific and gender-specific risk and protective factors for AD. In medical research, sex refers to biological differences such as chromosomal differences (eg, XX versus XY chromosomes), gonadal differences, or hormonal differences. In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation). Both factors play an important role in the development and progression of diseases, including AD. Understanding both sex- and gender-specific risk and protective factors for AD is critical for developing individualized interventions for the prevention and treatment of AD. © 2014 Mielke et al.

Wijdicks E.F.,Mayo Medical School
Neurology | Year: 2014

Neurologic determination of brain death is a complex assessment that may be misunderstood by nonspecialists and families. Recent guidelines clarify how to proceed with such an examination and are available to physicians, with the time of death in adults and children being determined by the last defining test-the apnea test. This core principle in neurology has been challenged recently in court and resulted in an unprecedented continuation of care in a 13-year-old child declared dead. This review comments on the medical, legal, and ethical quandaries introduced by this case and highlights the major elements of consensus on matters related to brain death that have been forged over 3 decades of sustained medical and societal debate. A clear appreciation by physicians and the public of the diagnostic determination of death following loss of brain function will help to prevent similar conflicts from occurring in the future.

Reeves H.M.,University Hospitals Case Medical Center | Winters J.L.,Mayo Medical School
British Journal of Haematology | Year: 2014

The initial description of therapeutic plasma exchange (TPE) in an animal model was published almost 100 years ago. Since that time, this treatment has been applied to a wide variety of diseases but limited research has been published examining the mechanisms of action of TPE. The therapeutic effects of TPE could include the removal of pathological substances from the blood, such as monoclonal paraproteins and autoantibodies, as well as the replacement of deficient plasma components when plasma is used as a replacement fluid. Beyond these potential mechanisms, other possible mechanisms include possible alterations in lymphocyte proliferation and function that could sensitize these cells to immunosuppressant and chemotherapeutic agents and alterations in the immune system including changes in B and T cell numbers and activation, increased T suppressor function, and alteration in T-helper cell type 1/2 (Th1/Th2) ratio. Much remains unknown about the mechanisms of action of TPE, indicating a need for basic research into this therapy. © 2013 John Wiley & Sons Ltd.

Nath K.A.,Mayo Medical School
Current Opinion in Nephrology and Hypertension | Year: 2014

PURPOSE OF REVIEW: Heme oxygenase activity, possessed by an inducible heme oxygenase-1 (HO-1) and a constitutive isoform (HO-2), catalyzes the conversion of heme to biliverdin, liberates iron, and generates carbon monoxide. First shown in acute kidney injury (AKI), HO-1 is now recognized as a protectant against diverse insults in assorted tissues. This review summarizes recent contributions to the field of HO-1 and AKI. RECENT FINDINGS: Recent findings elucidate the following: the transcriptional regulation and significance of human HO-1 in AKI; the protective effects of HO-1 in age-dependent and sepsis-related AKI, cardiorenal syndromes, and acute vascular rejection in renal xenografts; the role of heme oxygenase in tubuloglomerular feedback and renal resistance to injury; the basis for cytoprotection by HO-1; the protective properties of ferritin and carbon monoxide; HO-1 and the AKI-chronic kidney disease transition; HO-1 as a biomarker in AKI; the role of HO-1 in mediating the protective effects of specific cytokines, stem cells, and therapeutic agents in AKI; and HO-2 as a protectant in AKI. SUMMARY: Recent contributions support, and elucidate the basis for, the induction of HO-1 as a protectant against AKI. Translating such therapeutic potential into a therapeutic reality requires well tolerated and effective modalities for upregulating HO-1 and/or administering its products, which, optimally, should be salutary even when AKI is already established. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Shih J.J.,Mayo Medical School | Krusienski D.J.,Old Dominion University | Wolpaw J.R.,New York State Department of Health
Mayo Clinic Proceedings | Year: 2012

Brain-computer interfaces (BCIs) acquire brain signals, analyze them, and translate them into commands that are relayed to output devices that carry out desired actions. BCIs do not use normal neuromuscular output pathways. The main goal of BCI is to replace or restore useful function to people disabled by neuromuscular disorders such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. From initial demonstrations of electroencephalography- based spelling and single-neuron-based device control, researchers have gone on to use electroencephalographic, intracortical, electrocorticographic, and other brain signals for increasingly complex control of cursors, robotic arms, prostheses, wheelchairs, and other devices. Brain-computer interfaces may also prove useful for rehabilitation after stroke and for other disorders. In the future, they might augment the performance of surgeons or other medical professionals. Brain-computer interface technology is the focus of a rapidly growing research and development enterprise that is greatly exciting scientists, engineers, clinicians, and the public in general. Its future achievements will depend on advances in 3 crucial areas. Brain-computer interfaces need signal-acquisition hardware that is convenient, portable, safe, and able to function in all environments. Brain-computer interface systems need to be validated in long-term studies of real-world use by people with severe disabilities, and effective and viable models for their widespread dissemination must be implemented. Finally, the day-to-day and moment-to-moment reliability of BCI performance must be improved so that it approaches the reliability of natural muscle-based function. © 2012 Mayo Foundation for Medical Education and Research.

Gibbons R.J.,Mayo Medical School
JACC: Cardiovascular Imaging | Year: 2010

The potential risk of fatal malignancy related to cardiac imaging with ionizing radiation is frequently discussed in the medical literature and in the lay press. Clinicians must weigh this risk against the potential benefits of cardiac imaging, which are typically not considered in these reports about radiation risk. This review summarizes the evidence regarding both the radiation risks and clinical benefits of cardiac imaging to provide guidance to the clinician in specific clinical scenarios. Choosing the right test for the right patient, and performing it with the lowest possible radiation dose, remains a challenge. © 2010 American College of Cardiology Foundation.

Ngamruengphong S.,Mayo Medical School | Wallace M.B.,Mayo Medical School
Gut | Year: 2015

Objective Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) allows preoperative tissue confirmation of malignancy, but fear of tumour cell dissemination along the needle track has limited its use. We hypothesised that if tumour cell dissemination occurs with EUS-FNA, survival after complete resection would be impaired. We aimed to evaluate the association of preoperative EUS-FNA with long-term outcomes of patients with resected pancreatic cancer. Design Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified patients with locoregional pancreatic cancer who underwent curative intent surgery from 1998 to 2009. The patients who received EUS-FNA within the peridiagnostic period were included in the EUS-FNA group. Patients who did not receive EUS evaluation or who underwent EUS without FNA were included in the non-EUS-FNA group. Overall survival and pancreatic cancer-specific survival were compared after controlling for relevant covariates. Results A total of 2034 patients with pancreatic cancer were included (90% pancreatic adenocarcinoma). Of these, 498 (24%) patients were in EUS-FNA group. Patients with multiple comorbidities and more recent diagnosis were more likely to receive EUS-FNA. In multivariate analysis, after controlling for age, race, gender, tumour histology, tumour stage, tumour grade, tumour location, SEER site, year of diagnosis, undergoing percutaneous aspiration/biopsy, Charlson Comorbidity Index, radiation and chemotherapy, EUS-FNA was marginally associated with improved overall survival (HR 0.84, 95% CI 0.72 to 0.99), but did not affect cancer-specific survival (HR 0.87, 95% CI 0.74 to 1.03). Conclusions Preoperative EUS-FNA was not associated with increased risk of mortality. These data suggest that EUS-FNA can be safely performed for the work-up of suspicious pancreatic lesions. © 2015 BMJ Publishing Group Ltd & British Society of Gastroenterology.

There is marked racial disparity in the incidence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma, with a two to threefold increased risk in blacks compared with whites. The increased risk has been seen both in Africans and African Americans. Similarly, an increased risk of monoclonal gammopathies in blacks compared with whites has been noted after adjusting for socioeconomic and other risk factors, suggesting a genetic predisposition. The higher risk of multiple myeloma in blacks is likely a result of the higher prevalence of the premalignant MGUS stage; there are no data to suggest that blacks have a higher progression rate of MGUS to myeloma. Studies are emerging that suggest the baseline cytogenetic characteristics, and progression may differ by race. In contrast, to the increased risk noted in blacks, studies suggest that the risk may be lower in certain racial and ethnic groups, notably persons from Japan and Mexico. We review the literature on racial disparity in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites. We also discuss future directions for research that could inform management of these conditions and positively influence patient outcomes. © 2012 Macmillan Publishers Limited All rights reserved.

Miller J.D.,Mayo Medical School | Heistad D.D.,University of Iowa
Circulation Research | Year: 2011

Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, nonosseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High-resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research. © 2011 American Heart Association, Inc.

Keegan M.T.,Mayo Medical School | Gajic O.,Mayo Medical School
Critical Care Medicine | Year: 2011

Objective: Adult intensive care unit prognostic models have been used for predicting patient outcome for three decades. The goal of this review is to describe the different versions of the main adult intensive care unit prognostic models and discuss their potential roles. Data source: PubMed search and review of the relevant medical literature. Summary: The main prognostic models for assessing the overall severity of illness in critically ill adults are Acute Physiology and Chronic Health Evaluation, Simplified Acute Physiology Score, and Mortality Probability Model. Simplified Acute Physiology Score and Mortality Probability Model have been updated to their third versions and Acute Physiology and Chronic Health Evaluation to its fourth version. The development of prognostic models is usually followed by internal and external validation and performance assessment. Performance is assessed by area under the receiver operating characteristic curve for discrimination and Hosmer-Lemeshow statistic for calibration. The areas under the receiver operating characteristic curve of Simplified Acute Physiology Score 3, Acute Physiology and Chronic Health Evaluation IV, and Mortality Probability Model0 III were 0.85, 0.88, and 0.82, respectively, and all these three fourth-generation models had good calibration. The models have been extensively used for case-mix adjustment in clinical research and epidemiology, but their role in benchmarking, performance improvement, resource use, and clinical decision support has been less well studied. Conclusions: The fourth-generation Acute Physiology and Chronic Health Evaluation, Simplified Acute Physiology Score 3, Acute Physiology and Chronic Health Evaluation IV, and Mortality Probability Model0 III adult prognostic models, perform well in predicting mortality. Future studies are needed to determine their roles for benchmarking, performance improvement, resource use, and clinical decision support. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Zhang L.,Mayo Medical School | Cheville J.C.,Mayo Medical School
Cell | Year: 2010

Stability and localization of p53 is essential for its tumor suppressor function. Ubiquitination by the E3 ubiquitin ligase Mdm2 is the major regulatory mechanism of p53, which induces p53 nuclear export and degradation. However, it is unclear whether ubiquitinated cytoplasmic p53 can be recycled. Here, we report that USP10, a cytoplasmic ubiquitin-specific protease, deubiquitinates p53, reversing Mdm2-induced p53 nuclear export and degradation. After DNA damage, USP10 is stabilized, and a fraction of USP10 translocates to the nucleus to activate p53. The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337. Finally, USP10 suppresses tumor cell growth in cells with wild-type p53, with USP10 expression downregulated in a high percentage of clear cell carcinomas, known to have few p53 mutations. These findings reveal USP10 to be a novel regulator of p53, providing an alternative mechanism of p53 inhibition in cancers with wild-type p53. © 2010 Elsevier Inc. All rights reserved.

Mesa R.A.,Mayo Medical School
Blood | Year: 2014

Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating thesymptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression(pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combinationtrials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs. © 2014 by The American Society of Hematology. All rights reserved.

Rakela J.,Mayo Medical School
Liver Transplantation | Year: 2014

Hepatitis E virus (HEV) infection (genotype 3) has been described in developed countries as a cause of chronic hepatitis in recipients of solid organ transplantation (SOT), with the first cases reported in 2008. Immunosuppression seems to play a major role in the pathogenesis of chronic infections. The current gold standard for the diagnosis of HEV infection is the detection of HEV RNA in serum, stools, or both. In liver transplant recipients, HEV infection is considered an uncommon disease; however, a high index of suspicion is needed for patients with graft hepatitis of an unclear etiology. Liver transplant recipients seem more likely to develop chronic HEV after an acute infection, and there is accelerated progression to advanced fibrosis and cirrhosis. A decrease in immunosuppression is considered the first line of treatment, and pegylated interferon can be considered the second line of treatment for liver transplant recipients. At the present time, there are not enough data to recommend treatment with ribavirin for adult liver transplant recipients, although this has been tried in other SOT populations. Liver Transpl 20:15-24, 2014. © 2013 AASLD. © 2013 American Association for the Study of Liver Diseases.

Clavien P.-A.,University of Zürich | Lesurtel M.,University of Zürich | Gores G.J.,Mayo Medical School | Langer B.,University of Toronto | Perrier A.,University of Geneva
The Lancet Oncology | Year: 2012

Although liver transplantation is a widely accepted treatment for hepatocellular carcinoma (HCC), much controversy remains and there is no generally accepted set of guidelines. An international consensus conference was held on Dec 2-4, 2010, in Zurich, Switzerland, with the aim of reviewing current practice regarding liver transplantation in patients with HCC and to develop internationally accepted statements and guidelines. The format of the conference was based on the Danish model. 19 working groups of experts prepared evidence-based reviews according to the Oxford classification, and drafted recommendations answering 19 specific questions. An independent jury of nine members was appointed to review these submissions and make final recommendations, after debates with the experts and audience at the conference. This report presents the final 37 statements and recommendations, covering assessment of candidates for liver transplantation, criteria for listing in cirrhotic and non-cirrhotic patients, role of tumour downstaging, management of patients on the waiting list, role of living donation, and post-transplant management. © 2012 Elsevier Ltd.

Eaton J.E.,Mayo Medical School | Talwalkar J.A.,Mayo Medical School | Lazaridis K.N.,Mayo Medical School | Gores G.J.,Mayo Medical School
Gastroenterology | Year: 2013

Primary sclerosing cholangitis (PSC), first described in the mid-1850s, is a complex liver disease that is heterogeneous in its presentation. PSC is characterized by chronic cholestasis associated with chronic inflammation of the biliary epithelium, resulting in multifocal bile duct strictures that can affect the entire biliary tree. Chronic inflammation leads to fibrosis involving the hepatic parenchyma and biliary tree, which can lead to cirrhosis and malignancy. The etiology of PSC is not fully understood, which in part explains the lack of effective medical therapy for this condition. However, we have begun to better understand the molecular pathogenesis of PSC. The recognition of specific clinical subtypes and their pattern of progression could improve phenotypic and genotypic classification of the disease. We review our current understanding of this enigmatic disorder and discuss important topics for future studies. © 2013 by the AGA Institute.

Petersen R.C.,Mayo Medical School | Duara R.,The Medical Memory
The Lancet Neurology | Year: 2011

Background: Neurofibrillary pathology has a stereotypical progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme; however, some AD cases are atypical and do not fit into this scheme. We aimed to compare clinical and neuropathological features between typical and atypical AD cases. Methods: AD cases with a Braak neurofibrillary tangle stage of more than IV were identified from a brain bank database. By use of thioflavin-S fluorescence microscopy, we assessed the density and the distribution of neurofibrillary tangles in three cortical regions and two hippocampal sectors. These data were used to construct an algorithm to classify AD cases into typical, hippocampal sparing, or limbic predominant. Classified cases were then compared for clinical, demographic, pathological, and genetic characteristics. An independent cohort of AD cases was assessed to validate findings from the initial cohort. Findings: 889 cases of AD, 398 men and 491 women with age at death of 37-103 years, were classified with the algorithm as hippocampal sparing (97 cases [11%]), typical (665 [75%]), or limbic predominant (127 [14%]). By comparison with typical AD, neurofibrillary tangle counts per 0.125 mm2 in hippocampal sparing cases were higher in cortical areas (median 13, IQR 11-16) and lower in the hippocampus (7.5, 5.2-9.5), whereas counts in limbic-predominant cases were lower in cortical areas (4.3, 3.0-5.7) and higher in the hippocampus (27, 22-35). Hippocampal sparing cases had less hippocampal atrophy than did typical and limbic-predominant cases. Patients with hippocampal sparing AD were younger at death (mean 72 years [SD 10]) and a higher proportion of them were men (61 [63%]), whereas those with limbic-predominant AD were older (mean 86 years [SD 6]) and a higher proportion of them were women (87 [69%]). Microtubule-associated protein tau (MAPT) H1H1 genotype was more common in limbic-predominant AD (54 [70%]) than in hippocampal sparing AD (24 [46%]; p=0.011), but did not differ significantly between limbic-predominant and typical AD (204 [59%]; p=0.11). Apolipoprotein E (APOE) e{open}4 allele status differed between AD subtypes only when data were stratified by age at onset. Clinical presentation, age at onset, disease duration, and rate of cognitive decline differed between the AD subtypes. These findings were confirmed in a validation cohort of 113 patients with AD. Interpretation: These data support the hypothesis that AD has distinct clinicopathological subtypes. Hippocampal sparing and limbic-predominant AD subtypes might account for about 25% of cases, and hence should be considered when designing clinical, genetic, biomarker, and treatment studies in patients with AD. Funding: US National Institutes of Health via Mayo Alzheimer's Disease Research Center, Mayo Clinic Study on Aging, Florida Alzheimer's Disease Research Center, and Einstein Aging Study; and State of Florida Alzheimer's Disease Initiative. © 2011 Elsevier Ltd.

Izumi N.,Red Cross | Charlton M.R.,Mayo Medical School
Hepatology | Year: 2011

Branched-chain amino acids (BCAAs) are a group of essential amino acids comprising valine, leucine, and isoleucine. A low ratio of plasma BCAAs to aromatic amino acids is a physiological hallmark of liver cirrhosis, and BCAA supplementation was originally devised with the intention of normalizing amino acid profiles and nutritional status. However, recent studies on BCAAs have revealed that, in addition to their role as protein constituents, they may have a role as pharmacological nutrients for patients with chronic liver disease. Large-scale, multicenter, randomized, double-blinded, controlled trials on BCAA supplementation have been performed in Italy and Japan, and results demonstrate that BCAA supplementation improves not only nutritional status, but also prognosis and quality of life in patients with liver cirrhosis. Moreover, accumulating experimental evidence suggests that the favorable effects of BCAA supplementation on prognosis may be supported by unforeseen pharmacological actions of BCAAs. This review summarizes the possible effects of BCAAs on albumin synthesis and insulin resistance from clinical and basic viewpoints. We also review the newly discovered clinical impact of BCAAs on hepatocellular carcinoma and the prognosis and quality of life of patients with liver cirrhosis. © 2011 American Association for the Study of Liver Diseases.

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-05-2014 | Award Amount: 6.46M | Year: 2015

Breast cancer affects more than 360,000 women per year in the EU and causes more than 90,000 deaths. Identification of women at high risk of the disease can lead to disease prevention through intensive screening, chemoprevention or prophylactic surgery. Breast cancer risk is determined by a combination of genetic and lifestyle risk factors. The advent of next generation sequencing has opened up the opportunity for testing in many disease genes, and diagnostic gene panel testing is being introduced in many EU countries. However, the cancer risks associated with most variants in most genes are unknown. This leads to a major problem in appropriate counselling and management of women undergoing panel testing. In this project, we aim to build a knowledge base that will allow identification of women at high-risk of breast cancer, in particular through comprehensive evaluation of DNA variants in known and suspected breast cancer genes. We will exploit the huge resources established through the Breast Cancer Association Consortium (BCAC) and ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles). We will expand the existing datasets by sequencing all known breast cancer susceptibility genes in 20,000 breast cancer cases and 20,000 controls from population-based studies, and 10,000 cases from multiple case families. Sequence data will be integrated with in-silico and functional data, with data on other known risk factors, to generate a comprehensive risk model that can provide personalised risk estimates. We will develop online tools to aid the interpretation of gene variants and provide risk estimates in a user-friendly format, to help genetic counsellors and patients worldwide to make informed clinical decisions. We will evaluate the acceptability and utility of comprehensive gene panel testing in the clinical genetics context.

News Article | November 16, 2016

PHOENIX -- Researchers at Mayo Clinic, Harvard Medical School and the Massachusetts Institute of Technology are developing a biomaterial that has potential to protect patients at high risk for bleeding in surgery. The Nov. 16 cover article, "An Injectable Shear-Thinning Biomaterial for Endovascular Embolization," in the journal Science Translational Medicine reports on a universal shear-thinning biomaterial that may provide an alternative for treating vascular bleeding. Endovascular embolization is a minimally invasive procedure that treats abnormal blood vessels in the brain and other parts of the body beginning with a pinhole puncture in the femoral artery. This procedure is accomplished by inserting metallic coils through a catheter into a vessel, which induces clotting to prevent further bleeding. For patients unable to form a clot within the coiled artery or patients on high doses of blood thinners for their mechanical valves or cardiac assist devices, coil embolization could lead to complications, such as breakthrough bleeding, according to the study. Despite its improvement over open surgical procedures, rebleeding after coil embolization is common and can be life-threatening, states the study. The study's lead co-author Rahmi Oklu, M.D., Ph.D., a vascular interventional radiologist at Mayo Clinic's Arizona campus, explains shear-thinning biomaterial offers many advantages over metallic coils, the current gold standard. "Coils require your body's ability to create a clot in order to create that occlusion. Our shear-thinning biomaterial, regardless of how anticoagulated the patient may be, will still create that occlusion," says Dr. Oklu, who began researching the shear-thinning biomaterial three years ago while working at Massachusetts General Hospital, Harvard Medical School, in collaboration with his colleague, Ali Khademhosseini, Ph.D., of Brigham and Women's Hospital in Boston. Dr. Oklu says the shear-thinning biomaterial, which can be injected through an endovascular catheter, creates an impenetrable cast of the vessel, preventing further bleeding. This shear-thinning biomaterial is easier to deliver and see on a CT and on MRI, enabling physicians to better assess the outcomes of the procedure, says Dr. Oklu. Research on the shear-thinning biomaterial continues at Mayo Clinic. The goal is to address unmet patient needs, including possible treatment of vascular malformations, varicose veins, aneurysms and traumatic vascular injuries, as well as a drug delivery device in cancer treatment. Dr. Oklu has a financial interest related to the technology referenced in this news release. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

News Article | December 19, 2016

ROCHESTER, Minn. -- Mayo Clinic researchers and a team of collaborating scientists from across the country have determined the comparative effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin and several supplements in preventing the recurrence of advanced neoplasia (polyps that are the precursor of colorectal cancer) after polyp removal. According to the World Cancer Research Fund, colorectal cancer is the third most common cancer in the world. In the U.S., more than one-third of people who develop colorectal cancer will die of the disease, with most of those cancers arising from advanced neoplasia (also known as advanced adenomas or adenomatous polyps). In their study, published this month in The BMJ, the research team showed that, for most patients, nonaspirin NSAIDs (e.g., ibuprofen) work better than aspirin or a host of nutritional supplements to prevent the growth of advanced adenomas. In the paper, they say that due to most colorectal cancers developing from this type of polyps, preventing them is a good proxy for colorectal cancer prevention. "Approximately 85 percent of all colorectal cancers are thought to result from untreated adenomatous polyps," says M. Hassan Murad, M.D., a clinical epidemiologist and preventive medicine physician at Mayo Clinic, and the study's senior author. "If we can find a way to stop their growth, we could prevent a majority of these cases." "We knew that aspirin and other NSAIDs have a protective effect, and that a number of other nutritional supplements have also been studied for their effectiveness in preventing cancer," says Dr. Murad. "What we didn't know is how they compared to each other." The team conducted a meta-analysis (a statistical research method that involves combining data from multiple studies to obtain a single consolidated observation) of clinical trial data from 15 randomized control trials, reviewing information from 12,234 patients. These studies included low- and high-dose aspirin therapy, calcium, vitamin D and folic acid, and compared them each alone or in various combinations. Dr. Murad and his colleagues showed that nonaspirin NSAIDs are better than all the other compared therapies for preventing recurrence of adenomatous polyps within three to five years following initial polyp removal. However, because of some of the other health risks of nonaspirin NSAIDs, they may not be the best choice for everyone. Aspirin had nearly as good of results, with much less additional risk. Dr. Murad and his colleagues cautioned that, although low-dose aspirin was ranked second in preventive capabilities, "the excess benefit over risk might therefore be favorable for many patients." "It is important that patients and doctors have a discussion on the various risks and benefits of any medication or other therapy," says Dr. Murad. "While a research publication may contain promising findings, it is generalized information, and each individual is different. So their care will be individualized, as well." Dr. Murad is part of the Mayo Clinic Robert D. and Patricia E. Kern Center, where he leads the Knowledge Synthesis Program. In addition, he heads Mayo Clinic's Evidence-based Practice Center. His group conducts systematic reviews, such as this study, where they collect, appraise and summarize the available evidence on a topic. These evidence summaries help patients, physicians, guideline developers, and other stakeholders make decisions consistent with the best available evidence. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit or

News Article | November 2, 2016

Mark Hutchinson could read the anguish on the participants’ faces in seconds. As a graduate student at the University of Adelaide in Australia in the late 1990s, he helped with studies in which people taking methadone to treat opioid addiction tested their pain tolerance by dunking a forearm in ice water. Healthy controls typically managed to stand the cold for roughly a minute. Hutchinson himself, “the young, cocky, Aussie bloke chucking my arm in the water,” lasted more than 2 minutes. But the methadone patients averaged only about 15 seconds. “These aren’t wimps. These people are injecting all sorts of crazy crap into their arms. … But they were finding this excruciating,” Hutchinson says. “It just fascinated me.” The participants were taking enormous doses of narcotics. How could they experience such exaggerated pain? The experiment was Hutchinson’s first encounter with a perplexing phenomenon called opioid-induced hyperalgesia (OIH). At high doses, opioid painkillers actually seem to amplify pain by changing signaling in the central nervous system, making the body generally more sensitive to painful stimuli. “Just imagine if all the diabetic medications, instead of decreasing blood sugar, increased blood sugar,” says Jianren Mao, a physician and pain researcher at Massachusetts General Hospital in Boston who has studied hyperalgesia in rodents and people for more than 20 years. But how prevalent hyperalgesia is, and whether it plays a role in the U.S. epidemic of opioid abuse and overdose, is unclear. A lack of reliable testing methods and a series of contradictory papers have created believers and skeptics. A few researchers, like Mao, think hyperalgesia is an underappreciated puzzle piece in the opioid epidemic—a force that can pile on pain, drive up doses, and make it harder for chronic users to come off their drugs. Some of those researchers are looking for ways to turn down hyperalgesia, to help patients function on lower doses of their oxycodone, for example, or make it easier to taper off it altogether. Others see OIH as an oddity in the literature—real, and a powerful clue to the workings of  pain pathways, but unlikely to tighten the grip of opioids on most patients. Hutchinson thinks the majority of physicians are either unaware of hyperalgesia or unconvinced of its importance. “I think if you surveyed prescribers of opioids, they would be divided probably 60–40.” Paradoxical as it may seem, OIH makes evolutionary sense. “Nature didn’t come up with pain just to torture mankind,” says Martin Angst, an anesthesiologist and clinical pharmacologist at Stanford University in Palo Alto, California. Pain causes us to recoil from a hot stove and to stay off an injured leg while it heals. And when it’s crucial that we temporarily ignore pain—say, when we run on that injured leg to evade a charging lion—the body has a way of numbing it, in part by releasing its own opioids. These natural molecules bind to receptors on neurons to block pain signals and activate reward centers in the brain. But doses of prescription opioids are orders of magnitude higher than our endogenous levels, Angst says. Confronted by these, “your biology fights back and says, ‘I’m blindfolded to pain by all these chemicals. I need to be able to sense pain again.’” Mao was among the first to delve into potential mechanisms of OIH in an animal model. In 1994, while at Virginia Commonwealth University in Richmond,  he and his colleagues showed that after 8 days of spinal morphine injections, rats were quicker to pull their paws away from a gradually heated glass surface. The animals’ baseline pain threshold had changed, and the effect was something more than tolerance, in which the body requires increasing doses of a drug to get the same effect. In this case, a higher dose could actually increase sensitivity to pain. The researchers found they could reverse the hyperalgesic effect by blocking certain receptors on neurons in the animals’ spinal cord. These N-methyl-D-aspartate (NMDA) receptors pick up chemical signals—notably an excitatory molecule called glutamate—released by sensory neurons projecting from the skin and organs, and transmit pain signals up to the brain. Researchers already knew that even without opioids, some people with chronic pain from nerve damage or fibromyalgia, for example, experience hyperalgesia when normal pain signaling gets reinforced and amplified over time. It appeared that, at least in animals, opioids had a similar effect. By 2000, Mao was turning his attention to patients, and the population of opioid users was expanding. Doctors had begun to consider the drugs relatively safe options for managing chronic pain. With the release and aggressive marketing of the long-acting narcotic OxyContin in 1996, a class of drugs that had largely been reserved for cancer patients was becoming a go-to treatment for conditions such as lower back pain. As prescribing skyrocketed, so did overdoses. U.S. deaths from prescription opioids have roughly quadrupled in the last 2 decades, reaching 21,000 in 2014. Making things worse, abundant prescription opioids have been diverted for recreational use, which has driven up rates of heroin addiction as users have sought cheaper or more accessible alternatives. Both prescription and illegal opioids kill when high doses slow breathing, especially when combined with alcohol or antianxiety drugs called benzodiazepines. “I’m not sure you could find an example of physicians doing more harm to human beings than we have achieved in our liberal opiate prescribing,” says David Clark, an anesthesiologist at Stanford. Mao and others wondered whether hyperalgesia was another important opioid side effect. People might be seeking a higher dose as drug-induced pain compounded the original pain, he thought. If so, doctors who ignore hyperalgesia might bump up the dose when the right decision was to reduce it. And when a patient tried to taper off a drug, a temporarily lowered pain threshold might make it harder for them to manage without it. “If they’re hyperalgesic, they can just go back to the drug again to feel okay,” says Jose Moron-Concepcion, a neuroscientist at the Washington University School of Medicine in St. Louis in Missouri. The evidence for hyperalgesia is clearest in people taking extreme doses—for instance, in opioid abusers or terminal cancer patients managing severe pain. Surgical patients given large amounts of the opioid remifentanil have shown signs of hyperalgesia; they have larger areas of soreness around their wounds and seem predisposed to chronic pain following surgery. But what about patients who take lower doses of opioids daily over months or years to manage chronic pain? As a pain specialist at a large teaching hospital, Mao frequently encounters patients who can’t find relief from increasing opioid doses and who tell him that their pain has become worse—diffuse, nagging, and harder to pinpoint. But just how many people experience OIH, and at what opioid dose, is hard to say. The phenomenon can be very hard to distinguish from tolerance, when pain increases as the drug loses its effectiveness over time. (It’s also possible that a patient’s underlying condition has changed, or that the chronic pain itself has kicked their pain signaling into high gear.) Because diagnosing hyperalgesia can be a guessing game in the clinic, some researchers have turned to the lab. They have tried to document changing pain thresholds with quantitative sensory tests, like the so-called cold pressor test Hutchinson witnessed in the methadone patients in Australia, or contraptions that apply heat or pressure to the skin. But the studies have been small and the results inconsistent. “Nobody has actually shown that that particular stimulus in a human being is a valid way to say, ‘Yes, this person has become hyperalgesic,’” Angst says. In 2006, for instance, a team that included Angst and Clark gave the cold pressor test to six people with chronic lower back pain before and after a monthlong course of morphine pills. After the drug treatment, the team found signs of hyperalgesia: On average, the subjects registered pain from the ice water about 2 seconds earlier, and removed their hands about 8 seconds earlier, than they had beforehand. But those results didn’t hold up in a larger group of 139 patients randomized to take opioids or placebo, nor did they appear in a different pain test that applied a gradually heated probe to the forearm. Then in 2013, a study with a different methodology seemed to confirm the effect. A research team in Israel reported evidence of hyperalgesia in 17 of 30 patients with radiating spinal nerve pain by asking them to rate the intensity of heat pain on a numerical scale before and after a 4-week course of hydromorphone. If you can’t reliably diagnose hyperalgesia, it’s hard to predict its long-term effects, says Michael Hooten, an anesthesiologist at the Mayo Medical School in Rochester, Minnesota. His group found evidence in 91 patients tapering off opioids that those whose doses were higher at the start, forcing them to make greater reductions over the 3-week program, had worse measures of heat pain hyperalgesia. But the team wasn’t able to track these patients long-term to ask the bigger questions: How long until their pain thresholds bounced back to normal? Do hyperalgesic patients who manage to quit taking opioids ultimately see improvements in pain? Are hyperalgesic patients more or less prone to addiction or relapse? For some, this lack of evidence makes research into hyperalgesia look like a dead end. “When I go to work every day, I don’t think about opioid-induced hyperalgesia,” says Gary Bennett, a pain researcher at the University of California in San Diego. “We know that it’s real. We don’t know how important it is, and it’s really, really hard to answer that question, so let’s move on.” Mao isn't ready to move on. He believes the risk of hyperalgesia should motivate doctors to try tapering patients off their opioids when their pain worsens without an obvious cause. But in his experience, only about a third of chronic pain patients are willing to try that. So he’s hoping for a different solution: a drug that targets the mechanisms behind hyperalgesia and that might be given alongside an opioid, either when it’s first prescribed or when a doctor suspects OIH. Mao is recruiting patients for clinical trials to test two candidate drugs. One is ketamine, an anesthetic that blocks NMDA receptors. The other, guanfacine, is currently used to treat high blood pressure and is thought to keep sensory neurons from releasing glutamate into the spinal cord. A team led by Peggy Compton of Georgetown University in Washington, D.C., meanwhile, is investigating a pain and antiseizure drug called gabapentin that may block neural transmission to reduce excessive pain signals. Other groups are attacking opioid side effects, including hyperalgesia, from a very different angle. In the early 2000s, researchers began exploring the role of glia, star-shaped immune cells in the brain and spinal cord, which were traditionally thought to function as mere “housekeepers,” offering structural support for neurons and removing debris. But when the immune system becomes activated in response to an illness or injury, glia in regions associated with pain processing seem to take on another role: They release inflammatory molecules that interact with nearby neurons to amplify pain signals. In 2001, researchers at the Chinese Academy of Sciences in Shanghai reported that chronic morphine administration in rats activated glial cells called astrocytes in the spinal cord. Subsequent studies showed that inhibiting the inflammatory molecules released by glia could reverse hyperalgesia and tolerance in the rats. The results suggested that opioids may trigger glia to set off system-wide pain signaling that both counteracts the pain relief from the drug and makes the body generally more sensitive to pain. Many see dampening this inflammatory response as a promising way to fight hyperalgesia, because it would not interfere with opioids’ pain-relieving activity on neural receptors. Several efforts are underway. The San Diego, California–based biotech company MediciNova recently completed a phase II trial of a glia-inhibiting drug called ibudilast, already approved as an asthma treatment in Japan, to relieve pain and treat withdrawal in opioid abusers. A study led by researchers at Yale University is testing the antibiotic acne medication minocycline, which is also thought to block glial activation in the brain. And research spun out of neuroscientist Linda Watkins’s group at the University of Colorado in Boulder is testing a new pain drug that may tame glia in the spinal cord by blocking a signaling protein on their surface. If inflammation turns out to be a key driver of OIH, it might also point the way to a better test for the effect, says Lesley Colvin, a pain researcher at the University of Edinburgh. Markers of inflammation in the blood might correlate with clinical signs of hyperalgesia or declining pain thresholds on sensory tests. Colvin says she already sees strong evidence of hyperalgesia in high-dose opioid users at the clinic where she works. With so much at stake, she is eager to understand the phenomenon and how it might affect them long term. “Although it’s complicated,” she says, “that doesn’t mean we shouldn’t try and work out the details.”

News Article | April 16, 2016

Feeling sick? Just fire up an app on your phone, talk to a nurse or doctor and have your drugs sent to the nearest pharmacy within the hour. Sounds too good to be true, right? But that’s exactly what I did on a recent evening, when I couldn’t get myself to my doctor’s office during a terrible cold. They’re known as “telemedicine” services, and if you haven’t heard of them by now, they’re one of Silicon Valley’s ever-expanding ventures into the health space. As part of a larger push for a data-based healthcare system—and on the heels of the Affordable Care Act’s rules and regulations—the tech industry isn’t waiting around when it comes to innovating the patient experience. Because Obamacare’s law includes incentives for innovation and cost-cuts, tech startups can become a booming byproduct of the looming new generation of healthcare. But while many startups are scrambling to provide similar medical services, not everyone is impressed with tech’s plans to disrupt healthcare—at least not without valid apprehensiveness—with misdiagnosis being the main concern among the medical field. The prominence of apps such as Pager and Doctor On Demand proves that tech entrepreneurs are hoping to make virtual healthcare a reality for every patient. Even UnitedHealthcare has announced its own virtual care program; the latest giant insurance company joining the ranks in providing telemedicine services. While they all have their own variations on the telemedicine idea, one thing all of these apps have in common is a triage system that filters a patient’s needs and eventual treatment. In my experience, getting an instant diagnosis for your health problems becomes addicting. This is especially true for millennials like myself already used to exhaustingly WebMD’ing symptoms until we find an answer we like. For my first “visit”, I decided to use my health insurance’s app, Oscar, which comes loaded with a free, unlimited “Doctor on Call” feature as part of my monthly member plan. After requesting a call through the mobile app, I received a phone call that spurred a 10-minute consultation with a board-certified physician about my symptoms. By the time I hung up, the doctor had already sent my pharmacy the prescription treatment that I agreed to try. Overall, a painless, easy experience. Oscar CEO and Co-Founder Mario Schlosser told me that its Doctor on Call “can be a very powerful feature, and work very well, but you cannot rely on just tele-visits. Patients have to have it as part of a bigger healthcare system.” Given that these telemedicine features are being built to quickly treat common ailments and point the patient in the right direction, thus far, the benefits have outweighed the concerns. Since its inception about two years ago, Oscar's “Doctor on Call” system has already made an impact, the startup claims. “To use bronchitis as an example, with the use of Oscar's telemedicine, bronchitis treatment increased 60 percent and general consultation increased 55 percent," Schlosser said. "In terms of cost, Oscar's telemedicine program has also caused a 91 percent increase in free and successful solutions to bronchitis.” With such positive reinforcement, I got more comfortable with the idea of trying out virtual doctors in the comfort of my own home. And so, I kept going as I saw fit for my ongoing health issues. Of course, the idea of telemedicine is nothing new, and has been around long before tech brought it to our mobile phones. “There is literature on older ways of doing this, like telemedicine and ‘ask a nurse’ services that would let patients call in and ask for help with their illness. It’s not too terribly different,” Dr. Peter Muennig, a professor at Columbia University’s Mailman School of Public Health, told me. And so, next up was the Pager app. A beautifully designed, clean interface drew me in, but asking for help on a medical app can be intimidating, especially when I started to calculate the potential financial costs. Luckily, many of these services tend to offer a free first time “visit”, which I immediately took advantage of (after which "visits" cost between $25 to $200). This time around, I wanted a second opinion about my chronic digestive issues, which often trigger vomiting spurts. Glamourous, I know. After explaining my symptoms away to the certified Pager nurse on the other side of the smartphone screen, she suggested I call my regular specialist for further consultation. What these apps all have in common is they work exactly how I imagine a well-oiled “triage” system to operate—and so off I went with my quick advice. It feels, really, no different than asking your local pharmacist a question about over-the-counter meds. In my experience, these telemedicine apps do exactly what they’re intended for. They’re by no means intended for emergency diagnosis, but they get the patient that first nudge of professional opinion to start their treatment. Pager hopes to bring telemedicine to the masses, and is going one step further by providing doctor visits to your home or office. Pager Chief Exec and Co-Founder Gaspard De Dreuzy told me that when it comes to innovating an-already struggling and wasteful healthcare system, you must implement multiple care facets. “Is it opportunistic? Sure. There’s nothing wrong with that,” Boston-based pediatrician Lisa Coray said. “The solutions from Silicon Valley can absolutely improve the system, but at the same time, with the reliance on tech, if there isn’t some sober realistic thinking about inherent limitations in tech-based diagnosis—not that there aren’t already—systematizing these failures is a problem.” Pager acknowledges that diagnosing a patient incorrectly is a big risk that the startup is mindful of. “Misdiagnosis can happen on a lot of levels," Pager’s CMO and Operations Director Andrew Chomer said. "What we solve for is largely urgent care. If it’s not urgent care upfront, we get them to the right course. That’s how triage and chat-based tech can be a guide, and how our satisfaction rate is so high. It’s about filtering cases right up front." Despite all the precautions that startups are taking, along with the realities of high-tech vs. traditional triage systems provide, some traditional physicians feel that “doctor-hailing apps” just can’t deliver the same type of quality as a visit to your trusted doctor’s office. “There’s nothing like seeing a patient," Colorado-based family physician Dr. Mark Hailey said. "There’s an art to medicine that needs human element, and a computer is merely a tool that helps us diagnose the patient correctly.” A few weeks after my Pager call, I found myself back at my primary physician’s office for a follow up visit to a routine checkup. After reassessing my physical and mental health due to recent stressful life events, my long-term doctor (whom I’ve become close with over the years) suggested it’d be the perfect time to give the anti-anxiety medication I previously resisted. I knew it was going to be a big change, but I trusted my doctor to steer me on the right path, given the context and medical history she has on record. What I wasn’t ready for were the severe side effects. Fortunately, there weren’t any signs of mania or suicide (as the label warns), but my previously-mentioned nausea problems kicked into full effect right away. And so I found the perfect opportunity to try out the Doctor On Demand app to get some advice on calming my dizziness and upset stomach. By now, I was becoming a pro at talking to virtual healthcare professionals while in agonizing pain, and quickly entered my question following the signup prompt. While Doctor On Demand doesn’t have the clean lines and design that I prefer, it still got the job done. Within minutes, I was once again offered a complimentary first video visit with a doctor, which I decided to forgo given my anxiety (ironically) about my unsightly physical state. The near-retirement doctors I talked to may want to stick to their face-to-face doctor-patient relationships, but many members of the medical community are willing to embrace telemedicine in the name of improving America’s healthcare system. For example, Pager’s mission is to overhaul traditional medicine by “combining elements of house visits and virtual care.” “We have advantages for being a new company, so we can leverage new technology when it comes to concerns such as patient data,” explains Pager’s De Dreuzy. “We can do this at a faster pace and a lower cost than traditional health providers.” Telemedicine tech providers still have a way to go before perfecting their formulas to truly implement a perfect healthcare system, but even so, there’s a sense of optimism that “virtual doctor” services can make a difference when it comes to certain medical field issues. These include the current shortage of general practitioners and wasteful ER visits that we’re all familiar with. “Doctor shortages are more common in rural communities, and this would give those areas a chance to connect to more doctors,” Humza Ansari, a third-year student at Mayo Medical School, told me. “Additionally, the role of mid-level providers (nurse practitioners, physician assistants) in primary-care is growing in many states, and I would envision mid-levels playing a big role in ‘staffing’ primary care done through tech. At the end of the day, with or without this technology, America will need more primary care physicians, especially in under-served communities.” At this point, there is still a push and pull in what can be deemed as the Wild West when it comes to healthcare apps under the new tech era of medicine, with only time as the telling factor of whether technology can truly step up to solve the issues that the lagging medical industry hasn’t been able to do for decades. Thus far for me, using telemedicine apps definitely enhanced my healthcare experience to an extent. And when used as part of a larger aforementioned triage system, they have the ability to not only be effective, but potentially save both patients and providers time and money, like they did during my anecdotal experiment. There’s no denying that technology is seeping through our healthcare system to improve it. The decision to use these tech-based health services depends on the personal preference and lifestyle of the patient. I do plan on using at least one of these apps in the future for its intended purposes: quick diagnosis for simple issues. However, when it comes to major medical decision—like starting a new long term prescription treatment—I’d feel more comfortable, psychologically anyway, doing it “in real life” at my trusted doctor’s office.

News Article | November 22, 2016

ROCHESTER, Minn. -- Researchers at Mayo Clinic Center for Individualized Medicine have discovered a potential cause and a promising new treatment for inflammatory myofibroblastic tumors, a rare soft tissue cancer that does not respond to radiation or chemotherapy. New research from Aaron Mansfield, M.D., an oncologist at Mayo Clinic, and George Vasmatzis, Ph.D., the co-director of the Biomarker Discovery Program of Mayo Clinic Center for Individualized Medicine, finds the drug ceritinib shows promise as a new treatment for inflammatory myofibroblastic tumors, a form of sarcoma. The study also traced tumor growth to chromoplexy: a complex chromosomal rearrangement that causes genes to scramble, break DNA strands and then reassemble in a defective way. Dr. Mansfield's research, "Chromoplectic TPM3-ALK Rearrangement in a Patient With Inflammatory Myofibroblastic Tumor Who Responded to Ceritinib After Progression on Crizotinib," is published in the Annals of Oncology, Volume 27, No. 11, November 2016. Investigators made the connection when a 32-year old man failed to respond to a nonsteroidal anti-inflammatory drug to shrink tumors in his lung, chest and buttock. Because there were no available clinical trials, researchers sought and gained U.S. Food and Drug Administration approval for compassionate use of ceritinib. Within two weeks, the patient started responding to the drug. After 18 months, he was well enough to undergo surgery to remove tumors from his lung and buttock. Mayo researchers were able to conduct a new DNA test on the tumors known as mate pair sequencing. That test scans the entire genome, pinpointing genetic defects and chromosomal breaks. They found 142 genes had been impacted, many of which have known links to cancerous tumors. "Mate pair sequencing helped identify these rearrangements, which may not have been seen with normal sequencing techniques," says Aaron Mansfield, M.D., the first author of the study. "We look forward to offering more patients this new, advanced type of DNA testing to discover potential causes and treatments for diseases." Inflammatory myofibroblastic tumors often strike in children and young adults. The main form of treatment for patients with an inflammatory myofibroblastic tumor is surgery, but the tumors often reappear in different parts of the body. There is no standard of care for patients with inflammatory myofibroblastic tumors, thus making the discovery of tumor response to ceritinib all the more important. Mayo Clinic investigators are recommending further study of this drug to determine whether it should be approved for individualized treatments. Additional authors on the research team -- all of Mayo Clinic -- are: The National Institutes of Health and Mayo Clinic Center for Individualized Medicine's Biomarker Discovery Program supported this work. Mayo Clinic Center for Individualized Medicine discovers and integrates the latest in genomic, molecular and clinical sciences into personalized care for each Mayo Clinic patient. For more information, visit Mayo Clinic is a nonprofit organization committed to medical research and education, and providing expert, whole-person care to everyone who needs healing. For more information, visit or

Sambhara S.,Centers for Disease Control and Prevention | Poland G.A.,Mayo Medical School
Annual Review of Medicine | Year: 2010

Avian influenza H5N1 viruses that have spread to a number of countries in Asia, the Middle East, and Africa have the potential to cause a pandemic. The most effective public health intervention strategy is to combine preventive vaccination with nonpharmaceutical intervention strategies and enhanced surveillance activities. H5N1 vaccines are poorly immunogenic even at high doses; an adjuvant is needed for enhancement of immunogenicity and for dose-sparing. Lack of effective, yet safe, adjuvants is the limiting factor for candidate vaccines that utilize egg-dependent or egg-independent manufacturing technologies. Hence, developing novel adjuvants is crucial for pandemic influenza vaccine development. Although the use of antiviral drugs is also an important public health countermeasure for preventing and treating influenza, the emergence of drug-resistant strains of avian H5N1 viruses underscores the need to develop not only new drugs but other novel preventive and therapeutic strategies such as vaccines. © 2010 by Annual Reviews All rights reserved.

Tefferi A.,Mayo Medical School | Barbui T.,Papa Giovanni XXIII Hospital
American Journal of Hematology | Year: 2015

Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ~14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life-expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk-adapted therapy: The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low-dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. © 2014 Wiley Periodicals, Inc.

Berry D.J.,Mayo Medical School | Bozic K.J.,University of California at San Francisco
Journal of Arthroplasty | Year: 2010

A poll was conducted at the 2009 Annual Meeting of the American Association of Hip and Knee Surgeons to determine current practices among its members in primary total hip arthroplasty and total knee arthroplasty. This article summarizes the audience responses to a number of multiple choice questions concerning perioperative management and operative practice patterns and preferences including anesthetic choices, blood management, surgical approaches, implant selection, implant fixation, bearing surface choice, postoperative rehabilitation, recommended postoperative activity restrictions, and antibiotic prophylaxis. © 2010.

Ma L.,University of Illinois at Urbana - Champaign | Kohli M.,Mayo Medical School | Smith A.,University of Illinois at Urbana - Champaign
ACS Nano | Year: 2013

Nanoparticles have recently emerged as a promising class of carriers for the co-delivery of multiple drugs. Combination therapies of small-molecule drugs are common in clinical practice, and it is anticipated that packaging into single macromolecular carriers will enable drug release in precisely balanced ratios and rates and in selectively targeted tissues and cells. This vast level of pharmacological control is intriguing, especially from the perspective of tailoring personalized treatments with maximized therapeutic synergy for individual patients. Here, we discuss promising formulations and opportunities to employ advanced screening tools and new animal models of disease that can improve chances for successful clinical translation. © 2013 American Chemical Society.

Gershlick A.H.,University of Leicester | Banning A.P.,Oxford Radcliffe Hospitals | Myat A.,King's College London | Verheugt F.W.A.,Radboud University Nijmegen | Gersh B.J.,Mayo Medical School
The Lancet | Year: 2013

In the past ten years, primary percutaneous coronary intervention (PCI) has replaced thrombolysis as the revascularisation strategy for many patients presenting with ST-segment elevation myocardial infarction (STEMI). However, delivery of primary PCI within evidence-based timeframes is challenging, and health-care provision varies substantially worldwide. Consequently, even with the ideal circumstances of rapid initial diagnosis, long transfer delays to the catheter laboratory can occur. These delays are detrimental to outcomes for patients and can be exaggerated by variations in timing of patients' presentation and diagnosis. In this Series paper we summarise the value of immediate out-of-hospital thrombolysis for STEMI, and reconsider the potential therapeutic interface with a contemporary service for primary PCI. We review recent trial data, and explore opportunities for optimisation of STEMI outcomes with a pharmacoinvasive approach.

Younes A.,University of Houston | Connors J.M.,Cancer Agency Center for Lymphoid Cancer | Park S.I.,University of North Carolina at Chapel Hill | Fanale M.,University of Houston | And 4 more authors.
The Lancet Oncology | Year: 2013

Background: Roughly 70-80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma. Methods: We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB-IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with, number NCT01060904. Findings: Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]). Interpretation: Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma. Funding: Seattle Genetics Inc and Takeda Pharmaceuticals International Co. © 2013 Elsevier Ltd.

Tefferi A.,Mayo Medical School | Thiele J.,University of Cologne | Vannucchi A.M.,University of Florence | Barbui T.,Papa Giovanni XXIII Hospital
Leukemia | Year: 2014

Disease-specific mutations facilitate diagnostic precision and drug target discovery. In myeloproliferative neoplasms (MPN), this is best exemplified by the chronic myeloid leukemia-associated BCR-ABL1. No other mutation in MPN has thus far shown a similar degree of diagnostic accuracy or therapeutic relevance. However, JAK2 and KIT mutations are detected in more than 90% of patients with polycythemia vera and systemic mastocytosis, respectively, and are therefore used as highly sensitive clonal markers in these diseases. JAK2 and MPL mutations also occur in essential thrombocythemia (ET) and primary myelofibrosis (PMF), but their diagnostic value is limited by suboptimal sensitivity and specificity. The molecular diagnostic gap in JAK2/MPL-unmutated ET/PMF is now partially addressed by the recent discovery of calreticulin (CALR) mutations in the majority of such cases. However, bone marrow morphology remains the central diagnostic platform and is essential for distinguishing ET from prefibrotic PMF and diagnosing patients those do not express JAK2, MPL or CALR (triple-negative). The year 2013 was also marked by the description of CSF3R mutations in the majority of patients with chronic neutrophilic leukemia (CNL). Herein, we argue for the inclusion of CALR and CSF3R mutations in the World Health Organization classification system for ET/PMF and CNL, respectively. © 2014 Macmillan Publishers Limited.

Njei B.,Yale University | Njei B.,University of Connecticut | Rotman Y.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Ditah I.,Mayo Medical School | Lim J.K.,Yale University
Hepatology | Year: 2015

The rise in incidence of hepatocellular carcinoma (HCC) in the United States has been well documented. The purpose of this analysis was to examine temporal trends in HCC incidence, mortality, and survival within the U.S. population. The Surveillance, Epidemiology, and End Results data were used to examine incidence and incidence-based (IB) mortality in HCC from 1973 to 2011. Secular trends in age-adjusted incidence and IB mortality by sex and cancer stage were characterized using the Joinpoint Regression program. In 1973, HCC incidence was 1.51 cases per 100,000, whereas in 2011, HCC incidence was 6.20 cases per 100,000. Although HCC incidence continues to increase, a slowing of the rate of increase occurs around 2006. In a sensitivity analysis, there was no significant increase in incidence and IB mortality from 2009 to 2011. There was a significant increase in overall median survival from the 1970s to 2000s (2 vs. 8 months; P<0.001). On multivariable Cox's regression analysis, age, sex, race, tumor grade, stage at diagnosis, lymph/vascular invasion, number of primary tumors, tumor size, and liver transplant were independently associated with mortality. Conclusion: Our results indicate a deceleration in the incidence of HCC around 2006. Since 2009 and for the first time in four decades, there is no increase in IB mortality and incidence rates for HCC in the U.S. population. The nonsignificant increase in incidence and IB mortality in recent years suggest that the peak of the HCC epidemic may be near. A significant survival improvement in HCC was also noted from 1973 to 2010, which seems to be driven by earlier detection of HCC at a curative stage and greater utilization of curative modalities (especially transplant). © 2014 by the American Association for the Study of Liver Diseases.

Ryan D.,Pennington Biomedical Research Center | Acosta A.,Mayo Medical School
Obesity | Year: 2015

Obective Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for treatment of type 2 diabetes since they mimic the actions of native GLP-1 on pancreatic islet cells, stimulating insulin release, while inhibiting glucagon release, in a glucose-dependent manner. The observation of weight loss has led to exploration of their potential as antiobesity agents, with liraglutide 3.0 mg day-1 approved for weight management in the US on December 23, 2014, and in the EU on March 23, 2015. This review examines the potential nonglycemic effects of GLP-1 receptor agonists. Methods A literature search was conducted to identify preclinical and clinical evidence on nonglycemic effects of GLP-1 receptor agonists. Results GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. Nonglycemic effects include weight loss, which is perhaps the most widely recognized nonglycemic effect. In addition, effects on the cardiovascular, neurologic, and renal systems and on taste perception may occur independently of weight loss. Conclusions GLP-1 receptor agonists may provide other nonglycemic clinical effects besides weight loss. Understanding these effects is important for prescribers in using GLP-1 receptor agonists for diabetic patients, but also if approved for chronic weight management. © 2015 The Obesity Society.

Tefferi A.,Mayo Medical School | Barbui T.,Papa Giovanni XXIII Hospital
Mayo Clinic Proceedings | Year: 2015

Bone marrow (BM) morphologic features remain the cornerstone of diagnosis in both essential thrombocythemia (ET) and polycythemia vera (PV). In addition, recently discovered mutations, such as JAK2, CALR, and MPL, have proven useful in facilitating the diagnostic process. A JAK2 mutation is expected in PV, and its absence makes the diagnosis unlikely. However, JAK2 mutations also occur in about 60% of patients with ET, which underlines the need for BM examination in distinguishing JAK2-mutated ET from PV when the hemoglobin/hematocrit level is diagnostically equivocal (ie, as in "masked" PV). Most patients with JAK2-unmutated ET express CALR or MPL mutations, with respective estimated incidences of 22% and 3%, while approxmately 15% are wild-type for all 3 mutations (ie, they are triple-negative). As such, CALR first, followed by MPL if CALR is absent, mutation screening is appropriate in the diagnostic work-up of JAK2-unmutated ET but does not replace the need for BM morphologic examination in (1) confirming the diagnosis in triple-negative ET and (2) distinguishing ET from other myeloproliferative neoplasms that share the same mutations, including masked PV and early/prefibrotic myelofibrosis. Young patients (aged <60 years) with ET or PV and no history of thrombosis are conventionally regarded as having "low-risk" disease. First-line treatment in low-risk PV is phlebotomy to achieve a hematocrit target of 45% and low-dose aspirin, and first-line treatment in ET is observation alone in the absence of additional risk factors for arterial thrombosis (ie, JAK2 mutation and cardiovascular risk factors) or low-dose aspirin therapy, once or twice daily, in the presence of one or both of these risk factors, respectively. Cytoreductive therapy is indicated in high-risk (patients aged ≥60 years or a history of thrombosis) PV or ET in the form of hydroxyurea as first-line and interferon alfa or busulfan as second-line drugs of choice. We do not use ruxolitinib in patients with PV unless they have severe pruritus or symptomatic splenomegaly that is proved to be refractory to hydroxyurea, interferon alfa, and busulfan. © 2015 Mayo Foundation for Medical Education and Research.

Ansell S.M.,Mayo Medical School | Armitage J.O.,University of Nebraska at Omaha
Mayo Clinic Proceedings | Year: 2012

The use of sensitive and specific imaging techniques for accurate initial staging and evaluation of response to therapy in patients with lymphoma is essential for their optimal management. Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with computed tomography (CT) has emerged as a powerful imaging tool and is being routinely used in staging, response evaluation, and posttreatment surveillance in patients with non-Hodgkin lymphoma and Hodgkin lymphoma. PET/CT is currently widely used in clinical practice, but the established clinical benefit is currently restricted to the posttreatment evaluation of Hodgkin lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. Although used in other histologic subtypes and in other clinical situations including response assessment, its impact on patient outcome remains to be demonstrated. We performed a literature search of PubMed from 1999 to 2011 using the following keywords: PET scan, FDG-PET, PET/CT, lymphoma. This review addresses the challenges and controversies in the use of PET/CT scans in the management of patients with lymphoma. © 2012 Mayo Foundation for Medical Education and Research.

Mathison B.A.,Centers for Disease Control and Prevention | Pritt B.S.,Mayo Medical School
Clinical Microbiology Reviews | Year: 2014

The collection, handling, identification, and reporting of ectoparasitic arthropods in clinical and reference diagnostic laboratories are discussed inthisreview.Includedaredataonticks,mites,lice, fleas,myiasis-causing flies, and bed bugs. The public health importance of these organisms is briefly discussed. The focus is on the morphological identification and proper handling and reporting of cases involving arthropod ectoparasites, particularly those encountered in the United States. Other arthropods and other organisms not of public health concern, but routinely submitted to laboratories for identification, are also briefly discussed. © 2014, American Society for Microbiology. All Rights Reserved.

Gerson L.B.,University of California at San Francisco | Fidler J.L.,Mayo Medical School | Cave D.R.,University of Massachusetts Medical School | Leighton J.A.,Mayo Medical School
American Journal of Gastroenterology | Year: 2015

Bleeding from the small intestine remains a relatively uncommon event, accounting for ∼5-10% of all patients presenting with gastrointestinal (GI) bleeding. Given advances in small bowel imaging with video capsule endoscopy (VCE), deep enteroscopy, and radiographic imaging, the cause of bleeding in the small bowel can now be identified in most patients. The term small bowel bleeding is therefore proposed as a replacement for the previous classification of obscure GI bleeding (OGIB). We recommend that the term OGIB should be reserved for patients in whom a source of bleeding cannot be identified anywhere in the GI tract. A source of small bowel bleeding should be considered in patients with GI bleeding after performance of a normal upper and lower endoscopic examination. Second-look examinations using upper endoscopy, push enteroscopy, and/or colonoscopy can be performed if indicated before small bowel evaluation. VCE should be considered a first-line procedure for small bowel investigation. Any method of deep enteroscopy can be used when endoscopic evaluation and therapy are required. VCE should be performed before deep enteroscopy if there is no contraindication. Computed tomographic enterography should be performed in patients with suspected obstruction before VCE or after negative VCE examinations. When there is acute overt hemorrhage in the unstable patient, angiography should be performed emergently. In patients with occult hemorrhage or stable patients with active overt bleeding, multiphasic computed tomography should be performed after VCE or CTE to identify the source of bleeding and to guide further management. If a source of bleeding is identified in the small bowel that is associated with significant ongoing anemia and/or active bleeding, the patient should be managed with endoscopic therapy. Conservative management is recommended for patients without a source found after small bowel investigation, whereas repeat diagnostic investigations are recommended for patients with initial negative small bowel evaluations and ongoing overt or occult bleeding. © 2015 by the American College of Gastroenterology.

Rodriguez F.J.,Johns Hopkins University | Folpe A.L.,Mayo Medical School | Giannini C.,Mayo Medical School | Perry A.,University of California at San Francisco
Acta Neuropathologica | Year: 2012

Peripheral nerve sheath tumors are common neoplasms, with classic identifiable features, but on occasion, they are diagnostically challenging. Although well-defined subtypes of peripheral nerve sheath tumors were described early in the history of surgical pathology, controversies regarding the classification and grading of these tumors persist. Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches. In this review, we discuss current concepts and problematic areas in the pathology of peripheral nerve sheath tumors. Diagnostic criteria and differential diagnosis for the major categories of nerve sheath tumors are proposed, including neurofibroma, schwannoma, and perineurioma. Diagnostically challenging variants, including plexiform, cellular and melanotic schwannomas are highlighted. A subset of these affects the childhood population, and has historically been interpreted as malignant, although current evidence and outcome data suggest they represent benign entities. The growing current literature and the author's experience with difficult to classify borderline or "hybrid tumors" are discussed and illustrated. Some of these classification gray zones occur with frequency in the gastrointestinal tract, an anatomical compartment that must always be entertained when examining these neoplasms. Other growing recent areas of interest include the heterogeneous group of pseudoneoplastic lesions involving peripheral nerve composed of mature adipose tissue and/or skeletal muscle, such as the enigmatic neuromuscular choristoma. Malignant peripheral nerve sheath tumors (MPNST) represent a diagnostically controversial group; difficulties in grading and guidelines to separate "atypical neurofibroma" from MPNST are provided. There is an increasing literature of MPNST mimics which neuropathologists must be aware of, including synovial sarcoma and ossifying fibromyxoid tumor. Finally, we discuss entities that are lacking from the section on cranial and paraspinal nerves in the current WHO classification, and that may warrant inclusion in future classifications. In summary, although the diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer, yet borderline and difficult-to-classify neoplasms continue to be problematic. In the current review, we attempt to provide some useful guidelines for the surgical neuropathologist to help navigate these persistent, challenging problems. © 2012 Springer-Verlag.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 212.37K | Year: 2011

DESCRIPTION (provided by applicant): Translational research in the field of liver disease has been limited by a shortage of large animal models, which in turn has limited development of new therapies for metabolic liver disorders, acute liver failure, chronic (cirrhotic) liver disease, an hepatocellular carcinoma. While new transgenic and knockout rodent models of liver disease have facilitated basic research, the development of bioengineered large animal models of liver disease has been problematic. To address the shortage of large animal models, we have utilized a novel strategy combining gene targeting by recombinant adeno-associated virus DJ serotype (rAAVdj) and somatic cell nuclear transfer (SCNT) for the production of bioengineered pigs. Our prototypemodel is hereditary tyrosinemia type 1 (HT1) accomplished by knocking out the gene coding for fumarylacetoacetate hydrolase (FAH) in pigs. In humans, FAH deficiency is associated with a unique phenotype, which includes metabolic derangement (tyrosinemia),acute liver failure, cirrhosis, and hepatocellular carcinoma (HCC). In mice, FAH deficiency combined with immune modulation has been used to produce mice with humanized livers (Azuma 2007 Nature Biotechnology; Bissig 2010 J Clinical Investigation). TheseFAH deficient mice serve as in vivo bioreactors for the robust expansion of normal human hepatocytes. We postulate that scale up of the FAH deficient platform to pigs is possible, and that FAH deficient pigs will also serve as surrogate hosts for much larger scale in vivo expansion of normal human hepatocytes. An abundant supply of human hepatocytes is needed for applications including toxicity testing of new drugs, human hepatocyte transplantation, and cell- based liver support devices such as the bioartificial liver. With regard to commercialization of this novel technology, we have already produced Fah-null heterozygote female pigs by rAAVdj and SCNT methodology. This phase 1 STTR (R41) application will establish a herd of FAH-deficient pigs and characterize the phenotype of Fah-null homozygote pigs. In future phase 2 studies, FAH-deficient pigs will be evaluated as in vivo bioreactors for the large-scale production of human hepatocytes. We expect that the FAH-deficient pig will serve as a valuable resource for the development of novel therapeutic modalities and to facilitate translational research in the field o liver disease. Furthermore, the rAAVdj and SCNT methodology may be utilized to produce other bioengineered large animal models of human disease.PUBLIC HEALTH RELEVANCE: The goal of the current research program is to develop a bioengineered pig with the metabolic disorder of human hereditary tyrosinemia type 1 (HT1). Phase 1 studies are designed to establish a herd of HT1 pigs and characterize the phenotype of these pigs. Phase 2 studies will determine if HT1 pigs can serve as in vivo bioreactors for large scale production of human hepatocytes. There are many therapeutic applications for normal human hepatocytes such as a cell-source in a bioartificial liver or for hepatocyte transplantation in humans, or industrial applications for safety and toxicity screening, or for use by pharmaceutical companies in the drug discovery process. Thus the demand for these new pigs is worthy of commercialization.

Agency: Department of Defense | Branch: Navy | Program: STTR | Phase: Phase II | Award Amount: 741.10K | Year: 2010

Current issues with forward deployed flight simulator sickness prevent flight simulators from being used to their fullest potential. Infoscitex and the Mayo Clinic have been jointly developing a system for incorporating a vestibular display into flight simulators. In the Phase I program, we successfully demonstrated that using the vestibular display with a fixed-base simulator reduces both the incidence and severity of symptoms associated with simulator sickness. We propose to further our studies in Phase II, leading to complete system integration and final testing in an operationally relevant environment. During the base period we will redesign and fabricate the hardware so that it meets all of the needs identified for this application. We will use this new hardware in a broad demonstration of the system across civilian subjects. In the first Option period we will further the tests and move into an operationally relevant testbed and military trainees, demonstrating the capabilities of our system to our military sponsors and other potential stakeholders.

Agency: European Commission | Branch: FP7 | Program: CSA | Phase: ICT-2013.5.1 | Award Amount: 391.83K | Year: 2013

Motivated by the transatlantic eHealth Cooperation Roadmap, Trillium Bridge aims to bridge patient summary specifications in the EU and US to support interoperability for improved health and healthcare delivery, economic growth and innovation.\nWith an outstanding well-balanced consortium, Trillium Bridge leverages epSOS patient access and Meaningful Use/Transitions of Care use cases:\n Mobilizes people and resources creating a forum of collaboration and knowledge sharing\n Compares patient summary specifications and associated policies including eIdentification, privacy & security to select pilot use cases and complete a gap analysis\n Assembles interoperability assets to align structure and terminology (semantic mapping services for value sets published by the National Library of Medicine & epSOS, clinical document structures, testing and validation tools)\n Develops testing tools and validation reports from committed US providers and epSOS sites.\n Informs development of implementation guides and template libraries for patient summaries in liaison with Standards Development Organizations decreasing standards development costs\n Creates a feasibility analysis for patient and provider-mediated exchange of patient summaries.\nOnline social tools engage input from eHealth stakeholders at all project stages. Interoperability resources assembled for the eHealth industry to use push the envelope in interoperability and fostering transatlantic cooperation and business engagement.\nTrillium Bridge will join forces with support actions, projects and initiatives contributing to policy alignment and sustainability upholding safety, empowerment, and well-being for European and US citizens when abroad. Thus, Trillium Bridge brings concrete measurable interoperability results at the technical, semantic, organizational, and legal levels, building on major initiatives to advance eHealth innovation and contribute the triple win: quality care, sustainability and economic growth.

Agency: GTR | Branch: EPSRC | Program: | Phase: Research Grant | Award Amount: 99.53K | Year: 2015

Suppose that you are sitting alone at a table in a crowded restaurant where you can hear a mixture of several conversations. This mixed sound is not particularly interesting, but suppose you could record it and then use some sort of algorithm to extract the individual conversations that were going on in the restaurant, that would certainly be much more informative. In statistical jargon this is called a mixture model, and there is a surprisingly large number of real-life situations where they are very useful. As a motivating application we consider an important biomedical problem called alternative splicing. Although all humans have the same genes encoded in our DNA, it turns out that each of our genes can be expressed in several variations (called splicing variants), and that each of these variations performs different functions in the organism; some may even help cause complex neurodegenerative diseases or cancer. Fortunately, technologies from recent years produce data that allow us for the first time to study this phenomenon in detail. We can now observe the overall expression of the gene from which, similar to the restaurant example, we would like to learn what are the individual contributions of each gene variant (indeed, to learn whether a given variant was even present at all). These technologies are becoming cheaper every year, and one can easily envision a nearby future where they are part of our regular medical check-ups, but solving this mixture problem poses formidable methodological and practical challenges. For instance, the number of possible solutions even when considering a single gene is larger than the number of atoms in the universe, and the required calculations can be prohibitive even on the latest computers. This example highlights some of the most important challenges that are common to many modern applications of mixture models, hence solving them would have positive implications in a much wider range of areas (e.g. technology, industry, public policy, social sciences). In this project we aim to develop a framework that can be used to solve the alternative splicing and other challenging mixture model problems. Our first goal is to propose a novel formulation for general mixture models that has proven highly successful in other complex settings, studying both theoretical and practical aspects. In our example this formulation says that, when identifying different conversations in the restaurant, we cannot have two tables uttering exactly the same words (else these should be regarded as a single conversation). This apparently simple consideration turns out to have important mathematical consequences that greatly simplify the problem. Our second goal is to apply these general principles to solve the alternative splicing problem, where we will also bring to bear scientific considerations to ensure that the solution is useful in practice. Our third goal is to propose and study strategies to make fast and accurate calculations, which can quickly become prohibitive, so that a computer can find the solution in reasonable time. As part of this project we will provide open-source software that others can use freely for their own research or applied data analysis. Given the technical challenges involved the bulk of the research will be carried at the Dept. of Statistics at the University of Warwick by the PI working with other members of the department and several further statistical and biomedical collaborators from prestigious overseas universities and hospitals who will be actively involved in the project, e.g. helping translate our methodology to biomedical research and clinical practice, or ensuring that our statistical predictions are indeed accurate.

Tollefson M.M.,Mayo Medical School | Frieden I.J.,University of California at San Francisco
Pediatrics | Year: 2012

BACKGROUND AND OBJECTIVES: Infantile hemangiomas (IH) are recognized as growing rapidly during the first months of life, but details of early growth before 3 months of age have not been well-characterized. Our goal was to study early IH growth by using parental photographs of infant children with facial IHs to better understand early hemangioma growth, with the aim of improving guidance for physicians and parents of infants with high-risk IH. METHODS: Serial images of 30 infants showing IH at intervals of 1 to 2 weeks up to 6 months were analyzed for characteristics of color, thickness, and distortion of anatomic landmarks. The presence or absence of an IH precursor at birth was noted. Mean scores per age interval were compiled. Results were analyzed by using signed rank test. An assessment of "optimal time for referral" was made. RESULTS: IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age. The mean "optimal age for referral"was 4 weeks of age. Hemangioma precursors were present at birth in 65% of patients. CONCLUSIONS: The most rapid hemangioma growth occurs before 8 weeks of age, much earlier than previously appreciated. Specialty evaluation and initiation of treatment, however, typically occur after the age of most rapid growth. Our findings suggest a need for a paradigm shift in the timing of referral and initiation of treatment of high-risk IH so that therapy can be initiated before or early in the course of most rapid growth, rather than after it is already completed. Copyright © 2012 by the American Academy of Pediatrics.

News Article | November 2, 2016

ROCHESTER, Minn. -- Dementia with Lewy bodies is a progressive disease that causes hallucinations, decline in mental abilities, rigid muscles, slow movement and tremors. With symptoms similar to Alzheimer's disease and Parkinson's disease, a correct diagnosis can be difficult. A new study published today in the online issue of Neurology, a medical journal of the American Academy of Neurology, shows that a lack of shrinkage in the area of the brain called the hippocampus may be a sign that people with thinking and memory problems may develop dementia with Lewy bodies rather than Alzheimer's disease. Atrophy of the hippocampus, the area of the brain responsible for thinking and memory, is an early sign of Alzheimer's disease. "Identifying people with mild cognitive impairment at risk for dementia with Lewy bodies is critical for early interventions," says the study's lead author Kejal Kantarci, M.D., a Mayo Clinic radiologist. "Early diagnosis helps target appropriate treatments, including what medications not to give. For example, as many as 50 percent of people with Lewy body disease have severe reactions to antipsychotic drugs." Lewy bodies are protein deposits that develop in nerve cells in regions of the brain involved in thinking, memory and movement. In the study, 160 people with mild cognitive impairment had brain MRI scans to measure hippocampus size. They also had yearly tests for an average of two years. During that time, 61 people, or 38 percent, developed Alzheimer's disease, and 20 people, or 13 percent, progressed to probable dementia with Lewy bodies. Because Lewy body disease can be diagnosed only by an autopsy after death, it is called probable dementia with Lewy bodies. The researchers note that their results should be confirmed with studies that use autopsies for final diagnoses. The people who had no shrinkage in the hippocampus were 5.8 times more likely to develop probable dementia with Lewy bodies than those who had hippocampal atrophy. Seventeen of 20, or 85 percent, of people who developed dementia with Lewy bodies had a normal hippocampus volume; whereas, 37 of the 61, or 61 percent, of people who developed Alzheimer's disease had hippocampus atrophy. The relationship of hippocampus volume and disease was stronger among people without memory issues. Dementia with Lewy bodies does not always affect memory. Affected thinking skills usually include attention, problem-solving and interpreting visual information. The study was supported by the National Institutes of Health, the Mangurian Foundation, Robert H. and Clarice Smith and the Abigail Van Buren Alzheimer's Disease Research Program. In addition to Dr. Kantarci, Mayo Clinic study co-authors are: Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit and

News Article | February 21, 2017

BEIJING--(BUSINESS WIRE)--Today, Delos™, a U.S.-based wellness real estate and technology firm, announced plans to build and operate its second Well Living Lab, which is slated to open in Beijing, China in the Fall of 2018. The Well Living Lab (China) will be the first scientific research center in Asia to integrate building science, behavioral science, and health science to help quantify and ultimately improve the impact that indoor environments have on human health, wellness, comfort, and performance. Through this research, the Lab aims to spur innovations that will help address indoor environmental challenges specifically related to the local climate, environment and culture in China. “As we look for more efficient ways to address indoor environmental challenges related to human health and wellness, it is important to localize our scientific efforts,” said Peter Scialla, Chief Operating Officer of Delos. “China is faced with serious environmental challenges, and we hope the new Well Living Lab in China will pioneer internationalization efforts to find solutions that will help improve the health of building occupants throughout China.” In addition to its Beijing location, the Well Living Lab (China) intends to establish several satellite research facilities in major Chinese cities, and will work closely with Chinese research institutions and real estate partners to integrate local research goals into a broader global agenda. The launch of the Well Living Lab (China) follows the May 2016 opening of the Well Living Lab (U.S.), extending its groundbreaking technology platform and human-subject research approach to the Chinese market. The Well Living Lab (U.S.) is a collaboration between Delos and Mayo Clinic, ranked by U.S. News and World Reports as the number one hospital overall as well as number one in more specialties than any other hospital in the United States. “Mayo Clinic offers hope to millions of people around the world who are asking medical questions and seeking answers they can’t find anywhere else,” states Dr. Brent Bauer, Medical Director of the Well Living Lab and Mayo Clinic Professor and Medical Director of the Mayo Clinic Complementary and Integrative Medicine Program. “The science behind indoor environments that supports people’s health and wellness is a new frontier. We are excited to be part of this movement.” The Well Living Lab (China) will conduct research on the ways in which air, light, water, thermal conditions, acoustics, occupant behavior, and policy in buildings can impact occupants’ health, wellness, comfort, and performance, subject to local conditions, including public health concerns, geographic issues, and economic statuses, as well as local codes, standards and regulations. This will be made possible by the state-of-the-art infrastructure of the Lab, which will feature 25,000 square feet of sensor rich, reconfigurable space where researchers can monitor and test products and systems with human subjects in simulated, real-world environments. The Lab will feature a wide array of sensors, including environmental and biometric sensors, as well as the ability to control environmental conditions with a high degree of precision. The Lab’s sensors and control capabilities will be managed through a custom, state-of-the-art cloud infrastructure, which can be extended for use with other research facilities or real-world buildings for larger studies. “We are excited to launch a new lab in China and to dedicate our efforts to research how wellness focused building techniques can apply to local conditions, public health concerns, in China,” said Dana Pillai, president of Delos Labs and executive director of the Well Living Lab (U.S.). “We look forward to working closely with local experts and our Chinese colleagues in related fields, in the hopes of spearheading new findings that can be applied to improve people’s lives throughout China.” The Well Living Lab (China) will be located in the northeast quarter of Beijing in China’s first wellness-oriented industrial park, which is being developed by Sino-Ocean Group. Delos is also working with Sino-Ocean Group to develop the Well Living Lab (China). “We welcome the Well Living Lab (China) into Yingchuang Wellness Industrial Park,” said Ming Li, chairman and CEO of Sino-Ocean Group. “The Park is a successful result of Sino-Ocean’s continuous efforts to promote ‘Healthy Building’, and is positioned to incubate and nurture the growth of a new sector of wellness-oriented businesses in China, and we believe the Lab will be the driving force and an engine to attract enterprises focused on health, wellness and innovation.” A feature story about the Well Living Lab in Rochester, Minnesota was published in the journal Nature, recognizing the Lab’s unique, human-centered, simulated environment and contribution to an emerging, important field of research. Through the Well Living Lab Alliance program, the Rochester Lab currently offers collaboration opportunities for organizations that wish to help generate new knowledge and support the Lab’s mission of transforming human health in the indoor environment. The highest level of commitment available is the Well Living Lab Founding Alliance Membership. Current Founding Alliance Members include: Arup, CBRE Group, Inc., Essentia, HOK, IBM, IFF, Ketra, Lendlease, Sino-Ocean Group Holding Limited and View Inc. To learn more about membership opportunities, please visit View a narrated tour of the Rochester Well Living Lab here. As the pioneer of Wellness Real Estate™, Delos is transforming our homes, offices, schools, and other indoor environments by placing health and wellness at the center of design and construction decisions. Delos helps create spaces that actively contribute to human health, performance and well-being by marrying the best innovations in technology, health, science, and real estate. The Delos platform includes programming, design, consulting, research, and an array of innovative solutions and technologies designed to improve health and well-being. More information on Delos is available at About the Well Living Lab (U.S.) A collaboration of Delos and Mayo Clinic, the Well Living Lab (U.S.) is the first human-centered research facility dedicated to identifying how buildings—and everything that goes in them—impacts human health and well-being. The purpose of the Well Living Lab (U.S.) is to study these indoor environments and create healthier indoor spaces in which to work, live and play. A world-class, multi-disciplinary research approach guides the work of the Well Living Lab (U.S.), as scientific and medical experts from Mayo Clinic and around the world conduct and translate research that leads to solutions for healthier indoor environments. The Well Living Lab (U.S.) is unique in that research is conducted on real people, in real-world settings. This is made possible by the revolutionary infrastructure of the Well Living Lab (U.S.), which features 7,500 square feet of sensor rich, reconfigurable space where researchers can monitor and test products and systems on human subjects in simulated, real-world, built environments. Mayo Clinic is a nonprofit organization committed to medical research and education, and providing expert whole-person care to everyone who needs healing. For more information, visit, and Founded in 1993, Sino-Ocean Group was listed on the Main Board of the Hong Kong Stock Exchange on September 28, 2007 and has become one of the top ten Mainland real estate companies listed in Hong Kong. In March 2008 Sino-Ocean Group was selected as a constituent of the Hang Seng Hong Kong Composite Index and the Hang Seng China-Affiliated Corp Index. The Company is mainly engaged in four business sectors which are respectively the development of mid to high-end residential properties, premium office buildings and retail properties, real estate financing and customer services which consisting of property management and senior living business. With “Health and Wellness in Built Environment” as the product concept, Sino-Ocean Group has already set up the “Sino-Ocean” brand awareness in Beijing-Tianjin-Hebei region, northeast China, Central China and Southern China by the consistent high quality projects and service. For more information, please visit:

News Article | November 22, 2016

ROCHESTER, Minn. -- Approximately 10 percent of newborns require help breathing after birth, and 1 in 1,000 newborns require more intensive resuscitation measures. These infrequent, high-risk deliveries may present challenges to community hospitals less familiar with advanced newborn resuscitation interventions. Telemedicine consultations are a good option to help meet these challenges and positively impact patient care, according to a study published in Mayo Clinic Proceedings. "Following a complicated delivery, a newborn's outcome is associated with the quality of care provided during the first minutes of life," says Jennifer Fang, M.D., a Mayo Clinic fellow in Neonatal-Perinatal Medicine and one of the study's authors. "Because of this reason, it is critical to understand how telemedicine can be used to positively impact those outcomes." During a 20-month study, Mayo Clinic's Division of Neonatal Medicine worked with six health system sites to provide newborn telemedicine consultations. During the study, 84 telemedicine consultations were conducted. "The enhanced access to neonatologists, who could remotely assess the newborn and guide the local care team through the resuscitation, allowed one-third of the babies to stay with their families in the local hospital," says Dr. Fang. "This allowed the patients to receive the correct level of care in the right location -- increasing the value of care. Also, the potential cost savings can be substantial." This study also looked at how the local care team and neonatologist collaborated. "Other research has shown that teamwork and communication are critical during neonatal emergencies. We wanted to assess how telemedicine affected teamwork and communication," according to Dr. Fang. Providers responded positively to surveys that assessed teamwork and the impact of the telemedicine consult on patient safety and quality of care. "These results speak to the acceptability and clinical impact of this type of telemedicine project in community hospitals," says Dr. Fang. In addition to Dr. Fang, the paper's co-authors are: Mayo Clinic Proceedings is a monthly peer-reviewed medical journal that publishes original articles and reviews dealing with clinical and laboratory medicine, clinical research, basic science research and clinical epidemiology. Mayo Clinic Proceedings is sponsored by the Mayo Foundation for Medical Education and Research as part of its commitment to physician education. It publishes submissions from authors worldwide. The journal has been published for more than 80 years and has a circulation of 130,000. Articles are available at Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. . MULTIMEDIA ALERT: Video and audio are available for download on the Mayo Clinic News Network.

News Article | October 27, 2016

ROCHESTER, Minn. -- Atherosclerosis is a disease in which arteries narrow due to plaques. That narrowing can lead to heart attacks and strokes -- both of which are leading causes of death in the U.S. Now, in a paper published in Science, Mayo Clinic researchers and colleagues show that senescent cells drive plaque formation in animal models of atherosclerosis. When stressed, healthy cells undergo senescence. In this process, cells are blocked from growing or dividing. The cells also release bioactive molecules called the senescence-associated secretory phenotype, or SASP. These molecules break down the normal tissue structure. They also attract immune cells that cause local inflammation. Using three mouse models, the team, led by Mayo Clinic scientist Jan van Deursen, Ph.D., discovered that senescent cells have negative effects at all three stages of the disease process: Healthy mice on a high-fat diet that promotes atherosclerosis develop plaque-promoting lesions within days. Bennett Childs, Mayo graduate student, the lead author of the study, found that these so-called "fatty streaks" contained many senescent cells. When mice were treated with a drug that selectively eliminates senescent cells, these fatty streaks disappeared within days. Fatty streaks progress to larger plaques through the recruitment of white blood cells from the circulation. Two molecules present in streaks and plaques, VCAM1 and MCP1, drive this process. Dr. van Deursen and the team discovered that senescent cells are responsible for the production of VCAM1 and MCP1 in plaques. Selective elimination of senescent cells in growing plaques resulted in fewer and smaller plaques. In advanced disease, plaques become unstable and are at high risk for rupture. That is a major determining factor in acute heart attacks and strokes. At this stage, senescent cells drove plaque growth. Senescent cells also produced enzymes that dissolve the fibrous cap that initially forms around plaques to provide stability. Selective elimination of senescent cells from mature plaques inhibited further growth of plaque and preserved the integrity of the cap structure and, thus, its stability. Based on their work, the authors conclude that senescent cells are key drivers of plaque formation and maturation. In addition to Dr. van Deursen and Childs, other authors are: Funding for this research was provided by the Paul F. Glenn Foundation and the National Institutes of Health. Drs. van Deursen and Campisi are scientific co-founders of Unity Biotechnology, a company developing senolytic medicines, including small molecules that selectively eliminate senescent cells. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit or

ROCHESTER, Minn. -- Using a shared decision-making aid to involve patients more in their own care decisions can prevent unnecessary hospitalization or advanced cardiac tests for patients reporting low-risk chest pain -- for the cost of about 1 minute of time. So says a study from Mayo Clinic researchers, published online today in The BMJ. MULTIMEDIA ALERT: Video and audio are available for download on the Mayo Clinic News Network. According to the Centers for Disease Control and Prevention, the second highest cause of emergency department visits is chest pain. "Chest pain can be caused by a wide variety of problems," says Erik Hess, M.D., study lead author and emergency medicine physician at Mayo Clinic. "While we recommend that people seek immediate medical help when experiencing chest pain, the next steps can vary - and be unnecessarily costly." Patients at low risk for acute coronary syndrome - a range of conditions that includes a heart attack and is associated with sudden, reduced blood flow to the heart - are frequently admitted for observation and cardiac testing. Dr. Hess and his colleagues say this is because, "Given the potential for missing a diagnosis of acute coronary syndrome, clinicians have a very low risk threshold to admit patients for observation and advanced cardiac testing." "Despite little possibility that these low-risk patients are experiencing acute coronary syndrome, emergency physicians are more likely to default to admission for observation and additional testing," says Dr. Hess. "This presents a substantial unnecessary burden and cost to the patient and the health care system." The research team felt that introducing a shared decision-making approach might not only increase patients' understanding of their symptoms and risks, but also allow them to participate more actively in deciding whether hospital admission and advanced cardiac testing were necessary. Using the Chest Pain Choice decision aid, emergency department physicians and patients with low-risk chest pain can estimate the risk for acute coronary syndrome within the next 45 days. Based on that risk, they can then have a joint discussion on whether hospital admission and advanced cardiac testing is warranted, or whether a follow-up appointment with primary care or cardiology is a more appropriate step. In a randomized clinical trial across six emergency departments in five states, the researchers compared usual care for 447 patients to 451 patients receiving the Chest Pain Choice decision aid intervention. The primary outcome, selected by patient and caregiver representatives, was patient knowledge. Secondary outcomes were involvement in the decision to be admitted, proportion of patients admitted for cardiac testing, and the 30-day rate of major adverse cardiac events. The team showed that using the decision aid resulted in: Both patients and physicians were satisfied with the decision aid and its use, which, according to the study authors, "took an average of one additional minute of clinician time." Shared decision-making resulted in significantly less overuse of hospitalization and advanced cardiac testing, thereby reducing the overall burden on the health care system, as well as potential costs for patients. "When patients are involved with their care decisions, it is more likely they will get the right care for their concerns," says Dr. Hess. "We believe that the Chest Pain Choice decision aid will make it easier for patients and physicians to have a thoughtful discussion and make an individualized care plan that is less likely to overuse unnecessary services." Dr. Hess first presented the Chest Pain Choice decision aid at the American College of Cardiology's 65th Annual Scientific Session (Read news release.). The study was funded by the Patient-Centered Outcomes Research Institute and the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. It was conducted in collaboration with the Knowledge and Evaluation Research Unit. This unit focuses much of its efforts on developing and validating shared decision aids across health care. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit and

ROCHESTER, Minn.­ -- A common way of scheduling surgeries to expand patient access to care and improve hospital efficiency, known as "overlapping surgeries," is as safe and provides the same outcomes for patients as non-overlapping surgeries, a Mayo Clinic study has found. Spacing operations so a surgeon has two patients in operating rooms at the same time is a common practice in surgery at Mayo and other leading medical institutions. It gives patients greater access to qualified surgeons, allows more efficient use of operating rooms, and avoids unnecessary downtime for surgeons. A Mayo Clinic study compared the outcomes of thousands of such overlapping surgeries with non-overlapping operations at its Rochester campus and found no difference in the rates of postoperative complications or deaths within a month after surgery between the two groups. The findings are published in the Annals of Surgery. The researchers used Mayo Clinic data from the University HealthSystem Consortium, an alliance of academic medical centers whose members include Mayo Clinic, to match 10,614 overlapping surgeries to 16,111 non-overlapping procedures performed at Mayo in Rochester. An additional sample using more than 10,000 operations including over 3,000 with overlap, matched by surgeon, was analyzed using data from Mayo Clinic's Rochester campus in the American College of Surgeons-National Surgical Quality Improvement Program. That analysis also found no differences in outcomes. "Our data shows that overlapping surgery as practiced here is safe," says co-author Robert Cima, M.D., a colorectal surgeon and chair of surgical quality at Mayo Clinic's Rochester campus. "We think it provides value to our patients because it allows more patients timely access to surgery and care by expert teams." In medical parlance, overlapping surgery differs from concurrent surgery. In overlapping surgeries, operations are staggered so the key parts, called the "critical portions," do not occur at the same time; the surgeon is present for the critical portions of each operation and immediately available for non-critical portions such as closing the wound. In concurrent surgery, a surgeon also has two patients in operating rooms at the same time, but the critical portions of the surgeries overlap. Concurrent surgery is rare and is not allowed by Medicare. Mayo Clinic has long studied its surgical outcomes to improve quality and refine operating room scheduling and other surgical systems and procedures to improve patients' experience, patient access and hospital efficiency. Key findings over the years include the importance of scheduling surgeries early in the day when possible, rather than at night, when data shows complications are likelier. Planning cases to overlap during the day helps avoid needless night surgeries. Teams with multiple surgeons are common at Mayo, which has the skill and surgical infrastructure to perform complex operations that involve two or more surgical specialties; cases also may overlap to make surgeons available when needed in multi-surgeon procedures. Dr. Cima is medical director of surgical outcomes research at the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. The study's senior author is Elizabeth Habermann, Ph.D., scientific director of surgical outcomes research. The first author is Joseph Hyder, M.D., Ph.D., an anesthesiologist and associate medical director of surgical outcomes research. Dr. Hyder received research support from the Anesthesia Patient Safety Foundation and the Anesthesia Quality Institute. Co-author Daryl Kor, M.D., a Mayo Clinic anesthesiologist and medical director of the Center for the Science of Health Care Delivery's health care systems engineering program, received funding from National Institutes of Health grants U01-HL108712 and R01-HL121232. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit or

News Article | December 19, 2016

ROCHESTER, Minn. -- In a recent Science Advances article, Mayo Clinic researchers show how hungry human liver cells find energy. This study, done in rat and human liver cells, reports on the role of a small regulatory protein that acts like a beacon to help cells locate lipids and provides new information to support the development of therapies for fatty liver disease. "Between 30 and 40 percent of our population have, or are leading toward getting, nonalcoholic fatty liver disease," says Mark McNiven, Ph.D., senior author on the paper and director of Mayo Clinic's Center for Biomedical Discovery. "And that is not including those with alcohol-induced fatty liver; that is also quite prevalent." While the mechanisms involved in fat accumulation are the usual targets of research for fatty liver disease, clarifying the cell's mechanism for breaking down fat also could provide valuable information to fuel the discovery of breakthrough treatments in the future. In a well-fed cell, fat deposits, called lipid droplets, are nutritional insurance. They are ignored by the cell as it fuels growth and division via its normal pathway. But, in a starving cell, the normal pathway switches off, and a recycling process, called autophagy, switches on. Autophagy is a way for cells to break down macromolecules, such as protein and fat, into their component parts to be used in cell processes. Under starvation conditions, the cell's recycling pathway directs specialized vessels to engulf lipid droplets. These vessels, called autophagosomes, then link with another organelle, called a lysosome, which is filled with acidic enzymes. When these two merge, the resulting structure is called an autolysosome. Within the autolysosome, the enzymes break apart the fat droplet free fatty acids. Zhipeng Li, first author and a student at Mayo Clinic Graduate School of Biomedical Sciences, noticed that, within the hungry cells, one protein, called Rab10, was intimately associated with many of the lipid droplets. Rab proteins operate like switches; when bound to a substance, they switch on and facilitate interactions in the cell. There are more than 60 different Rab switches, or small regulatory GTPases, in the human genome. "In this paper, we show that, when Rab10 is switched on, it will bind to a lipid droplet and cause the autophagosome to dock on the droplet surface, recruit other proteins, and digest the lipid into a free fatty acid energy source," says Li. Dr. McNiven explains that cells have sensors that detect low energy levels and respond. "Rab10 switches on and builds up around the lipid droplet," says Dr. McNiven. "Then, the cell activates its lysosomes that then targets these lipid droplets and goes after them. So this was an important step that we provided between the sensing mechanism of starvation and how that is signaling to this switch to go after lipid droplets." This study was funded by two National Institutes of Health grants to Dr. McNiven, the Robert and Arlene Kogod Center on Aging, and the Optical Morphology Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology. The authors report no conflicts of interest. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit or

News Article | February 15, 2017

PHOENIX - Mayo Clinic and University of Washington researchers have discovered a new culture method that unlocks the natural fighter function of immune T cells when they are passing through the bloodstream. This allows T cell armies to be raised directly from blood that naturally recognize and target proteins that are present on most human cancers. The results are published in the Feb. 14 issue of Oncotarget. "Even though it is relatively easy to collect billions of T cells directly from patient blood, it has historically proved difficult or impossible to unleash those T cells' natural ability to recognize and target cancer cells," says Peter Cohen, M.D., a Mayo Clinic immunotherapist who co-led the study with Mayo Clinic immunologist Sandra Gendler, Ph.D., and University of Washington immunotherapist Nora Disis, M.D. "Our method strictly employs natural signals to activate the immune blood cells outside the body," says Dr. Disis. "This gives rise to expanded armies of T cells, which specifically recognize proteins that are present on cancer cells and which can be reinfused into patients for therapeutic evaluations in future clinical trials." The research team tested the method's ability to stimulate T cell responses against MUC1, a protein expressed by a large majority of patients' cancers, including breast, pancreatic, lung, colorectal, ovarian, kidney, bladder, and multiple myeloma. Also tested were HER2/neu, a protein present in one-quarter to half of many types of cancer, and CMVpp65, a protein present in half of primary brain tumors. "Our culture method is similar to performing a vaccination procedure entirely outside the body, and it was successful for all three proteins," adds Dr. Gendler. The researchers found that T cells traveling within the bloodstream naturally remained locked in a resting state unless they were exposed to natural alarm signals normally triggered only by serious infections. Once outside the body, however, the T cells could be exposed safely to such alarm signals to unleash their fighter function. When the T cell cultures also were exposed to MUC1, HER2/neu, CMVpp65 or other cancer-associated proteins, it only required three weeks to grow out natural T cell armies trained to recognize and target cancers expressing these proteins. "The cancer-associated proteins we have tested so far already target the majority of human cancers, and it is likely that this culture method will extend to many additional proteins present on cancer cells," explains Dr. Gendler. Dr. Cohen adds, "We are pleased to help other investigators implement our culture method for their own cancer-associated proteins of interest." Other key contributors to the study are: Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

Imperiale T.F.,Indiana University | Imperiale T.F.,Center for Innovation | Ransohoff D.F.,University of North Carolina at Chapel Hill | Itzkowitz S.H.,Mount Sinai School of Medicine | And 5 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening. METHODS: We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings. RESULTS: Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P = 0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P = 0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT. CONCLUSIONS: In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. Copyright © 2014 Massachusetts Medical Society.

Dave M.,Mayo Medical School | Purohit T.,New York Medical College | Razonable R.,Mayo Medical School | Loftus Jr. E.V.,Mayo Medical School
Inflammatory Bowel Diseases | Year: 2014

The use of biological agents and immunomodulators for inflammatory bowel disease (IBD) has remarkably improved disease management in the current era but at the same time has increased the risk of infectious complications. Patients with IBD on corticosteroids, immunomodulators, and biological agents are considered immunocompromised and are at risk for opportunistic infections. These are infections caused by organisms that take advantage of a weakened immune system, and cause disease, when they ordinarily would cause mild illness or no disease in an immunocompetent host. Risk factors for opportunistic infections include malnutrition, older age, congenital immunodeficiency, HIV infection, chronic diseases, and use of corticosteroids, immunomodulators, and anti- tumor necrosis factor alpha therapy. Apart from immunosuppressive medications and older age, there is only indirect evidence for above risk factors contributing directly to opportunistic infection risk in patients with IBD. Opportunistic infections in patients with IBD include viral infections (herpes viruses, human papillomavirus, influenza virus, and JC virus), bacterial infections (tuberculosis, nocardiosis, Clostridium difficile infection, pneumococcal infection, legionellosis, and listeriosis), fungal infections (histoplasmosis, cryptococcosis, Pneumocystis jirovecii infection, aspergillosis, and candidiasis), and parasite infections (Strongyloides stercoralis). Although these infections lead to high morbidity and mortality, only a minority of patients with IBD develop opportunistic infections. Currently, we lack a test to accurately predict patients at risk of opportunistic infection, and future research needs to focus on biomarkers or predictive models for risk stratification. Until such a test is developed, we need to screen, prevent, diagnose, and treat opportunistic infections in all patients with IBD in a timely manner. Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.

Shah D.J.,Oakland University | Dronca R.S.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2014

Melanoma is the most dangerous form of skin cancer owing to its metastatic potential and is an important public health concern. The melanoma incidence has been increasing worldwide. Although potentially curable when diagnosed early, metastatic melanoma carries a poor prognosis. Until recently, systemic therapy for metastatic melanoma was ineffective, but the recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, antiecytotoxic T-lymphocyteeassociated antigen-4 (CTLA-4), and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blocking antibodies, as well as combination strategies of cytotoxic chemotherapy and inhibitors of angiogenesis, have all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with this disease. The aim of this review was to summarize the evolution of and recent advances in the treatment of metastatic melanoma. Therefore, we conducted a comprehensive PubMed search between January 1, 1960, and February 1, 2014, using the search term melanoma or metastatic melanoma combined with terms such as chemotherapy, immunotherapy, CTLA-4, PD-1, PD-L1, adoptive T cell, targeted therapy, MAPK, molecular biology, and survival. © 2014 Mayo Foundation for Medical Education and Research.

Couch F.J.,Mayo Medical School | Nathanson K.L.,University of Pennsylvania | Offit K.,Sloan Kettering Cancer Center | Offit K.,New York Medical College
Science | Year: 2014

The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Emerging tick-borne infections continue to be observed in the United States and elsewhere. Current information on the epidemiology, clinical and laboratory features, and treatment of infections due to Ehrlichia muris-like agent, deer tick virus, Borrelia miyamotoi sensu lato, and Heartland virus was provided and critically reviewed. More research is needed to define the incidence and to understand the clinical and the laboratory features of these infections. There is also a growing need for the development of sensitive and specific serologic and molecular assays for these infections that are easily accessible to clinicians. © 2015 Elsevier Inc.

Theel E.S.,Mayo Medical School | Ramanan P.,Mayo Clinic Health System
Journal of Clinical Microbiology | Year: 2014

Histoplasma urine antigen (UAg) detection is an important biomarker for histoplasmosis. The clinical significance of low-positive (<0.6 ng/ml) UAg results was evaluated in 25 patients without evidence of prior Histoplasma infection. UAg results from 12/25 (48%) patients were considered falsely positive, suggesting that low-positive UAg values should be interpreted cautiously. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Landgren O.,U.S. National Cancer Institute | Kyle R.A.,Mayo Medical School | Rajkumar S.V.,Mayo Medical School
Clinical Cancer Research | Year: 2011

Since monoclonal gammopathy of undetermined significance (MGUS) was first described more than 30 years ago, the definition of the entity has evolved. Today, 3 distinct clinical MGUS subtypes have been defined: non-immunoglobulin M (IgM; IgG or IgA) MGUS, IgM MGUS, and light chain MGUS. Each clinical MGUS subtype is characterized by unique intermediate stages and progression events. Although we now have strong evidence that multiple myeloma is consistently preceded by a precursor state at the molecular level, there is urgent need to better understand mechanisms that regulate transformation from precursor to full-blown multiple myeloma. In the future, if such knowledge was available, it would allow clinicians to define high-risk and low-risk precursor patients for a more tailored clinical management. Also, it would provide insights on the individual patient's disease biology, which, in turn, can be used for targeted and more individualized treatment strategies. On the basis of current clinical guidelines, patients diagnosed with MGUS and smoldering myeloma should not be treated outside of clinical trials. In the near future, it seems reasonable to believe that high-risk precursor patients will likely become candidates for early treatment strategies. In this review, we discuss novel insights from recent studies and propose future directions of relevance for clinical management and research studies. ©2011 AACR.

Clark A.E.,University of Arizona | Kaleta E.J.,Mayo Medical School | Arora A.,University of Arizona | Wolk D.M.,University of Arizona | Wolk D.M.,Geisinger Health Systems
Clinical Microbiology Reviews | Year: 2013

Within the past decade, clinical microbiology laboratories experienced revolutionary changes in the way in which microorganisms are identified, moving away from slow, traditional microbial identification algorithms toward rapid molecular methods and mass spectrometry (MS). Historically, MS was clinically utilized as a high-complexity method adapted for protein-centered analysis of samples in chemistry and hematology laboratories. Today, matrix- assisted laser desorption ionization-time of flight (MALDITOF) MS is adapted for use in microbiology laboratories, where it serves as a paradigm-shifting, rapid, and robust method for accurate microbial identification. Multiple instrument platforms, marketed by well-established manufacturers, are beginning to displace automated phenotypic identification instruments and in some cases genetic sequence-based identification practices. This review summarizes the current position of MALDI-TOF MS in clinical research and in diagnostic clinical microbiology laboratories and serves as a primer to examine the "nuts and bolts" of MALDI-TOF MS, highlighting research associated with sample preparation, spectral analysis, and accuracy. Currently available MALDI-TOF MS hardware and software platforms that support the use of MALDI-TOF with direct and precultured specimens and integration of the technology into the laboratory workflow are also discussed. Finally, this review closes with a prospective view of the future of MALDI-TOF MS in the clinical microbiology laboratory to accelerate diagnosis and microbial identification to improve patient care. © 2013, American Society for Microbiology. All Rights Reserved.

Fotuhi M.,Neurology Institute for Brain Health and Fitness | Do D.,Johns Hopkins University | Jack C.,Mayo Medical School
Nature Reviews Neurology | Year: 2012

The hippocampus is particularly vulnerable to the neurotoxic effects of obesity, diabetes mellitus, hypertension, hypoxic brain injury, obstructive sleep apnoea, bipolar disorder, clinical depression and head trauma. Patients with these conditions often have smaller hippocampi and experience a greater degree of cognitive decline than individuals without these comorbidities. Moreover, hippocampal atrophy is an established indicator for conversion from the normal ageing process to developing mild cognitive impairment and dementia. As such, an important aim is to ascertain which modifiable factors can have a positive effect on the size of the hippocampus throughout life. Observational studies and preliminary clinical trials have raised the possibility that physical exercise, cognitive stimulation and treatment of general medical conditions can reverse age-related atrophy in the hippocampus, or even expand its size. An emerging concept - the dynamic polygon hypothesis - suggests that treatment of modifiable risk factors can increase the volume or prevent atrophy of the hippocampus. According to this hypothesis, a multidisciplinary approach, which involves strategies to both reduce neurotoxicity and increase neurogenesis, is likely to be successful in delaying the onset of cognitive impairment with ageing. Further research on the constellation of interventions that could be most effective is needed before recommendations can be made for implementing preventive and therapeutic strategies. © 2012 Macmillan Publishers Limited. All rights reserved.

Saito Y.A.,Mayo Medical School | Mitra N.,University of Pennsylvania | Mayer E.A.,Center for Neurobiology of Stress
Gastroenterology | Year: 2010

Functional gastrointestinal disorders are complex symptom-based disorders without agreed upon biomarkers or pathophysiology. A better understanding of the genetic architecture of these disorders would help to better identify their complex biology and explain the common comorbidity with other disorders of persistent pain, mood, and affect, as well as possibly make it possible to identify subgroups of patients who respond to customized therapies. In contrast to monogenic diseases, polygenic diseases and traits are characterized by the contribution of common variants in a large number of genes, as well as environmental factors, to the vulnerability of an individual. Family and twin studies have clearly established a genetic component in irritable bowel syndrome. Although candidate gene studies have identified a few gene polymorphisms that may be correlated with the syndrome, small sample size, lack of reproducibility in large data sets, and the unreliability of the clinical phenotype require caution when extrapolating to a major role of any of the reported polymorphisms in the pathophysiology of irritable bowel syndrome. Future progress in this area will require better characterization of intermediate phenotypes with large effect size for the clinical phenotype, as well as consideration of gene-gene, environment-gene (epigenetics), and sex-gene interactions, genome-wide association, and whole genome sequencing approaches in large data sets. © 2010 AGA Institute.

Holmes Jr. D.R.,Mayo Medical School | Lakkireddy D.R.,University of Kansas | Whitlock R.P.,McMaster University | Waksman R.,MedStar Washington Hospital Center | Mack M.J.,Baylor Healthcare System
Journal of the American College of Cardiology | Year: 2014

Stroke prevention in patients with atrial fibrillation is a growing clinical dilemma as the incidence of the arrhythmia increases and risk profiles worsen. Strategies in patients with nonvalvular atrial fibrillation have included anticoagulation with a variety of drugs. Knowledge that stroke in this setting typically results from thrombus in the left atrial appendage has led to the development of mechanical approaches, both catheter-based and surgical, to occlude that structure. Such a device, if it were safe and effective, might avoid the need for anticoagulation and prevent stroke in the large number of patients who are currently not treated with anticoagulants. Regulatory approval has been difficult due to trial design challenges, balance of the risk-benefit ratio, specific patient populations studied, selection of treatment in the control group, and specific endpoints and statistical analyses selected. Accumulating data from randomized trials and registries with longer-term follow-up continues to support a role for left atrial appendage exclusion from the central circulation as an alternative to anticoagulation in carefully-selected patient populations. © 2014 by the American College of Cardiology Foundation.

Russell S.J.,Mayo Medical School | Peng K.-W.,Mayo Medical School | Bell J.C.,Ottawa Hospital Research Institute | Bell J.C.,Jennerex Biotherapeutics
Nature Biotechnology | Year: 2012

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible. © 2012 Nature America, Inc. All rights reserved.

Gwathmey K.G.,University of Virginia | Burns T.M.,University of Virginia | Collins M.P.,Medical College of Wisconsin | Dyck P.J.B.,Mayo Medical School
The Lancet Neurology | Year: 2014

The vasculitic neuropathies are a diverse group of disorders characterised by the acute-to-subacute onset of painful sensory and motor deficits that result from inflammatory destruction of nerve blood vessels and subsequent ischaemic injury. They are common in patients with primary systemic vasculitis and are seen in vasculitis secondary to disorders such as rheumatoid arthritis, viral infections, and diabetic inflammatory neuropathies. It is imperative that neurologists recognise these disorders to initiate treatment promptly and thereby prevent morbidity and mortality. To simplify the approach to patients with vasculitis of the peripheral nerves, a straightforward, dichotomous classification scheme can be used in which the vasculitic neuropathies are divided into two groups-nerve large arteriole vasculitis and nerve microvasculitis-on the basis of the size of the involved vessels. The size of the affected blood vessels correlates with the clinical course and prognosis in patients with vasculitic neuropathy. © 2014 Elsevier Ltd.

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-03-2015 | Award Amount: 6.47M | Year: 2015

RELENT is multidisciplinary group of scientists and clinical investigators whose goal is to develop individualized treatment for chronic autoimmune diseases, such as rheumatoid arthritis and vasculitis, that cause considerable mortality and morbidity, both from uncontrolled disease and treatment associated co-morbidities, like infection and malignancy. This requires the need to stratify patients by their outcome and to tailor immunosuppression based on much deeper knowledge of the mechanisms that control initiation and persistence of the pathogenic immune responses. The RELENT Consortium has been formed to generate this knowledge with the ultimate goal of developing treatments tailored to the specific needs of individual patients. RELENT combines the resources of seven leading European Investigators and two from US and Australia whose expertise is not available elsewhere in the world but necessary for the ambitious work program. Three SMEs will supply specific reagents and translate the results to biomarker development. This will enable RELENT to deliver its four specific research aims, namely to: i) Combine subset analysis of genome wide association studies with classical cell biology to uncover pathways that influence and ii) use multiplexed antigen arrays, whole proteome analysis and rapid mass analysis to identify protein signatures that predict outcome and response to treatment in chronic autoimmune disease. iii) Characterise T and B cell abnormalities that predispose to autoimmunity and infection by studying the ageing immune system in health and disease. iv) Analyse pathogenic effector T cells and their control by macrophages and dendritic cells and the molecules they secrete using in vivo models. We anticipate to identify common mechanisms responsible for the persistence and outcomes in severe autoimmune and inflammatory diseases in females and males and that the results should be rapidly translatable into clinical practice for the benefit of patients.

ROCHESTER, Minn. -- Researchers at Mayo Clinic have identified an enzyme called UCHL3 that regulates the BRCA2 pathway, which is important for DNA repair. Results of this research are published online in Genes & Development. "DNA encodes the blueprints for our body, and DNA repair is a fundamental mechanism to prevent the accumulation of mutations in DNA and human disease," says senior author Zhenkun Lou, Ph.D., a molecular pharmacologist at Mayo Clinic. "The BRCA2 pathway is important for DNA repair, and mutation of the BRCA2 gene is linked to increased cancer risk, especially breast cancer and ovarian cancer." Dr. Lou says UCHL3 is highly expressed in some cancers, and mutated or deleted in other cancers. Cancer cells with high UCHL3 expression are resistant to chemotherapy; whereas, cancer cells with low UCHL3 are more sensitive to chemotherapy. Therefore, the expression of UCHL3 could be a guide to develop more precise cancer therapy. "UCHL3 could be a potential therapeutic target to overcome resistance to chemotherapy in cancer cells that have a high level of UCHL3," Dr. Lou says. He says UCHL3 gene also could be developed into a biomarker in the clinic to guide precision medicine. "While more research is needed, our studies may provide a novel therapeutic venue to treat women's cancer and thereby contribute to the health and welfare of women," says Dr. Lou. As a leading institution funded by the National Cancer Institute, Mayo Clinic Cancer Center conducts basic, clinical and population science research, translating discoveries into improved methods for prevention, diagnosis, prognosis and therapy. For information on cancer clinical trials, call the Clinical Trial Referral Office at 1-855-776-0015 (toll-free). Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

ROCHESTER, Minn. - People diagnosed with multiple myeloma are more likely to live longer if they are treated at a medical center that sees many patients with this blood cancer. Mayo Clinic researchers published these findings today in the Journal of Clinical Oncology. Multiple myeloma is a rare form of blood cancer that attacks plasma cells -- white blood cells that normally produce antibodies to fight infection. The study measures the difference in life expectancy for patients treated by doctors with varying degrees of experience with the disease. "Studies on cancer surgery have shown the more experience the center or practitioner has, the better the outcome," states study author Ronald Go, M.D., a hematologist and health care delivery researcher at Mayo Clinic. "It is very difficult to be proficient when doctors are seeing only one or two new cases of multiple myeloma per year. We wanted to see if volume matters when it comes to nonsurgical treatment of rare cancers such as multiple myeloma." The new research shows multiple myeloma patients benefit from treatment at more experienced centers. For example, patients treated at centers seeing 10 new patients per year had a 20 percent higher risk of death than those treated at centers seeing 40 new patients per year. Most cancer treatment centers in the United States see fewer than 10 new multiple myeloma patients per year. The researchers used the National Cancer Database, examining outcomes for 94,722 multiple myeloma patients at 1,333 centers. These findings previously were presented at the American Society of Hematology Annual Meeting in December 2015. This study was made possible by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. The center's goal is to uses data-driven science to improve the quality, safety and value of health care, and create better patient experiences. Dr. Go is a Kern Health Care Delivery Scholar in the center. Additional support came from the Eagles Cancer Research Fund Pilot Grant, Mayo Clinic Cancer Center, and the Division of Hematology. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit or

News Article | December 19, 2016

ROCHESTER, Minn. -- A study of unprecedented scale has led researchers to identify four previously unknown genetic risk locations for primary sclerosing cholangitis, a liver disease that lacks effective medical therapy. A Dec. 19 article in Nature Genetics highlights the undertaking, which is the largest genome-wide association study of primary sclerosing cholangitis to date and a step toward providing breakthrough treatments for the unmet needs of primary sclerosing cholangitis patients. The study was led by Mayo Clinic's Konstantinos Lazaridis, M.D., and Carl Anderson, Ph.D., of the Wellcome Trust Sanger Institute, along with collaborators from six other U.S. medical centers and co-investigators from the U.K., Germany and Norway and collaborators from other European countries. Primary sclerosing cholangitis affects 1 in 10,000 individuals, with about 75 percent developing inflammatory bowel disease (IBD), most often in the form of ulcerative colitis. However, only 5 to 7 percent of those affected by pre-existing IBD alone later develop primary sclerosing cholangitis. Researchers compared the genetic information of 4,796 primary sclerosing cholangitis patients against a control population of nearly 20,000 individuals, the specimens of which were provided by patients from the U.S. and Europe, including healthy controls from Mayo Clinic Biobank. "Considering the rarity of those affected by primary sclerosing cholangitis, the contribution of specimens by multiple centers across the globe allowed us to view the genetic comparisons of this disease in a much bigger picture," says Dr. Lazaridis. "This is a testament of trust from the primary sclerosing cholangitis patients to this investigative team to whom we are grateful. We feel a strong spirit of collaboration among the medical centers involved." Using these data, researchers identified four new markers of primary sclerosing cholangitis risk on the human genome, bringing the total number of known predisposing locations to 20. One of the four new reported loci is expected to lower the protein expression of UBASH3A, a molecule that regulates T-cell signaling and correlates with lowering the risk of primary sclerosing cholangitis. Dr. Lazaridis says this molecule therefore should be further examined as a target of therapy for the disease. The study also allowed for clearer estimations as to how primary sclerosing cholangitis and IBD may share genetic risk factors. "The immense scale of this genetic study allowed us to analyze for the first time the complex genetic relationship between primary sclerosing cholangitis and IBD," says Lazaridis. "Additional scientific efforts for genome sequencing of primary sclerosing cholangitis patients will give us more opportunities to find the specific genetic underpinnings that contributing to the risk of primary sclerosing cholangitis and to explain what makes the correlation between primary sclerosing cholangitis and IBD." Dr. Lazaridis says such knowledge will be important in facilitating the development of medical therapies for primary sclerosing cholangitis -- an urgent need for patients. The study was supported by: Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

News Article | December 7, 2016

ROCHESTER, Minn. -- Inherited pathogenic variants in protein coding genes BARD1 and RAD51D increase a woman's likelihood of developing breast cancer, according to research conducted at Mayo Clinic and presented today at the 2016 San Antonio Breast Cancer Symposium. Pathogenic variants are changes in DNA that have a negative impact on a gene's ability to function properly. "The BARD1 and RAD51D genes, have been included in clinical testing panels to determine breast cancer risk," says Fergus Couch, Ph.D., a geneticist at Mayo Clinic and lead author of the study. "However, the genes were identified as 'breast cancer' genes through very small studies, so there has never been strong evidence indicating that they are important in driving breast cancer risk." Dr. Couch and his colleagues studied data from 65,000 women with breast cancer to obtain risk estimates associated with 21 cancer predisposition genes from testing panels. They found that pathogenic variants in certain genes, such as BARD1 and RAD51D, caused moderately increased risks of breast cancer. These researchers also confirmed the involvement of the ATM, CHEK2 and PALB2 genes in breast cancer. They also found that the RAD50 and MRE11A genes did not increase risks of breast cancer. "Our findings are important, because genes that do not increase risk of breast cancer can now be ignored and potentially removed from clinical testing panels," Dr. Couch says. "I am hopeful this work will lead to much better interpretation of results from clinical, hereditary [and] genetic testing." Dr. Couch's research included data supplied by Ambry Genetics. Dr. Couch has no relevant financial disclosures. As a leading institution funded by the National Cancer Institute, Mayo Clinic Cancer Center conducts basic, clinical and population science research, translating discoveries into improved methods for prevention, diagnosis, prognosis and therapy. For information on cancer clinical trials, call the Clinical Trial Referral Office at 1-855-776-0015 (toll-free). Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

Stegall M.D.,Mayo Medical School | Gaston R.S.,University of Alabama at Birmingham | Cosio F.G.,Mayo Medical School | Matas A.,University of Minnesota
Journal of the American Society of Nephrology | Year: 2015

A common lament is that long-term kidney transplant outcomes remain the same despite improvements in early graft survival. To be fair, progress has been made - in both our understanding of chronic injury and modestly, graft survival. However, we are still a long way from actually solving this important and difficult problem. In this review, we outline recent data supporting the existence of several causes of renal allograft loss, the incidences of which peak at different time points after transplantation. On the basis of this broadened concept of chronic renal allograft injury, we examine the challenges of clinical trial design in longterm studies, including the use of surrogate end points and biomarkers. Finally, we suggest a path forward that, ultimately, may improve long-term renal allograft survival. Copyright © 2015 by the American Society of Nephrology.

Browne J.A.,University of Virginia | Hanssen A.D.,Mayo Medical School
Journal of Bone and Joint Surgery - Series A | Year: 2011

Background: Patellar tendon disruption associated with total knee arthroplasty is an uncommon but potentially disastrous complication. Repair with isolated suture fixation is insufficient, and autograft and allograft tendon reconstruction techniques have variable results. The purpose of this study was to determine the results of a novel surgical technique in which readily available synthetic mesh is used for patellar tendon reconstruction. Methods: We retrospectively reviewed thirteen consecutive patients who underwent extensor mechanism reconstruction for subacute or chronic patellar tendon disruption following total knee arthroplasty at an average age of sixty years (range, thirty-seven to seventy-seven years). Five patients had already been treated unsuccessfully with an allograft extensor mechanism reconstruction and eight had a prior revision knee arthroplasty. The surgical technique included use of a knitted monofilament polypropylene graft to reconstruct the patellar tendon and to facilitate fixation of adjacent host tissue into the graft. Follow-up was available for all patients at a mean of forty-two months (range, eleven to 118 months). Results: Three patients had evidence of failure of the graft reconstruction, all within six months. One patient with previous sepsis had recurrent infection and was treated with a knee arthrodesis. The remaining nine patients all demonstrated an extensor lag of no greater than 10° and have had no loss of extension at the time of final follow-up. Knee flexion was maintained in all patients (a mean of 103° preoperatively versus a mean of 107° postoperatively). The mean Knee Society scores for pain and function improved significantly (p < 0.01). Synthetic mesh was significantly less expensive than allograft for this reconstruction. Conclusions: The use of synthetic mesh to reconstruct a disrupted patellar tendon is a straightforward surgical procedure that was successful and durable in the majority of patients in our series. Compared with the use of an allograft, this technique eliminates the possibility of disease transmission and may be more cost-effective. No complications unique to the synthetic mesh were observed. Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.

Maron B.J.,Minneapolis Heart Institute Foundation | Yacoub M.,Imperial College London | Dearani J.A.,Mayo Medical School
European Heart Journal | Year: 2011

Hypertrophic cardiomyopathy (HCM), a heterogeneous genetic heart disease with global distribution, is an important cause of heart failure disability at any age. For 50 years, surgical septal myectomy has been the preferred and primary treatment strategy for most HCM patients with progressive, drug refractory functional limitation due to left ventricular (LV) outflow tract obstruction. With very low surgical mortality at experienced centres, septal myectomy reliably abolishes impedance to LV outflow and heart failure-related symptoms, restores quality of life, and importantly is associated with long-term survival similar to that in the general population. Nevertheless, alternatives to surgical management are necessary for selected HCM patients. For example, after a brief flirtation with dual-chamber pacing 20 years ago, percutaneous alcohol septal ablation has garnered a large measure of enthusiasm and a dedicated following in the interventional cardiology community, achieving benefits for patients, paradoxically, by virtue of producing a transmural myocardial infarct. However, an unintended consequence has been the virtual obliteration of the surgical option for HCM patients in Europe, where several robust myectomy programmes once existed. Therefore, clear differences are now evident internationally regarding management strategies for symptomatic obstructive HCM. The surgical option is now unavailable to many patients based solely on geography, including some who would likely benefit more substantially from surgical myectomy than from catheter-based alcohol ablation. It is our aspiration that this discussion will generate reconsideration and resurgence of interest in surgical septal myectomy as a treatment option for severely symptomatic obstructive HCM patients within Europe. © The Author 2011.

Needleman J.,University of California at Los Angeles | Buerhaus P.,Vanderbilt University | Pankratz V.S.,Mayo Medical School | Leibson C.L.,Mayo Medical School | And 2 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Cross-sectional studies of hospital-level administrative data have shown an association between lower levels of staffing of registered nurses (RNs) and increased patient mortality. However, such studies have been criticized because they have not shown a direct link between the level of staffing and individual patient experiences and have not included sufficient statistical controls. METHODS: We used data from a large tertiary academic medical center involving 197,961 admissions and 176,696 nursing shifts of 8 hours each in 43 hospital units to examine the association between mortality and patient exposure to nursing shifts during which staffing by RNs was 8 hours or more below the staffing target. We also examined the association between mortality and high patient turnover owing to admissions, transfers, and discharges. We used Cox proportional-hazards models in the analyses with adjustment for characteristics of patients and hospital units. RESULTS: Staffing by RNs was within 8 hours of the target level for 84% of shifts, and patient turnover was within 1 SD of the day-shift mean for 93% of shifts. Overall mortality was 61% of the expected rate for similar patients on the basis of modified diagnosis-related groups. There was a significant association between increased mortality and increased exposure to unit shifts during which staffing by RNs was 8 hours or more below the target level (hazard ratio per shift 8 hours or more below target, 1.02; 95% confidence interval [CI], 1.01 to 1.03; P<0.001). The association between increased mortality and high patient turnover was also significant (hazard ratio per high-turnover shift, 1.04; 95% CI, 1.02 to 1.06; P<0.001). CONCLUSIONS: In this retrospective observational study, staffing of RNs below target levels was associated with increased mortality, which reinforces the need to match staffing with patients' needs for nursing care. (Funded by the Agency for Healthcare Research and Quality.). Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Chey W.D.,University of Michigan | Camilleri M.,Mayo Medical School | Chang L.,University of California at Los Angeles
American Journal of Gastroenterology | Year: 2011

Objectives: A3309 is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor. We conducted an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, phase IIb study, which evaluated A3309 in patients with chronic idiopathic constipation (CIC). Methods: Patients with CIC (modified Rome III criteria and <3 complete (CSBM) spontaneous bowel movements (SBMs)/week during the 2-week baseline) were randomized to 5, 10, or 15 mg A3309 or placebo once daily. The primary end point was change in SBM number during week 1 compared with baseline. Other bowel and abdominal symptoms were assessed as secondary end points. Serum 7αC4 and lipids were evaluated as biomarkers of BA synthesis/loss. Results: In all, 190 patients (mean 48 years, 90% female) were randomized. Mean increase (95% confidence interval) in SBM for week 1 were 1.7 (0.7-2.8) for placebo vs. 2.5 (1.5-3.5), 4.0 (2.9-5.0), and 5.4 (4.4-6.4) for 5 mg, 10 mg (P<0.002), and 15 mg (P<0.001) A3309, respectively. Increased stool frequency was maintained over 8 weeks. Time to first SBM and CSBM were significantly reduced in the 10-and 15-mg A3309 groups compared with placebo. Straining and bloating decreased with A3309 compared with placebo (P<0.05). Increased 7αC4 and reduced low-density lipoprotein cholesterol with A3309 suggested increased BA synthesis and BA loss. The most common adverse events (AEs) were abdominal pain and diarrhea, which occurred most commonly in the 15-mg A3309 group. No drug-related serious AEs were observed. Conclusions: A3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 weeks of treatment. © 2011 by the American College of Gastroenterology.

Haidukewych G.J.,Orlando Regional Medical Center | Hanssen A.,Mayo Medical School
Journal of the American Academy of Orthopaedic Surgeons | Year: 2011

The need for revision total knee arthroplasty (TKA) is on the rise. Challenges to attaining durable, stable, well-functioning revision TKA include bony deficiency, periarticular osteopenia, deformity, and soft-tissue imbalance. Defect management often requires the use of stems, cement, metal augmentation, or allograft. Recently, there has been interest in obtaining fixation in the metaphyseal region in an attempt to improve construct stability while managing bony deficiency. Often, the metaphyseal bone is well vascularized, which provides an opportunity for additional fixation with cement, allograft, trabecular metal cones, or stepped porous-coated sleeves. Multiple series have documented good survivorship at short-term follow-up with trabecular metal cones and porous-coated sleeves. These newer technologies offer biologic fixation and are useful for treating bony defects that are not easily managed with other methods. Long-term studies are needed to determine the durability of these constructs. Concerns persist regarding stress shielding and difficulty of removal. Familiarity with the rationale and strategies for metaphyseal fixation in revision TKA is a valuable addition to the armamentarium of the revision surgeon. Copyright 2011 by the American Academy of Orthopaedic Surgeons.

Li X.,University of Alabama at Birmingham | Frye M.A.,Mayo Medical School | Shelton R.C.,Vanderbilt University
Neuropsychopharmacology | Year: 2012

After a series of serendipitous discoveries of pharmacological treatments for mania and depression several decades ago, relatively little progress has been made for novel hypothesis-driven drug development in mood disorders. Multifactorial etiologies of, and lack of a full understanding of, the core neurobiology of these conditions clearly have contributed to these development challenges. There are, however, relatively novel targets that have raised opportunities for progress in the field, such as glutamate and cholinergic receptor modulators, circadian regulators, and enzyme inhibitors, for alternative treatment. This review will discuss these promising new treatments in mood disorders, the underlying mechanisms of action, and critical issues of their clinical application. For these new treatments to be successful in clinical practice, it is also important to design innovative clinical trials that identify the specific actions of new drugs, and, ideally, to develop biomarkers for monitoring individualized treatment response. It is predicted that future drug development will identify new agents targeting the molecular mechanisms involved in the pathophysiology of mood disorders. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Vege S.S.,Mayo Medical School | Ziring B.,Thomas Jefferson University | Jain R.,Texas Digestive Disease Consultants | Moayyedi P.,Hamilton Health Sciences
Gastroenterology | Year: 2015

This article has an accompanying continuing medical education activity on page e12. Learning Objective: At the conclusion of this exercise, the learner will understand the approach to counseling patients regarding the optimal method and frequency of radiologic imaging, indications for invasive tests like endoscopic ultrasonography (EUS) and surgery, select patients for follow-up after surgery, decide the duration of such follow-up, and decide when to stop surveillance for those with and without surgery. © 2015 by the AGA Institute.

Jack Jr. C.R.,Mayo Medical School | Barrio J.R.,University of California at Los Angeles | Kepe V.,University of California at Los Angeles
Acta Neuropathologica | Year: 2013

The devastating effects of the still incurable Alzheimer's disease (AD) project an ever increasing shadow of burden on the health care system and society in general. In this ominous context, amyloid (Aβ) imaging is considered by many of utmost importance for progress towards earlier AD diagnosis and for potential development of effective therapeutic interventions. Amyloid imaging positron emission tomography procedures offer the opportunity for accurate mapping and quantification of amyloid-Aβ neuroaggregate deposition in the living brain of AD patients. This review analyzes the perceived value of current Aβ imaging probes and their clinical utilization and, based on amyloid imaging results, offers a hypothesis on the effects of amyloid deposition on the biology of AD and its progression. It also analyzes lingering questions permeating the field of amyloid imaging on the apparent contradictions between imaging results and known neuropathology brain regional deposition of Aβ aggregates. As a result, the review also discusses literature evidence as to whether brain Aβ deposition is truly visualized and measured with these amyloid imaging agents, which would have significant implications in the understanding of the biological AD cascade and in the monitoring of therapeutic interventions with these surrogate Aβ markers. © 2013 Springer-Verlag Berlin Heidelberg.

Halliday G.M.,University of New South Wales | Leverenz J.B.,Cleveland Clinic | Schneider J.S.,Thomas Jefferson University | Adler C.H.,Mayo Medical School
Movement Disorders | Year: 2014

The recent formalization of clinical criteria for Parkinson's disease with dementia (PDD) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PDD occurs on the background of severe dopamine deficits with, the main pathological drivers of cognitive decline being a synergistic effect between alpha-synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin, and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the α-synuclein gene, lead to a clear increased risk of PDD, whereas others, such as parkin mutations, are associated with a reduced risk of PDD. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low-dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. Whereas dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies, and genetic factors in PD-MCI remains to be fully elucidated. © 2014 International Parkinson and Movement Disorder Society.

Silberstein S.D.,Thomas Jefferson University | Dodick D.W.,Mayo Medical School
Headache | Year: 2013

Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21-23. The defect is a new mutation in the α2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an α1 subunit of a neuronal voltage-gated Na+ channel. Genome-wide association studies have identified many non-coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two-pore domain potassium channel, TWIK-related spinal cord potassium channel. TWIK-related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. © 2013 Oxford University Press Headache: The Journal of Head and Face Pain © 2013 American Headache Society.

Kermani T.A.,Mayo Medical School | Kermani T.A.,University of California at Los Angeles | Warrington K.J.,Mayo Medical School
The Lancet | Year: 2013

Polymyalgia rheumatica is a chronic, infl ammatory disorder of unknown cause that aff ects people over age 50 years. Classic symptoms include pain and long-term morning stiff ness of the neck, shoulders, hips, upper arms, and thighs. Although markers of infl ammation are often raised, no specifi c laboratory test exists for the disorder and the diagnosis is based on clinical assessment. Provisional classifi cation criteria were published in April, 2012, by a collaborative initiative of the European League Against Rheumatism and the American College of Rheumatology. Several other disorders can mimic polymyalgia rheumatica. In particular, clinical manifestations can be diffi cult to diff erentiate from other forms of infl ammatory arthritis such as spondyloarthritis and rheumatoid arthritis. Imaging studies such as ultrasonography and MRI typically show a predominantly periarticular infl ammatory process. A subset of patients has an associated infl ammatory vasculopathy aff ecting large arteries (giant cell arteritis). The standard treatment is low-dose glucocorticoids, which provide symptomatic relief for most patients. However, disease relapses are common, and treatment with glucocorticoids is associated with substantial morbidity. Improved understanding of disease pathogenesis might allow for more targeted immunotherapy.

Glassock R.J.,University of California at Los Angeles | Rule A.D.,Mayo Medical School
Kidney International | Year: 2012

Aging is both a natural and inevitable biological process. With advancing age, the kidneys undergo anatomical and physiological changes that are not only the consequences of normal organ senescence but also of specific diseases (such as atherosclerosis or diabetes) that occur with greater frequency in older individuals. Disentangling these two processes, one pathologic and the other physiologic, is difficult. In this review we concentrate on the glomerular structural and functional alterations that accompany natural aging. We also analyze how these changes affect the identification of individuals of advancing age as having chronic kidney disease (CKD) and how these changes can influence prognosis for adverse outcomes, including all-cause mortality, end-stage renal disease, cardiovascular events and mortality, and acute kidney injury. This review describes important shortcomings and deficiencies with our current approach and understanding of CKD in the older and elderly adult. © 2012 International Society of Nephrology.

Browne J.A.,University of Virginia | Pagnano M.W.,Mayo Medical School
Clinical Orthopaedics and Related Research | Year: 2012

Background: Posterior soft tissue repair after posterior THA reportedly decreases the risk of dislocation. Previously described techniques often require drill holes through the greater trochanter, do not include both the short external rotators and the capsule, or require a complex series of multiple sutures. We therefore describe a technique to address these issues. Description of Technique: The posterior soft tissues were repaired with a single nonabsorbable suture passed through the external rotators and posterior capsule and then through the capsule and posterior border of minimus in a figure-of-eight pattern. This repair remains pliable and obliterates the dead space. Methods: We retrospectively reviewed 165 patients who underwent 178 primary THAs through a mini-posterior THA and also underwent soft tissue repair using our technique. We determined the rate of dislocation and complications associated with this technique. The minimum clinical followup was 1 year (mean, 23 months; range, 12-37 months). Results: This repair was associated with a low risk of dislocation at 1 year (one of 178 hips, 0.56%) and no apparent complications related to the technique. Conclusions: This soft tissue to soft tissue repair technique after posterior-approach THA is technically straightforward and reliable with a low associated dislocation rate. Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. © 2011 The Association of Bone and Joint Surgeons®.

ROCHESTER, Minn. -- Research from Mayo Clinic included in the November issue of JAMA Neurology identifies a new biomarker for brain and spinal cord inflammation, allowing for faster diagnosis and treatment of patients. Vanda Lennon, M.D., Ph.D., and colleagues identified the new biomarker in spinal fluid and blood serum of patients with a neurological disorder called autoimmune meningoencephalomyelitis. The biomarker is an antibody. Antibodies are molecules used by the immune system to fight infections or cancer. When an antibody is directed against healthy tissue by a misguided immune system, as it is in this disorder, it is called an autoantibody. In autoimmune meningoencephalomyelitis, the autoantibody targets a protein called glial fibrillary acidic protein within cells called astrocytes that are found in the brain and spinal cord. "Headache is a prominent symptom reported by the patients," says Dr. Lennon, who is senior author on the study. "It is accompanied by neurological findings of varying severity. Inflammatory cells in the spinal fluid and MRI images raise suspicion for brain infection, other inflammatory brain disease or a cancer spreading to the lining of the brain." Dr. Lennon notes that this disease rapidly reverses with therapy directed at the immune system, such as prednisone, in contrast to infections that need antibiotics and cancer that requires aggressive treatment. A positive test for glial fibrillary acidic protein autoantibody should bring the correct diagnosis earlier and hasten the most appropriate treatment. The glial fibrillary acidic protein antibody biomarker initially was identified in Mayo Clinic's Neuroimmunology Laboratory, which is within the Department of Laboratory Medicine and Pathology. The biomarker was identified using a test developed in the 1960s. The process involves applying a patient's serum or spinal fluid to thin sections of mouse tissues. If an autoantibody is present, it will stick to the targeted tissue. After the serum or spinal fluid is washed off, a probe in the form of another antibody is applied to the tissue to detect any human antibody that remains bound to the tissue. The probe antibody is tagged with a fluorescent dye. When viewed under a fluorescence microscope, the tagged antibody shows the location of the bound human autoantibody, revealing the cells targeted by the immune system. In this case, the pattern of binding to mouse brain tissue resembles the pattern of abnormalities seen in MRI images of the patients' brain and spinal cord. "That method has been a tremendous tool of discovery as well as a diagnostic tool for the last 35 years since I set up this lab," says Dr. Lennon. "It had fallen out of fashion about 20 years ago when we were encouraged to use modern molecular techniques. Well, we certainly do use molecular techniques, which are important validation steps, but we did not give up on the valuable older technology as a component of our 21st-century screening protocol to detect informative autoantibodies. In the process, we have continued to discover new autoantibodies of clinical importance." With the discovery of this biomarker, Dr. Lennon and the team expect that diagnosis and treatment for patients will improve in another important way. "At this stage, we've identified about 103 patients," says Dr. Lennon. "And about a third of them are turning out to have an unsuspected cancer in a remote part of the body." The research team suspects that, because cancer cells and the nervous system use some of the same mechanisms for communication, the immune response that is attacking a cancer is causing collateral damage to the nervous system in the process. "It appears from evidence to date that the antibody does not itself cause the brain inflammation," says Dr. Lennon. "It is a proxy marker of a more aggressive component of the immune system called killer T cells, which target the same brain protein." The next steps are to verify the glial fibrillary acidic protein autoantibody's diagnostic performance. At that point, Mayo Clinic's Neuroimmunology Laboratory anticipates offering this test for diagnostic purposes. This study was funded by the Mayo Clinic Foundation. Dr. Fang, a visiting associate professor of neurology, was supported by the China Scholarship Council Exchange. The authors and Mayo Clinic in general disclose conflicts of interest related to this research in the published paper. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit or

News Article | December 1, 2016

CHICAGO, Dec. 1, 2016 /PRNewswire-USNewswire/ -- As increasing rates of stress, depression and fatigue fuel concern about physician well-being, the Accreditation Council for Graduate Medical Education (ACGME), the American Foundation for Suicide Prevention (AFSP) and Mayo Clinic today...

Objective: To examine the association between accelerometer-derived sedentary and physical activity and prostate-specific antigen (PSA) in a nationally representative sample of men in the United States. Participants and Methods: Data from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey cycles were used in the present study, with data from 1672 adult male participants used in the analyses. The manuscript was prepared between July 7, 2012, and September 26, 2012. Sedentary and physical activity was objectively measured using an accelerometer. Covariates included various demographic, dietary, biological, and immunologic variables including age, height, weight, body mass index, race/ethnicity, marital status, education, and poverty-income ratio; dietary fiber, fat, protein, and carbohydrate intake and total energy intake; vitamin C and vitamin E; alcohol intake; medication use; concentrations of cotinine, total cholesterol, and high-density lipoprotein cholesterol; blood pressure (elevated or not elevated); diabetes; C-reactive protein; and white blood cell count and number of basophils and eosinophils. Results: Only after controlling for all covariates, for every 1-hour increase in sedentary behavior, participants were 16% more likely to have an elevated PSA concentration (odds ratio, 1.16 [95% CI, 1.06- 1.27]; P=.001). For every 1-hour increase in light physical activity, participants were 18% less likely to have an elevated PSA concentration (odds ratio, 0.82 [95% CI, 0.68-1.00]; P=.05). Conclusion: Individuals who engage in more sedentary behavior and lower levels of light physical activity have higher PSA concentrations. Future studies are needed to better identify the potential underlying mechanisms delineating the association between sedentary and physical activity and PSA concentration. © 2013 Mayo Foundation for Medical Education and Research.

Nannapaneni S.,Mayo Medical School | Ramar K.,Center for Sleep Medicine
Sleep Medicine | Year: 2014

Periodic limb movements during sleep (PLMS) is a sleep-related movement disorder characterized by repetitive limb movements during sleep, seen predominantly in the legs but also occasionally involving the arms. These movements may be associated with arousals that can lead to increases in sympathetic tone, resulting in tachycardia and elevated systolic blood pressure. Chronic sustained tachycardia and elevated systolic blood pressure are known to be associated with the development of arrhythmias, hypertension, left ventricular hypertrophy, and congestive heart failure. However, the data are not entirely clear on whether untreated PLMS is associated with these cardiovascular risks. This review examines the current evidence on whether PLMS has any effect on the cardiovascular system. © 2014 Elsevier B.V.

Rubio-Tapia A.,Mayo Medical School | Hill I.D.,Wake forest University | Kelly C.P.,Beth Israel Deaconess Medical Center | Calderwood A.H.,Boston University | Murray J.A.,Mayo Medical School
American Journal of Gastroenterology | Year: 2013

This guideline presents recommendations for the diagnosis and management of patients with celiac disease. Celiac disease is an immune-based reaction to dietary gluten (storage protein for wheat, barley, and rye) that primarily affects the small intestine in those with a genetic predisposition and resolves with exclusion of gluten from the diet. There has been a substantial increase in the prevalence of celiac disease over the last 50 years and an increase in the rate of diagnosis in the last 10 years. Celiac disease can present with many symptoms, including typical gastrointestinal symptoms (e.g., diarrhea, steatorrhea, weight loss, bloating, flatulence, abdominal pain) and also non-gastrointestinal abnormalities (e.g., abnormal liver function tests, iron deficiency anemia, bone disease, skin disorders, and many other protean manifestations). Indeed, many individuals with celiac disease may have no symptoms at all. Celiac disease is usually detected by serologic testing of celiac-specific antibodies. The diagnosis is confirmed by duodenal mucosal biopsies. Both serology and biopsy should be performed on a gluten-containing diet. The treatment for celiac disease is primarily a gluten-free diet (GFD), which requires significant patient education, motivation, and follow-up. Non-responsive celiac disease occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms should lead to a review of the patient's original diagnosis to exclude alternative diagnoses, a review of the GFD to ensure there is no obvious gluten contamination, and serologic testing to confirm adherence with the GFD. In addition, evaluation for disorders associated with celiac disease that could cause persistent symptoms, such as microscopic colitis, pancreatic exocrine dysfunction, and complications of celiac disease, such as enteropathy-associated lymphoma or refractory celiac disease, should be entertained. Newer therapeutic modalities are being studied in clinical trials, but are not yet approved for use in practice. Given the incomplete response of many patients to a GFD-free diet as well as the difficulty of adherence to the GFD over the long term, development of new effective therapies for symptom control and reversal of inflammation and organ damage are needed. The prevalence of celiac disease is increasing worldwide and many patients with celiac disease remain undiagnosed, highlighting the need for improved strategies in the future for the optimal detection of patients. © 2013 by the american College of Gastroenterology.

Dellon E.S.,University of North Carolina at Chapel Hill | Gonsalves N.,Northwestern University | Hirano I.,Northwestern University | Furuta G.T.,University of Colorado at Denver | And 2 more authors.
American Journal of Gastroenterology | Year: 2013

Esophageal eosinophilia and eosinophilic esophagitis (EoE) are increasingly recognized and prevalent conditions, which now represent common clinical problems encountered by gastroenterologists, pathologists, and allergists. The study of EoE has become a dynamic field with an evolving understanding of the pathogenesis, diagnosis, and treatment. Although there are limited data supporting management decisions, clinical parameters are needed to guide the care of patients with eosinophilic-esophageal disorders. In this evidence-based review, recommendations developed by adult and pediatric gastroenterologists are provided for the evaluation and management of these patients. New terminology is emphasized, particularly the concepts of esophageal eosinophilia and proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) as entities distinct from EoE. © 2013 by the american College of Gastroenterology.

Fass R.,Southern Arizona VA Health Care System | Achem S.R.,Mayo Medical School
Journal of Neurogastroenterology and Motility | Year: 2011

Noncardiac chest pain is defined as recurrent chest pain that is indistinguishable from ischemic heart pain after a reasonable workup has excluded a cardiac cause. Noncardiac chest pain is a prevalent disorder resulting in high healthcare utilization and significant work absenteeism. However, despite its chronic nature, noncardiac chest pain has no impact on patients' mortality. The main underlying mechanisms include gastroesophageal reflux, esophageal dysmotility and esophageal hypersensitivity. Gastroesophageal reflux disease is likely the most common cause of noncardiac chest pain. Esophageal dysmotility affects only the minority of noncardiac chest pain patients. Esophageal hypersensitivity may be present in non-GERD-related noncardiac chest pain patients regardless if esophageal dysmotility is present or absent. Psychological co-morbidities such as panic disorder, anxiety, and depression are also common in noncardiac chest pain patients and often modulate patients' perception of disease severity. © 2011 The Korean Society of Neurogastroenterology and Motility.

Kitas G.D.,Dudley Group of Hospitals NHS Foundation Trust | Kitas G.D.,University of Manchester | Gabrie S.E.,Mayo Medical School
Annals of the Rheumatic Diseases | Year: 2011

Rheumatoid arthritis is associated with an increased risk for cardiovascular events, such as myocardial infarction and stroke. Epidemiological evidence suggests that classic cardiovascular risk factors, such as hypertension, dyslipidaemia, insulin resistance and body composition alterations are important but not sufficient to explain all of the excess risk. High-grade systemic inflammation and its interplay with classic risk factors may also contribute. Some associations between classic risk factors and cardiovascular risk in people with rheumatoid arthritis appear counterintuitive but may be explained on the basis of biological alterations. More research is necessary to uncover the exact mechanisms responsible for this phenomenon, develop accurate systems used to identify patients at high risk, design and assess prevention strategies specific to this population of patients.

Loeffelholz M.J.,University of Texas Medical Branch | Binnicker M.J.,Mayo Medical School
Journal of Clinical Microbiology | Year: 2012

Assays that detect treponema-specific antibodies, which are either automated or can be done as point-of-care tests, have been developed, some of which are FDA approved. These assays have the advantage of being easily performed and demonstrate high sensitivity, both key features of an infectious disease screening test. As a result, many high-volume clinical laboratories have begun to offer a reverse syphilis testing algorithm where a treponema-specific test is used for screening, followed by a nontreponemal test (i.e., rapid plasma reagin [RPR]) to assess disease activity and treatment status. Concerns about physicians being able to understand and apply this new testing algorithm have been expressed (8). In this point-counterpoint, Michael Loeffelholz of the University of Texas Medical Branch at Galveston explains why his laboratory has adopted this reverse algorithmic approach. Matthew Binnicker of the Mayo Clinic, Rochester, MN, explains why the reverse algorithm may not be suitable for all clinical laboratories and every clinical situation. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Bartalena L.,University of Insubria | Fatourechi V.,Mayo Medical School
Journal of Endocrinological Investigation | Year: 2014

Introduction: Graves' orbitopathy (GO), thyroid dermopathy (also called pretibial myxedema) and acropachy are the extrathyroidal manifestations of Graves' disease. They occur in 25, 1.5, and 0.3 % of Graves' patients, respectively. Thus, GO is the main and most common extrathyroidal manifestation. Dermopathy is usually present if the patient is also affected with GO. The very rare acropachy occurs only in patients who also have dermopathy. GO and dermopathy have an autoimmune origin and are probably triggered by autoimmunity to the TSH receptor and, likely, the IGF-1 receptor. Both GO and dermopathy may be mild to severe. Management: Mild GO usually does not require any treatment except for local measures and preventive actions (especially refraining from smoking). Currently, moderate-to-severe and active GO is best treated by systemic glucocorticoids, but response to treatment is not optimal in many instances, and retreatments and use of other modalities (glucocorticoids, orbital radiotherapy, cyclosporine) and, in the end, rehabilitative surgery are often needed. Dermopathy is usually managed by local glucocorticoid treatment. No specific treatment is available for acropachy. Perspectives: Novel treatments are presently being investigated for GO, and particular attention is paid to the use of rituximab. It is unknown whether novel treatments for GO might be useful for the other extrathyroidal manifestations. Future novel therapies shown to be beneficial for GO in randomized studies may be empirically used for dermopathy and acropachy. © 2014 Italian Society of Endocrinology (SIE).

Barbui T.,Ospedale Papa Giovanni XXIII | Thiele J.,University of Cologne | Vannucchi A.M.,University of Florence | Tefferi A.,Mayo Medical School
Leukemia | Year: 2014

The aim of this review is to critically address the validity and clinical applicability of three major diagnostic classification systems for polycythemia vera (PV), that is, those proposed by the Polycythemia Vera Study Group (PVSG), the British Committee for Standards in Haematology (BCSH) and the World Health Organization (WHO). Special focus is on which one of the three red cell parameters (hemoglobin - HB, hematocrit - HCT and red cell mass - RCM) should be used as the diagnostic hallmark of PV. The revised BCSH employed a persistently raised HCT level as the first diagnostic criterion in combination with the presence of a JAK2V617F mutation. On the other hand, the WHO classification used a raised HB value as a surrogate for increased RCM in association with molecular markers and for the first time, the bone marrow (BM) morphology was included as a minor criterion. Ongoing controversy and discussion regards the use of certain threshold values for HCT and HB as surrogates for RCM as well as the existence of prodromal-latent disease, so-called masked PV (mPV). It has been shown that mPV can be recognized in patients not meeting the required HB or HCT threshold levels by both the WHO and BCSH criteria. These cases present with the same baseline clinical features as overt PV but present worsened survival. A critical reappraisal of the WHO criteria may suggest either to reduce the thresholds for HB or to consider HCT values as major diagnostic criterion, as in the BCSH, in association with JAK2V617F mutation. The clinical utility of using HCT as reference variable is supported also by results of clinical trials which explicitly recommend to use the HCT threshold for monitoring treatment. In questionable cases as in mPV, BM biopsy examinations should be mandated together with mutation analysis. © 2014 Macmillan Publishers Limited.

Barbui T.,Ospedali Riuniti di Bergamo | Thiele J.,University of Cologne | Vannucchi A.M.,University of Florence | Tefferi A.,Mayo Medical School
Leukemia | Year: 2013

Reproducibility and clinical usefulness of the WHO classification of chronic myeloproliferative neoplasm (MPN) persist to be a controversial issue. Major arguments are focused on the critical impact of histopathology, particularly concerning the distinction between essential thrombocythemia (ET) versus early/prefibrotic primary myelofibrosis (PMF). Regarding bone marrow morphology, WHO guidelines strictly require the recognition of characteristic histological patterns based on standardized features and a consensus of clinical and molecular-genetic data. Molecular-genetic findings as JAK2V617F, may aid to exclude reactive thrombocytosis, although in ET and PMF only 50-60% of the cases show these aberrations. Considerable doubts over the existence of early/prefibrotic PMF have been expressed with the consequence to include this entity in the ET category. On the other hand, it has to be argued that some of the critical studies failed to adhere very strictly to the WHO guidelines. Contrasting this situation, recently published retrospective and prospective clinico-pathological studies featuring the WHO criteria provided an important information on disease outcomes supporting the existence of early/prefibrotic PMF as a distinct clinico-pathologic entity in patients presenting clinically with ET. Therefore, this controversy suggests a scientific project, including the community of pathologists and hematologists, for providing sound, objective and reproducible criteria for diagnosing early/prefibrotic PMF. © 2013 Macmillan Publishers Limited All rights reserved.

Edlow J.A.,Beth Israel Deaconess Medical Center | Rabinstein A.,Mayo Medical School | Traub S.J.,Mayo Medical School | Wijdicks E.F.M.,Mayo Medical School
The Lancet | Year: 2014

Because coma has many causes, physicians must develop a structured, algorithmic approach to diagnose and treat reversible causes rapidly. The three main mechanisms of coma are structural brain lesions, diffuse neuronal dysfunction, and, rarely, psychiatric causes. The first priority is to stabilise the patient by treatment of life-threatening conditions, then to use the history, physical examination, and laboratory findings to identify structural causes and diagnose treatable disorders. Some patients have a clear diagnosis. In those who do not, the first decision is whether brain imaging is needed. Imaging should be done in post-traumatic coma or when structural brain lesions are probable or possible causes. Patients who do not undergo imaging should be reassessed regularly. If CT is non-diagnostic, a checklist should be used use to indicate whether advanced imaging is needed or evidence is present of a treatable poisoning or infection, seizures including non-convulsive status epilepticus, endocrinopathy, or thiamine deficiency. © 2014 Elsevier Ltd.

Symmons D.P.M.,University of Manchester | Gabriel S.E.,Mayo Medical School
Nature Reviews Rheumatology | Year: 2011

The excess risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) have higher mortality compared with the general population. Over 50% of premature deaths in RA are attributable to CVD. Excess mortality in SLE follows a bimodal pattern, with the early peak predominantly a consequence of active lupus or its complications, and the later peak largely attributable to atherosclerosis. Patients with RA or SLE are also at increased risk of nonfatal ischemic heart disease. The management and outcome of myocardial infarction and congestive heart failure in patients with RA or SLE differs from that in the general population. Traditional CVD risk factors (TRF) include increasing age, male gender, smoking, hypertension, hypercholesterolemia and diabetes. Whereas some TRFs are elevated in patients with RA or SLE, several are not, and others exhibit paradoxical relationships. Risk scores developed for the general population based on TRFs are likely, therefore, to underestimate CVD risk in RA and SLE. Until additional research and disease-specific risk prediction tools are available, current evidence supports aggressive treatment of disease activity, and careful screening for and management of TRFs. © 2011 Macmillan Publishers Limited. All rights reserved.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

DESCRIPTION provided by applicant This project will develop an FDA approved process D printing system and advanced D printable material suitable for point of care manufacturing of custom fit continuous positive airway pressure CPAP masks for neonates In extremely low birth weight infants nasal CPAP therapy is delivered via soft biocompatible neonatal sized nasal masks suitable for long term direct skin contact inserted into the nares and held firmly against face For the desired pressure to be transmitted to the distal airways and to minimize complications a tight seal is required between the mask nasal prongs and the soft tissues of the internal circumference of the nostrils Currently there are limited often just sizes of CPAP nasal prongs available to clinicians that must serve growing babies weighing less than grams up to babies weighing over kg Ill fitting nasal prongs contribute to adverse outcomes in this fragile population Recent advances in D printing support the possibility of custom fit neonatal nasal CPAP prongs manufactured effectively at the patient point of care Unfortunately a polymer and printer system has not yet been fully developed that can make the proposed type of FDA approved medical device Materials and applied research are necessary to prove both the science and the commercial markets in order to drive development from D printer and D printable materials manufacturers and adoption from clinicians The objective of this innovative project is to develop a material and printing system combination able to produce a pliable medical device in this application that can meet or exceed the expectations applied to comparable devices through FDA guidance and international consensus standards PUBLIC HEALTH RELEVANCE The proposed research aims to improve the efficacy of nasal continuous positive airway pressure nCPAP in the neonatal care environment Respiratory support in neonates ranging in weight from grams up to babies weighing over kg is extremely consequential to long term health and development Therapy effectiveness at this stage of human development is life altering

News Article | November 29, 2016

JACKSONVILLE, Fla. -- Myocarditis, an assortment of heart disorders often caused by infection and inflammation, is known to be difficult to diagnose and treat. But the picture of who is affected is becoming a little clearer. Men may be as much as twice as likely as women to develop severe and possibly fatal reactions. And the risk of sudden cardiovascular death in the young is relatively high. Myocarditis accounts for about 5 percent of sudden cardiovascular infant deaths and up to 20 percent of sudden cardiovascular death in adolescents. And the chronic disease is responsible for up to 45 percent of heart transplants in the U.S. This assessment of the global state of myocarditis, published Nov. 29 in the Journal of the American College of Cardiology, points to the need for advanced therapies and prevention strategies, says Leslie Cooper Jr., M.D., cardiologist and chair, Cardiovascular Department, on Mayo Clinic's campus in Florida. Along with Dr. Cooper, who is an internationally recognized expert on myocarditis, researchers from the Netherlands, Switzerland and Finland contributed to the study. Dr. Cooper also authored the myocarditis section for the 2015 Global Burden of Disease Study, which was published Oct. 7 in the Lancet, and the American Heart Association scientific statement on specific dilated cardiomyopathies, which was published Nov. 3 in Circulation. Cardiomyopathies, which often feature enlarged hearts and heart failure, can result from myocarditis. Dr. Cooper reported in the Lancet global disease study that cases of myocarditis have increased from about 1.5 million annually to 2.2 million cases from 2013 to 2015. Although the exact incidence of myocarditis in the U.S. has not been reported, it is estimated that several thousand patients -- most of them 40 or younger -- are diagnosed. In the Journal of the American College of Cardiology study, he found that the rate of myocarditis and associated death is much higher in men than in women. This is likely due to testosterone-driven inflammation. Early diagnosis is key to preventing long-term heart damage from myocarditis, Dr. Cooper says. If chronic disease results, scarring in the heart can promote heart failure. Although standard therapies are used to control symptoms of heart failure, new investigational therapies soon may enter clinical trials, and new management of the disorder is being discussed, Dr. Cooper says. "We are on a quest for advances in treating this disorder," he says. Myocarditis is a difficult disorder to diagnose and treat, Dr. Cooper says. The most common cause of myocarditis is an infection ? usually viral ? that can damage heart muscle chronically or acutely in otherwise healthy people, Dr. Cooper says. Infections that affect the heart differ around the globe. In the U.S., a dozen common pathogens can be responsible. An example is coxsackie virus, which up to 70 percent of U.S. residents have been exposed to by the time they are 30. "But only 1 to 2 percent of people with acute coxsackie virus infection develop cardiac symptoms," Dr. Cooper says. Myocarditis has other causes, including autoimmune diseases, environmental toxins, and adverse reactions to medications. The most clinically important symptoms of the disorder are shortness of breath, which can indicate the start of heart failure, and chest pain ? a sign of heart inflammation, he says. To prevent the disorder from worsening in children, Dr. Cooper suggests that aerobic exercise be limited for several weeks after a suspected coxsackie virus infection, and "if a child or adolescent develops breathing difficulties or chest pain with evidence of myocarditis, my recommendation is to avoid competitive sports for at least three months," Dr. Cooper says. A cardiac MRI within two weeks of symptom onset is 80 percent effective in diagnosing cardiomyopathy, but diagnosis is difficult at more chronic stages. Most people (60-70 percent) with acute cardiomyopathy from myocarditis get better. About 10-15 percent develops irreversible chronic disease due to scars in the heart created by the infection, Dr. Cooper says. These patients are treated with standard heart failure therapies, but 20 percent die during the decade following infection due to heart failure. "I see patients everyday with this disorder," Dr. Cooper says. "We are on the cusp of trying more tailored treatment, and it can't come soon enough." There was no funding support or relationships with industry for the Journal of the American College of Cardiology study, which Dr. Cooper led. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

Rajkumar S.V.,Mayo Medical School | Landgren O.,Sloan Kettering Cancer Center | Mateos M.-V.,University of Salamanca
Blood | Year: 2015

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. © 2015 by The American Society of Hematology.

Gersh B.J.,Mayo Medical School | Sliwa K.,Hatter Institute of Cardiovascular Research | Mayosi B.M.,University of Cape Town | Yusuf S.,Hamilton General Hospital
European Heart Journal | Year: 2010

The epidemic of cardiovascular disease (CVD) is a global phenomenon, and the magnitude of its increase in incidence and prevalence in low-and middle-income countries (LIMIC) has potentially major implications for those high-income countries that characterize much of the developed world. Cardiovascular disease remains the leading cause of death in the world and approximately 80 of all cardiovascular-related deaths occur in LIMIC and at a younger age in comparison to high-income countries. The economic impact in regard to loss of productive years of life and the need to divert scarce resources to tertiary care is substantial. The 'epidemiologic transition' provides a useful framework for understanding changes in the patterns of disease as a result of societal and socioeconomic developments in different countries and regions of the world. A burning but as yet unanswered question is whether gains made over the last four decades in reducing cardiovascular mortality in high-income countries will be offset by changes in risk factor profiles, and in particular obesity and diabetes. Much of the population attributable risk of myocardial infarction is accountable on the basis of nine modifiable traditional risk factors, irrespective of geography. Developing societies are faced with a hostile cardiovascular environment, characterized by changes in diet, exercise, the effects of tobacco, socioeconomic stressors, and economic constraints at both the national and personal level in addition to exposure to potential novel risk factors and perhaps a genetic or programmed foetal vulnerability to CVD in later life. There are major challenges for primary and secondary prevention including lack of data, limited national resources, and the lack of prediction models in certain populations. There are two major approaches to prevention: public health/community-based strategies and clinic-based with a targeted approach to high-risk patients and combinations of these. There are concerns that in comparison with communicable diseases, cardiovascular and chronic diseases have a relatively low priority in the global health agenda and that this requires additional emphasis.The human race has had long experience and a fine tradition in surviving adversity, but we now face a task for which we have little experience, the task of surviving prosperity Alan Gregg 1890-1957, Rockefeller Foundation. © The Author 2010.

Wilke C.,University of Minnesota | Worrell G.,Mayo Medical School | He B.,University of Minnesota
Epilepsia | Year: 2011

Purpose: The current gold standard for the localization of the cortical regions responsible for the initiation and propagation of the ictal activity is through the use of invasive electrocorticography (ECoG). This method is utilized to guide surgical intervention in cases of medically intractable epilepsy by identifying the location and extent of the epileptogenic focus. Recent studies have proposed mechanisms in which the activity of epileptogenic cortical networks, rather than discrete focal sources, contributes to the generation of the ictal state. If true, selective modulation of key network components could be employed for the prevention and termination of the ictal state. Methods: Here, we have applied graph theory methods as a means to identify critical network nodes in cortical networks during both ictal and interictal states. ECoG recordings were obtained from a cohort of 25 patients undergoing presurgical monitoring for the treatment of intractable epilepsy at the Mayo Clinic (Rochester, MN, U.S.A.). Key Findings: One graph measure, the betweenness centrality, was found to correlate with the location of the resected cortical regions in patients who were seizure-free following surgical intervention. Furthermore, these network interactions were also observed during random nonictal periods as well as during interictal spike activity. These network characteristics were found to be frequency dependent, with high frequency gamma band activity most closely correlated with improved postsurgical outcome as has been reported in previous literature. Significance: These findings could lead to improved understanding of epileptogenesis. In addition, this theoretically allows for more targeted therapeutic interventions through the selected modulation or disruption of these epileptogenic networks. © 2010 International League Against Epilepsy.

Mesa R.A.,Mayo Medical School | Yasothan U.,IMS Health | Kirkpatrick P.,Nature Reviews Drug Discovery
Nature Reviews Drug Discovery | Year: 2012

In November 2011, ruxolitinib (Jakafi; Incyte/Novartis), a small-molecule inhibitor of Janus kinases, was approved by the US Food and Drug Administration for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis. © 2012 Macmillan Publishers Limited. All rights reserved.

Rodriguez F.J.,Mayo Medical School | Rodriguez F.J.,Johns Hopkins University | Lewis-Tuffin L.J.,Mayo Medical School | Anastasiadis P.Z.,Mayo Medical School
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2012

In the context of cancer, E-cadherin has traditionally been categorized as a tumor suppressor, given its essential role in the formation of proper intercellular junctions, and its downregulation in the process of epithelial-mesenchymal transition (EMT) in epithelial tumor progression. Germline or somatic mutations in the E-cadherin gene (. CDH1) or downregulation by epigenetic mechanisms have been described in a small subset of epithelial cancers. However, recent evidence also points toward a promoting role of E-cadherin in several aspects of tumor progression. This includes preserved (or increased) E-cadherin expression in microemboli of inflammatory breast carcinoma, a possible "mesenchymal to epithelial transition" (MET) in ovarian carcinoma, collective cell invasion in some epithelial cancers, a recent association of E-cadherin expression with a more aggressive brain tumor subset, as well as the intriguing possibility of E-cadherin involvement in specific signaling networks in the cytoplasm and/or nucleus. In this review we address a lesser-known, positive role for E-cadherin in cancer. © 2012 Elsevier B.V.

Korley F.K.,Johns Hopkins University | Jaffe A.S.,Mayo Medical School
Journal of the American College of Cardiology | Year: 2013

It is only a matter of time before the use of high-sensitivity cardiac troponin assays (hs-cTn) becomes common throughout the United States. In preparation for this inevitability, this article raises a number of important issues regarding these assays that deserve consideration. These include: the need for the adoption of a universal nomenclature; the importance of defining uniform criteria for reference populations; the challenge of discriminating between acute and nonacute causes of hs-cTn elevations, and between type 1 and type 2 acute myocardial infarction (AMI); factors influencing the analytical precision of hs-cTn; ascertaining the optimal duration of the rule-out period for AMI; the need for further evaluation to determine the causes of a positive hs-cTn in non-AMI patients; and the use of hs-cTn to risk-stratify patients with disease conditions other than AMI. This review elaborates on these critical issues as a means of educating clinicians and researchers about them. © 2013 American College of Cardiology Foundation.

Elamm C.,Mayo Medical School | Fairweather D.,Johns Hopkins University | Cooper L.T.,Mayo Medical School
Heart | Year: 2012

Acute myocarditis is an inflammatory disease of the heart muscle that may progress to dilated cardiomyopathy and chronic heart failure. A number of factors including the sex hormone testosterone, components of innate immunity, and profibrotic cytokines have been identified in animal models as important pathogenic mechanisms that increase inflammation and susceptibility to chronic dilated cardiomyopathy. The clinical presentation of acute myocarditis is non-specific and mimics more common causes of heart failure and arrhythmias. Suspected myocarditis is currently confirmed using advanced non-invasive imaging and histopathologic examination of heart tissue. However, the diverse presentations of myocarditis and the lack of widely available, safe, and accurate non-invasive diagnostic tests remain major obstacles to early diagnosis and population based research. Recent advances in the understanding of disease pathogenesis described in this review should lead to more accurate diagnostic algorithms and non-invasive tests.

Tefferi A.,Mayo Medical School | Barbui T.,Research Foundation
Leukemia | Year: 2013

The World Health Organization (WHO) classification system has recently strengthened the diagnostic criteria for essential thrombocythemia (ET) by lowering the threshold platelet count, underscoring its morphological distinction from early/prefibrotic myelofibrosis (MF) and incorporating molecular markers of clonality. The International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) examined the clinical relevance of this process in 1104 cases of locally diagnosed 'ET' and showed worse overall, leukemia-free and fibrosis-free survival, and a higher risk of bleeding in early/prefibrotic MF (n=180) vs WHO-defined ET (n=891). The risk of thrombosis was similar between the two entities and, in WHO-defined ET, was predicted by thrombosis history, older age, cardiovascular risk factors and JAK2V617F. A prognostic model based on these risk factors identified patient groups in ET with residual risk of thrombosis, despite treatment with conventional therapy. The main objectives of the current perspective are to underscore the prognostic importance of morphological confirmation in the diagnosis of ET and provide management recommendations, in both WHO-defined ET and early/prefibrotic MF, based on observations from the aforementioned IWG-MRT and other studies. In so doing, we are fully cognizant and sympathetic of the fact that some of our recommendations need to be tested in prospective controlled studies. © 2013 Macmillan Publishers Limited. All rights reserved.

Nath K.A.,Mayo Medical School | Hebbel R.P.,University of Minnesota
Nature Reviews Nephrology | Year: 2015

Sickle cell disease (SCD) substantially alters renal structure and function, and causes various renal syndromes and diseases. Such diverse renal outcomes reflect the uniquely complex vascular pathobiology of SCD and the propensity of red blood cells to sickle in the renal medulla because of its hypoxic, acidotic, and hyperosmolar conditions. Renal complications and involvement in sickle cell nephropathy (SCN) include altered haemodynamics, hypertrophy, assorted glomerulopathies, chronic kidney disease, acute kidney injury, impaired urinary concentrating ability, distal nephron dysfunction, haematuria, and increased risks of urinary tract infections and renal medullary carcinoma. SCN largely reflects an underlying vasculopathy characterized by cortical hyperperfusion, medullary hypoperfusion, and an increased, stress-induced vasoconstrictive response. Renal involvement is usually more severe in homozygous disease (sickle cell anaemia, HbSS) than in compound heterozygous types of SCD (for example HbSC and HbSβ + -thalassaemia), and is typically mild, albeit prevalent, in the heterozygous state (sickle cell trait, HbAS). Renal involvement contributes substantially to the diminished life expectancy of patients with SCD, accounting for 16-18% of mortality. As improved clinical care promotes survival into adulthood, SCN imposes a growing burden on both individual health and health system costs. This Review addresses the renal manifestations of SCD and focuses on their underlying mechanisms. © 2015 Macmillan Publishers Limited. All rights reserved.

Seeliger E.,Charité - Medical University of Berlin | Sendeski M.,Charité - Medical University of Berlin | Rihal C.S.,Mayo Medical School | Persson P.B.,Charité - Medical University of Berlin
European Heart Journal | Year: 2012

In general, iodinated contrast media (CM) are tolerated well, and CM use is steadily increasing. Acute kidney injury is the leading life-threatening side effect of CM. Here, we highlight endpoints used to assess CM-induced acute kidney injury (CIAKI), CM types, risk factors, and CIAKI prevention. Moreover, we put forward a unifying theory as to how CIAKI comes about; the kidney medulla's unique hyperosmolar environment concentrates CM in the tubules and vasculature. Highly concentrated CM in the tubules and vessels increases fluid viscosity. Thus, flow through medullary tubules and vessels decreases. Reducing the flow rate will increase the contact time of cytotoxic CM with the tubular epithelial cells and vascular endothelium, and thereby damage cells and generate oxygen radicals. As a result, medullary vasoconstriction takes place, causing hypoxia. Moreover, the glomerular filtration rate declines due to congestion of highly viscous tubular fluid. Effective prevention aims at reducing the medullary concentration of CM, thereby diminishing fluid viscosity. This is achieved by generous hydration using isotonic electrolyte solutions. Even forced diuresis may prove efficient if accompanied by adequate volume supplementation. Limiting the CM dose is the most effective measure to diminish fluid viscosity and to reduce cytotoxic effects. © 2012 The Author.

Dehm S.M.,University of Minnesota | Tindall D.J.,Mayo Medical School
Endocrine-Related Cancer | Year: 2011

Alternative splicing is an important mechanism for increasing functional diversity from a limited set of genes. Deregulation of this process is common in diverse pathologic conditions. The androgen receptor (AR) is a steroid receptor transcription factor with functions critical for normal male development as well as the growth and survival of normal and cancerous prostate tissue. Studies of AR function in androgen insensitivity syndrome (AIS) and prostate cancer (PCa) have demonstrated loss-of-function AR alterations in AIS and gain-of-function AR alterations in PCa. Over the past two decades, AR gene alterations have been identified in various individuals with AIS, which disrupt normal AR splicing patterns and yield dysfunctional AR protein variants. Recently, altered AR splicing patterns have been identified as a mechanism of PCa progression and resistance to androgen depletion therapy. Several studies have described the synthesis of alternatively spliced transcripts encoding truncated AR isoforms that lack the ligand-binding domain, which is the ultimate target of androgen depletion. Many of these truncated AR isoforms function as constitutively active, ligand-independent transcription factors that can support androgen-independent expression of AR target genes, as well as the androgen-independent growth of PCa cells. In this review, we will summarize the various alternatively spliced AR variants that have been discovered, with a focus on their role and origin in the pathologic conditions of AIS and PCa. © 2011 Society for Endocrinology.

Sliwa K.,University of Cape Town | Stewart S.,Baker IDI Heart and Diabetic Institute | Gersh B.J.,Mayo Medical School
Circulation | Year: 2011

In summary, there is ample evidence to suggest that the burden of hypertension is already having a profound effect on the health of populations in low- to middle-income countries.12 The phenomenon of epidemiological transition has certainly contributed to the rise of CVD and will, no doubt, cause a sustained epidemic of noncommunicable forms of CVD for the foreseeable future. Unfortunately, in resource-poor countries, there is often limited scope to respond to this growing problem. It is encouraging to see that the World Health Organization has developed an action plan that advocates key strategies for limiting the impact on noncommunicable diseases. © 2011 American Heart Association, Inc.

Sah R.P.,Mayo Medical School | Dawra R.K.,University of Minnesota | Saluja A.K.,University of Minnesota
Current Opinion in Gastroenterology | Year: 2013

PURPOSE OF REVIEW: In this article, we review important advances in our understanding of the mechanisms of pancreatitis. RECENT FINDINGS: The relative contributions of intrapancreatic trypsinogen activation and nuclear factor kappa B (NFκB) activation, the two major early independent cellular events in pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as the central pathogenic event of pancreatitis. However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis, which was shown to be induced by NFκB activation. Further, chronic pancreatitis developed independently of trypsinogen activation in the caerulein model. Sustained NFκB activation, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT (nuclear factor of activated T-cells) signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. Interleukin-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. SUMMARY: Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis. Copyright © 2013 Lippincott Williams & Wilkins.

Singh S.,Mayo Medical School | Garg S.K.,University of Minnesota | Singh P.P.,Mayo Medical School | Iyer P.G.,Mayo Medical School | El-Serag H.B.,Baylor College of Medicine
Gut | Year: 2014

Background and aims Acid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barrett's oesophagus (BO). We performed a systematic review with meta- Analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BOHGD) in patients with BO. Methods We performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated. Results We identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta- Analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose- response relationship with PPI use for >2-3 years protective against OAC or BO-HGD (three studies; PPI use >2-3 years vs <2-3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect. Conclusions Based on meta- Analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.

Robinson A.B.,Case Western Reserve University | Reed A.M.,Mayo Medical School
Nature Reviews Rheumatology | Year: 2011

Juvenile and adult dermatomyositis (DM) have multiple commonalities, yet display differing prevalence of features, outcomes and comorbidities. In general, compared with the disease in adults, children with DM have more vasculopathy and a greater likelihood of calcinosis, periungual and gingival telangiectasias, and ulceration, but have a better long-term prognosis with improved survival. Adults with DM are more likely to have myositis-specific antibodies, develop interstitial lung disease, have amyopathic disease, and have a marked association with malignancy and other comorbidities. Both diseases have similar features on muscle biopsy and interferon gene signature, although subtle differences can exist in pathogenesis and pathology, such as more capillary loss and a greater degree of C5b-9 complement deposition in affected muscle of juvenile patients. Initiatives are underway to improve classification, markers of disease activity and ability to predict outcome of juvenile and adult DM. The purpose of this Review is to compare and contrast the unique features between juvenile and adult disease and to outline new initiatives in the field. © 2011 Macmillan Publishers Limited. All rights reserved.

Schenck C.H.,University of Minnesota | Boeve B.F.,Mayo Medical School | Mahowald M.W.,University of Minnesota
Sleep Medicine | Year: 2013

Objective: To provide a 16-year update from the authors' 1996 report documenting a 38% conversion from idiopathic rapid eye movement sleep behavior disorder (iRBD) to a parkinsonian disorder at a mean interval of nearly 13. years after the onset of iRBD in a series of 29 males ≥50. years old. Methods: The methods of evaluation, diagnosis and follow-up were previously described in the 1996 report. All patients had video-polysomnography (vPSG) confirmed RBD. Results: 80.8% (21/26) of patients who were initially diagnosed with iRBD eventually developed parkinsonism/dementia (three of the original 29 patients were lost to follow-up). The distribution of diagnoses was as follows: n = 13, Parkinson's disease (PD); n = 3, dementia with Lewy bodies (DLB); n = 1, dementia (unspecified; profound); n = 2, multiple system atrophy (MSA); n = 2, clinically diagnosed Alzheimer's Disease (AD) with autopsy-confirmed combined AD plus Lewy body disease pathology. Among the 21 iRBD "converters," the mean age (±SD) of iRBD onset was 57.7 ± 7.7. years; mean age (±SD) of parkinsonism/dementia onset was 71.9 ± 6.6. years; and mean interval (±SD) from iRBD onset to parkinsonism/dementia onset was 14.2 ± 6.2. years (range: 5-29. years). Conclusion: The vast majority of men ≥50. years old initially diagnosed with iRBD in this study eventually developed a parkinsonian disorder/dementia, often after a prolonged interval from onset of iRBD, with the mean interval being 14. years while the range extended to 29. years. Also, the specificity of iRBD converting to parkinsonism/dementia is striking. These findings carry important clinical and research implications in the convergent fields of sleep medicine, neurology, and neuroscience, and identify an optimal clinical group for conducting prospective research studies utilizing putative neuroprotective agents to delay the emergence of, or halt the progression to, parkinsonism and/or cognitive impairment as manifestations of either PD, DLB or MSA. © 2012 Elsevier B.V.

Scantlebury D.C.,Mayo Medical School | Prasad A.,Mayo Medical School | Prasad A.,University of London
Circulation Journal | Year: 2014

Takotsubo cardiomyopathy, also known as left ventricular apical ballooning syndrome and stress-induced cardiomyopathy, is typically characterized by transient systolic dysfunction of the apical and mid-segments of the left ventricle, in the absence of obstructive coronary artery lesions. Patients may present with symptoms and signs of acute coronary syndrome, and the provider is challenged to differentiate between these conditions. In this review, we guide the reader through the diagnostic pathway, focusing on differential diagnoses and diagnostic criteria for takotsubo cardiomyopathy. © 2014 THE JAPANESE CIRCULATION SOCIETY.

Herrmann J.,Mayo Medical School | Kaski J.C.,St George's, University of London | Lerman A.,Mayo Medical School
European Heart Journal | Year: 2012

Far more extensive than the epicardial coronary vasculature that can be visualized angiographically is the coronary microcirculation, which foregoes routine imaging. Probably due to the lack of techniques able to provide tangible evidence of its crucial role, the clinical importance of coronary microvascular dysfunction is not fully appreciated. However, evidence gathered over the last several decades indicates that both functional and structural abnormalities of the coronary microvasculature can lead to myocardial ischaemia, often comparable with that caused by obstructive coronary artery disease. Indeed, a marked increase in coronary microvascular resistance can impair coronary blood flow and trigger angina pectoris, ischaemic ECG shifts, and myocardial perfusion defects, and lead to left ventricular dysfunction in patients who otherwise have patent epicardial coronary arteries. This condition-often referred to as 'chest pain with normal coronary arteries' or 'cardiac syndrome X'-encompasses several pathogenic mechanisms involving the coronary microcirculation. Of importance, coronary microvascular dysfunction can occur in conjunction with several other cardiac disease processes. In this article, we review the pathogenic mechanisms leading to coronary microvascular dysfunction and its diagnostic assessment, as well as the different clinical presentations and prognostic implications of microvascular angina. As such, this review aims to remove at least some of the mystery surrounding the notion of coronary microvascular dysfunction and to show why it represents a true clinical entity. © 2012 The Author.

News Article | October 31, 2016

ROCHESTER, Minn. -- The sudden death of a 13-year-old boy resulted in more than 20 relatives to be incorrectly diagnosed as having a potentially lethal heart rhythm condition. This erroneous diagnosis occurred as a result of inappropriate use of genetic testing and incorrect interpretation of genetic test results, according to Mayo Clinic research published in Mayo Clinic Proceedings. This case highlights the potential danger of genetic testing when it is used incorrectly and the great need to not only use this powerful tool carefully and wisely but to scrutinize the results with great caution, says senior author Michael J. Ackerman, M.D., Ph.D., genetic cardiologist and director of Mayo Clinic's Windland Smith Rice Sudden Death Genomics Laboratory. "While the technological advances in genetic sequencing have been exponential, our ability to interpret the results has not kept pace," he says. Following the boy's death, family members were diagnosed with long QT syndrome, an inherited heart rhythm condition that potentially can cause fast and chaotic heartbeats. In some cases, it can cause sudden cardiac death. People can be born with a genetic mutation that puts them at risk of long QT syndrome. As a result, the boy's brother prophylactically received an implantable cardioverter defibrillator, which can stop a potentially fatal arrhythmia. Specific genetic testing was performed throughout the father's side of the family, leading to the eventual, but incorrect, diagnosis of long QT syndrome in more than 20 family members, Dr. Ackerman says. The family then traveled to Mayo Clinic for a second opinion. During the course of their initial clinical evaluations, Dr. Ackerman became skeptical quickly of their previous diagnosis. Over the years, 40 percent of the patients who came to Mayo Clinic with the diagnosis of long QT syndrome left without the diagnosis, with the vast majority reclassified as normal. "This family's case appeared to be another case of mistaken identity with wrong conclusions being rendered to the data ascertained, especially the genetic test results," he says. "In fact, none of the relatives who sought a second opinion at Mayo Clinic had personal symptoms of long QT syndrome, and none exhibited any electrocardiographic evidence of long QT syndrome at rest or with treadmill stress testing." Since receiving the implantable cardioverter-defibrillator, the boy's brother has had two inappropriate shocks delivered. Then, with this clinical doubt raised, Dr. Ackerman and co-investigators worked to discover the true reason behind the boy's death. The research team used the molecular autopsy that was pioneered by Dr. Ackerman and his team. First performed in the late 1990s, the molecular autopsy has advanced to what Ackerman refers to as "the whole-exome molecular autopsy coupled with genomic triangulation." This strategy "provided closure and clarity" for the family, he says. "We discovered that the boy died tragically from an abnormal heart muscle condition caused by an entirely different genetic defect -- unrelated to long QT syndrome -- that was confined to only the sudden death victim," Dr. Ackerman says. "This family study highlights just how important it is to get things right on the first attempt, as it takes a tremendous amount of time, energy and money to reverse course and do it over again. It also depicts exactly the wrong way of using genetic testing and also precisely the right way of using and interpreting genetic testing. Ultimately, the clinician clinician's long-standing role to meticulously phenotype (characterize) his or her patient and his or her family is what matters most. When the pursuit of the genotype gets in front of the establishment of the phenotype, bad things happen," Dr. Ackerman says. Co-authors are: Jaeger Ackerman, Jamie Kapplinger, David Tester, all of Mayo Clinic; Daniel Bartos, Ph.D., University of Kentucky and University of California, Davis; and Brian Delisle, Ph.D., University of Kentucky. Mayo Clinic is a nonprofit organization committed to medical research and education, and providing expert, whole-person care to everyone who needs healing. For more information, visit or Mayo Clinic Proceedings is a monthly peer-reviewed medical journal that publishes original articles and reviews dealing with clinical and laboratory medicine, clinical research, basic science research and clinical epidemiology. Proceedings is sponsored by the Mayo Foundation for Medical Education and Research as part of its commitment to physician education. It publishes submissions from authors worldwide. The journal has been published for more than 80 years and has a circulation of 130,000. Articles are available at

Collins V.P.,University of Cambridge | Jones D.T.W.,German Cancer Research Center | Giannini C.,Mayo Medical School
Acta Neuropathologica | Year: 2015

Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90 %. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed. © 2015, The Author(s).

Rajkumar S.V.,Rochester College | Gahrton G.,Karolinska Institutet | Bergsagel P.L.,Mayo Medical School
Blood | Year: 2011

In this Perspective, we summarize some of the most contentious issues surrounding diagnosis and treatment of myeloma. We outline how a fundamental clash of philosophies, cure versus control, may be at the heart of many of the controversies. From the very definition of the disease to risk stratification to the validity of current clinical trial endpoints, we highlight the major areas of debate and provide alternative viewpoints that have implications for trial design and interpretation, as well as clinical practice. © 2011 by The American Society of Hematology.

Halliday G.M.,University of New South Wales | Holton J.L.,University College London | Revesz T.,University College London | Dickson D.W.,Mayo Medical School
Acta Neuropathologica | Year: 2011

Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype. © 2011 Springer-Verlag.

Hawley J.A.,Australian Catholic University | Hawley J.A.,Liverpool John Moores University | Hargreaves M.,University of Melbourne | Joyner M.J.,Mayo Medical School | And 2 more authors.
Cell | Year: 2014

Exercise represents a major challenge to whole-body homeostasis provoking widespread perturbations in numerous cells, tissues, and organs that are caused by or are a response to the increased metabolic activity of contracting skeletal muscles. To meet this challenge, multiple integrated and often redundant responses operate to blunt the homeostatic threats generated by exercise-induced increases in muscle energy and oxygen demand. The application of molecular techniques to exercise biology has provided greater understanding of the multiplicity and complexity of cellular networks involved in exercise responses, and recent discoveries offer perspectives on the mechanisms by which muscle "communicates" with other organs and mediates the beneficial effects of exercise on health and performance. ©2014 Elsevier Inc.

Weiss R.M.,University of Iowa | Miller J.D.,Mayo Medical School | Heistad D.D.,University of Iowa
Circulation Research | Year: 2013

Studies in vitro and in vivo continue to identify complex-regulated mechanisms leading to overt fibrocalcific aortic valve disease (FCAVD). Assessment of the functional impact of those processes requires careful studies of models of FCAVD in vivo. Although the genetic basis for FCAVD is unknown for most patients with FCAVD, several disease-associated genes have been identified in humans and mice. Some gene products which regulate valve development in utero also protect against fibrocalcific disease during postnatal aging. Valve calcification can occur via processes that resemble bone formation. But valve calcification can also occur by nonosteogenic mechanisms, such as formation of calcific apoptotic nodules. Anticalcific interventions might preferentially target either osteogenic or nonosteogenic calcification. Although FCAVD and atherosclerosis share several risk factors and mechanisms, there are fundamental differences between arteries and the aortic valve, with respect to disease mechanisms and responses to therapeutic interventions. Both innate and acquired immunity are likely to contribute to FCAVD. Angiogenesis is a feature of inflammation, but may also contribute independently to progression of FCAVD, possibly by actions of pericytes that are associated with new blood vessels. Several therapeutic interventions seem to be effective in attenuating the development of FCAVD in mice. Therapies which are effective early in the course of FCAVD, however, are not necessarily effective in established disease. © 2013 American Heart Association, Inc.

Joyner M.J.,Mayo Medical School | Joyner M.J.,University of Iowa | Casey D.P.,Mayo Medical School | Casey D.P.,University of Iowa
Physiological Reviews | Year: 2015

This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans. © 2015 the American Physiological Society.

Joyner M.J.,Mayo Medical School | Casey D.P.,University of Iowa
Journal of Applied Physiology | Year: 2014

Blood flow increases to exercising skeletal muscle, and this increase is driven primarily by vasodilation in the contracting muscles. When oxygen delivery to the contracting muscles is altered by changes in arterial oxygen content, the magnitude of the vasodilator response to exercise changes. It is augmented during hypoxia and blunted during hyperoxia. Because the magnitude of the increased vasodilation during hypoxic exercise tends to keep oxygen delivery to the contracting muscles constant, we have termed this phenomenon "compensatory vasodilation." In a series of studies, we have explored metabolic, endothelial, and neural mechanisms that might contribute to compensatory vasodilation. These include the contribution of vasodilating substances like nitric oxide (NO) and adenosine, along with altered interactions between sympathetic vasoconstriction and metabolic vasodilation. We have also compared the compensatory vasodilator responses to hypoxic exercise with those seen when oxygen delivery to contracting muscles is altered by acute reductions in perfusion pressure. A synthesis of our findings indicate that NO contributes to the compensatory dilator responses during both hypoxia and hypoperfusion, while adenosine appears to contribute only during hypoperfusion. During hypoxia, the NO-mediated component is linked to a ß-Adrenergic receptor mechanism during lower intensity exercise, while another source of NO is engaged at higher exercise intensities. There are also subtle interactions between a-Adrenergic vasoconstriction and metabolic vasodilation that influence the responses to hypoxia, hyperoxia, and hypoperfusion. Together our findings emphasize both the tight linkage of oxygen demand and supply during exercise and the redundant nature of the vasomotor responses to contraction. Copyright © 2014 the American Physiological Society.

Agency: Department of Defense | Branch: Defense Advanced Research Projects Agency | Program: STTR | Phase: Phase I | Award Amount: 100.00K | Year: 2012

Emergency departments, trauma centers, and military field physicians have a critical need for a simple, easy-to-use, and reliable method of monitoring the onset of hemorrhagic shock that is able to predict onset during the compensatory phase, before syncope and cardiac collapse signaled by a rapid drop in blood pressure. In collaboration with Dr. Michael Joyner"s laboratory at the Mayo Clinic, RMD is developing a near infrared capillary blood flow measurement system (CapFlowTM), based upon diffuse correlation spectroscopy (DCS), that will predict shock onset. In its final configuration this will be a small innocuous patch that wirelessly communicates with a remote station and noninvasively monitors physiological status, assessing soldier health either in the field or in an emergency/ triage setting. Using the lower body negative pressure model in humans in Phase I we will: 1. provide proof-of-principle of the value of using DCS blood flow measurement as a shock predictor; 2. determine the depth beneath the skin where blood flow correlates most strongly with cardiac output; and 3. determine the"best"site for attaching the DCS probe to the skin.

Brinjikji W.,Mayo Medical School | Murad M.H.,Center for Science of Healthcare Delivery | Lanzino G.,Mayo Medical School | Cloft H.J.,Mayo Medical School | Kallmes D.F.,Mayo Medical School
Stroke | Year: 2013

BACKGROUND AND PURPOSE - : Flow diverters are important tools in the treatment of intracranial aneurysms. However, their impact on aneurysmal occlusion rates, morbidity, mortality, and complication rates is not fully examined. METHODS - : We conducted a systematic review of the literature searching multiple databases for reports on the treatment of intracranial aneurysms with flow-diverter devices. Random effects meta-analysis was used to pool outcomes of aneurysmal occlusion rates at 6 months, and procedure-related morbidity, mortality, and complications across studies. RESULTS - : A total of 29 studies were included in this analysis, including 1451 patients with 1654 aneurysms. Aneurysmal complete occlusion rate was 76% (95% confidence interval [CI], 70%-81%). Procedure-related morbidity and mortality were 5% (95% CI, 4%-7%) and 4% (95% CI, 3%-6%), respectively. The rate of postoperative subarachnoid hemorrhage was 3% (95% CI, 2%-4%). Intraparenchymal hemorrhage rate was 3% (95% CI, 2%-4%). Perforator infarction rate was 3% (95% CI, 1%-5%), with significantly lower odds of perforator infarction among patients with anterior circulation aneurysms compared with those with posterior circulation aneurysms (odds ratio, 0.01; 95% CI, 0.00-0.08; P<0.0001). Ischemic stroke rate was 6% (95% CI, 4%-9%), with significantly lower odds of perforator infarction among patients with anterior circulation aneurysms compared with those with posterior circulation aneurysms (odds ratio, 0.15; 95% CI, 0.08-0.27; P<0.0001). CONCLUSIONS - : This meta-analysis suggests that treatment of intracranial aneurysms with flow-diverter devices is feasible and effective with high complete occlusion rates. However, the risk of procedure-related morbidity and mortality is not negligible. Patients with posterior circulation aneurysms are at higher risk of ischemic stroke, particularly perforator infarction. These findings should be considered when considering the best therapeutic option for intracranial aneurysms. © 2013 American Heart Association, Inc.

Neunert C.,University of Texas Southwestern Medical Center | Lim W.,McMaster University | Crowther M.,Worcestershire Royal Hospital | Cohen A.,Children's Hospital of Philadelphia | And 2 more authors.
Blood | Year: 2011

Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality - interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of "front-line" therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention. © 2011 by The American Society of Hematology.

McMurray C.T.,Lawrence Berkeley National Laboratory | McMurray C.T.,Molecular Therapeutics | McMurray C.T.,Mayo Medical School
Nature Reviews Genetics | Year: 2010

Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the gender of the parent who transmits the repeats. Repair and replication models for expansions have been described, but we do not know whether the pathway involved is the same under all conditions and for all repeat tract lengths, which differ among diseases. Currently, researchers rely on bacteria, yeast and mice to study expansion, but these models differ substantially from humans. We need now to connect the dots among human genetics, pathway biochemistry and the appropriate model systems to understand the mechanism of expansion as it occurs in human disease. © 2010 Macmillan Publishers Limited. All rights reserved.

Cil A.,University of Missouri - Kansas City | Sperling J.W.,Mayo Medical School | Cofield R.H.,Mayo Medical School
Journal of Shoulder and Elbow Surgery | Year: 2014

Background: Glenoid bone deficiencies may be addressed by specialized components. The purpose of this study is to evaluate the clinical and radiographic outcomes of 3 different types of nonstandard glenoid components. Materials and methods: Thirty-eight patients with a mean age of 65years (range, 34-84years) underwent a primary or revision anatomic shoulder arthroplasty with one of 3 nonstandard glenoid components: apolyethylene component with an angled keel for posterior glenoid wear without posterior subluxation; a polyethylene component with 2mm of extra thickness for central glenoid erosion; or a posteriorly augmented metal-backed glenoid component for posterior glenoid wear and posterior subluxation. Average clinical follow-up was 7.3years (range, 2-19years) or until revision surgery. Results: At the most recent follow-up, 24 patients had no, mild, or occasionally moderate pain. Mean elevation improved from 91° to 126°, and mean external rotation improved from 24° to 53°. Thirteen patients had moderate or severe subluxation preoperatively, and 11 had subluxation at follow-up. On radiographic evaluation, 3 glenoid components had loosened and 3 were at risk for loosening at an average 5.5years of follow-up. Seven patients had revision surgery: 4 for instability, 1 for osteolysis, 1 for component loosening with osteolysis, and 1 for a periprosthetic fracture. Three additional patients had removal of glenoid components, 2 for infection and 1 for loosening. Ten-year survival rate free of revision or removal of the angled keel component was 73% (95% CI: 75.3-70.7); of the extra thick (+2mm) component, 69% (95% CI: 65-73); and of the posteriorly augmented metal-backed glenoid component, 31% (95% CI: 35.6-26.4). Conclusions: The effectiveness of nonstandard glenoid components in addressing glenoid bone deficiencies is compromised by an increased rate of component loosening and by only partial success in eliminating subluxation. © 2014 Journal of Shoulder and Elbow Surgery Board of Trustees.

Katoh H.,Arizona State University | Wang D.,Arizona State University | Daikoku T.,Cincinnati Childrens Research Foundation | Sun H.,Arizona State University | And 3 more authors.
Cancer Cell | Year: 2013

A large body of evidence indicates that chronic inflammation is one of several key risk factors for cancer initiation, progression, and metastasis. However, the underlying mechanisms responsible for the contribution of inflammation and inflammatory mediators to cancer remain elusive. Here, we present genetic evidence that loss of CXCR2 dramatically suppresses chronic colonic inflammation and colitis-associated tumorigenesis through inhibiting infiltration of myeloid-derived suppressor cells (MDSCs) into colonic mucosa and tumors in a mouse model of colitis-associated cancer. CXCR2 ligands were elevated in inflamed colonic mucosa and tumors and induced MDSC chemotaxis. Adoptive transfer of wild-type MDSCs into Cxcr2-/- mice restored AOM/DSS-induced tumor progression. MDSCs accelerated tumor growth by inhibiting CD8+ Tcell cytotoxic activity. © 2013 Elsevier Inc.

Banks P.A.,Harvard University | Bollen T.L.,St Antonius Hospital | Dervenis C.,Agia Olga Hospital | Gooszen H.G.,Radboud University Nijmegen | And 4 more authors.
Gut | Year: 2013

Background and objective: The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the disease make a revision necessary. Methods: A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained. Results: The revised classi fication of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images. Conclusions: This international, web-based consensus provides clear de finitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption.

Johnson J.N.,Mayo Medical School | Ackerman M.J.,Mayo Medical School | Ackerman M.J.,Molecular Therapeutics
British Journal of Sports Medicine | Year: 2013

Background Competitive sports participation for athletes with congenital long QT syndrome (LQTS) is guided by the 2005 36th Bethesda Conference and the 2005 European Society of Cardiology (ESC) guidelines. The purpose of this study was to determine the prevalence and outcomes of patients with LQTS who chose to remain athletes following their diagnosis. Methods Records of all patients between 6 and 40 years of age who were first evaluated in Mayo Clinic's LQTS Clinic from July 2000 to November 2010 were reviewed, for documentation of athletic participation after LQTS diagnosis and LQTS-related events during follow-up. Average follow-up was 5.5±3.4 years. Results The cohort included 353 patients with LQTS (199 females, mean age 17±11 years, mean QTc 472 ±42 ms), of whom 182 had LQT1, 130 had LQT2, 37 had LQT3 and 4 had multiple LQTS mutations. The majority of patients (223, 63%) were either not involved in sports (88%) or chose to discontinue sports (12%) following evaluation. 130 patients (37%, 60 females, mean age 11±7 years, mean QTc 471±46 ms) remained in competitive athletics, including 20 with implantable cardioverter defibrillators (ICDs). Of these 130, 70 (54%) were genotype-positive/phenotype-negative and competing contrary to ESC guidelines but within the Bethesda guidelines. None of these athletes had a sportrelated event. Of the 60 LQTS athletes continuing in sports contrary to both the Bethesda and ESC guidelines (genotype-positive/phenotype-positive), only one had a sporting-related event with appropriate ICD shock. Conclusions Athletes and their families are fully capable of self-disqualification. Among those athletes with LQTS who chose to remain in competitive sports, a low rate of cardiac events and no deaths were observed in over 650 athlete-years of follow-up. Current guidelinebased recommendations for disqualification may be excessive for this disease.

Holmes D.R.,Mayo Medical School | Kar S.,Cedars Sinai Medical Center | Price M.J.,Scripps Research Institute | Whisenant B.,Intermountain Medical Center | And 4 more authors.
Journal of the American College of Cardiology | Year: 2014

BACKGROUND: In the PROTECT AF (Watchman Left Atrial Appendage Closure Technology for Embolic Protection in Patients With Atrial Fibrillation) trial that evaluated patients with nonvalvular atrial fibrillation (NVAF), left atrial appendage (LAA) occlusion was noninferior to warfarin for stroke prevention, but a periprocedural safety hazard was identified. OBJECTIVES: The goal of this study was to assess the safety and efficacy of LAA occlusion for stroke prevention in patients with NVAF compared with long-term warfarin therapy. METHODS: This randomized trial further assessed the efficacy and safety of the Watchman device. Patients with NVAF who had a CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and previous stroke/transient ischemic attack) score ≥2 or 1 and another risk factor were eligible. Patients were randomly assigned (in a 2:1 ratio) to undergo LAA occlusion and subsequent discontinuation of warfarin (intervention group, n = 269) or receive chronic warfarin therapy (control group, n = 138). Two efficacy and 1 safety coprimary endpoints were assessed. RESULTS: At 18 months, the rate of the first coprimary efficacy endpoint (composite of stroke, systemic embolism [SE], and cardiovascular/unexplained death) was 0.064 in the device group versus 0.063 in the control group (rate ratio 1.07 [95% credible interval (CrI): 0.57 to 1.89]) and did not achieve the prespecified criteria noninferiority (upper boundary of 95% CrI ≥1.75). The rate for the second coprimary efficacy endpoint (stroke or SE >7 days' postrandomization) was 0.0253 versus 0.0200 (risk difference 0.0053 [95% CrI: -0.0190 to 0.0273]), achieving noninferiority. Early safety events occurred in 2.2% of the Watchman arm, significantly lower than in PROTECT AF, satisfying the pre-specified safety performance goal. Using a broader, more inclusive definition of adverse effects, these still were lower in PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial than in PROTECT AF (4.2% vs. 8.7%; p = 0.004). Pericardial effusions requiring surgical repair decreased from 1.6% to 0.4% (p = 0.027), and those requiring pericardiocentesis decreased from 2.9% to 1.5% (p = 0.36), although the number of events was small. CONCLUSIONS: In this trial, LAA occlusion was noninferior to warfarin for ischemic stroke prevention or SE >7 days' post-procedure. Although noninferiority was not achieved for overall efficacy, event rates were low and numerically comparable in both arms. Procedural safety has significantly improved. This trial provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have an absolute contraindication to short-term warfarin therapy. © 2014 by the American College of Cardiology Foundation.

Giudicessi J.R.,Mayo Medical School | Ackerman M.J.,Molecular Therapeutics
Current Opinion in Cardiology | Year: 2013

PURPOSE OF REVIEW: In this review, we summarize the basic principles governing rare variant interpretation in the heritable cardiac arrhythmia syndromes, focusing on recent advances that have led to disease-specific approaches to the interpretation of positive genetic testing results. RECENT FINDINGS: Elucidation of the genetic substrates underlying heritable cardiac arrhythmia syndromes has unearthed new arrhythmogenic mechanisms and given rise to a number of clinically meaningful genotype-phenotype correlations. As such, genetic testing for these disorders now carries important diagnostic, prognostic, and therapeutic implications. Recent large-scale systematic studies designed to explore the background genetic 'noise' rate associated with these genetic tests have provided important insights and enhanced how positive genetic testing results are interpreted for these potentially lethal, yet highly treatable, cardiovascular disorders. SUMMARY: Clinically available genetic tests for heritable cardiac arrhythmia syndromes allow the identification of potentially at-risk family members and contribute to the risk-stratification and selection of therapeutic interventions in affected individuals. The systematic evaluation of the 'signal-to-noise' ratio associated with these genetic tests has proven critical and essential to assessing the probability that a given variant represents a rare pathogenic mutation or an equally rare, yet innocuous, genetic bystander. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.5-2 | Award Amount: 7.76M | Year: 2010

This proposal builds on existing expertise and collaborations of a multidisciplinary Consortium of basic scientists and clinical investigators each of whom has made a substantial individual contribution to understanding the links between infection and autoimmunity. The aim of the INTRICATE Consortium is to prosecute a programme of Translational Research that deliniates the role of infection in the induction and perpetuation of severe systemic autoimmune disease with the ultimate object of identifying new therapeutic strategies based on knowledge of pathogenesis. Our strategy will systematically analyse the complex and diverse processes involved in a model human disease: - Anti-neutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AAV). AAV is ideally suited because it is known to be caused by autoantibodies of defined specificity and second because it is strongly linked to infection to infection. INTRICATE will use mouse models to answer the specific question whether infection with clinically relevant bacteria induces autoimmune disease in transgenic mice that express the human autoantigen. The use of novel high-throughput antigen array technology in well-characterized patient cohorts and analysis of microbial and host specific mechanisms combined with genome wide association study (GWAS) will determine whether dysbiosis or infection with specific microorganisms triggers the induction or re-activation of AAV. Unraveling the pathogenic processes that are responsible for this chronic autoimmune disease and the knowledge gained will lead to the development of novel preventive and therapeutic strategies.

News Article | December 1, 2016

ROCHESTER, Minn. -- One in 10 patients who come to the hospital with the most severe type of heart attack have a history of cancer, showing that this is an emerging subgroup of heart patients, according to Mayo Clinic research published in Mayo Clinic Proceedings. In addition, the study found that these patients have a three times higher risk of noncardiac death. Meanwhile, their risk of cardiac death is not higher ? both at the time of their acute heart attack and over long-term follow-up. Researchers conducted a retrospective cohort study of 2,346 patients seen at Mayo Clinic's Rochester campus for an ST-elevation myocardial infarction ? the most severe acute heart attack. The retrospective covered a 10-year timeframe, beginning in 2000, when the newest and current types of stents were introduced into clinical practice. The patients were followed for acute and long-term outcomes for an average of six years. "We've watched cancer survivorship increase over the past 2½ decades, which is wonderful, but it has led to new challenges, such as handling of downstream illnesses and side effects to an extent never encountered before," says Joerg Herrmann, M.D., senior author and interventional cardiologist at Mayo Clinic. "In particular, as cardiologists, we wanted to know if cancer and its therapies left these patients debilitated from a cardiovascular disease standpoint." "This study supports the importance of cardiologists and oncologists working together to care for these patients," Dr. Herrmann says. "Clearly, our goal is that the cancer patients of today do not become the cardiac patients of the future and, if they do, that we comprehensively see them through." This concept of care, which has become known as "cardio-oncology," is an emerging medical discipline. Mayo Clinic Proceedings is a monthly peer-reviewed medical journal that publishes original articles and reviews dealing with clinical and laboratory medicine, clinical research, basic science research, and clinical epidemiology. Mayo Clinic Proceedings is sponsored by the Mayo Foundation for Medical Education and Research as part of its commitment to physician education. It publishes submissions from authors worldwide. The journal has been published for more than 80 years and has a circulation of 130,000. Articles are available at http://www. . Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

News Article | November 18, 2016

ROCHESTER, Minn. -- Researchers at Mayo Clinic have been documenting the rise and costs of physician burnout for more than a decade. Now, they are proposing nine strategies that health care organizations can use to reverse the trend and limit the risk to patients and their medical staff. Tait Shanafelt, M.D., director of Mayo Clinic's Program on Physician Well-being, and John Noseworthy, M.D., president and CEO, Mayo Clinic, offer the nine-point plan in the current issue of Mayo Clinic Proceedings. "Research has shown that more than half of U.S. physicians are experiencing symptoms of burnout, and the rate is increasing," says Dr. Shanafelt, first author of the article. "Unfortunately, many organizations see burnout as a personal problem to be addressed by the individual physician. It is clear, however, that burnout is a system issue, and addressing it is the shared responsibility of both the individuals and health care organizations." "The reasons we need to reverse this trend in physician burnout are compelling," says Dr. Noseworthy. "Professional exhaustion and disillusionment can adversely impact clinical performance, and result in medical errors and decreased quality of care. This situation hurts patients and providers, and we need to fix it." The organizational impact of physician burnout can include lower productivity, staff turnover, decreased quality of care and malpractice suits. For the individual physician, burnout can lead to broken relationships, alcoholism and suicide. The nine strategies suggest organizations should begin to resolve burnout by: The article details how these strategies have been applied at Mayo Clinic and their effect on physician burnout. The authors conclude that "deliberate, sustained and comprehensive efforts by the organization to reduce burnout and promote engagement can make a difference". The article ends with a clear challenge that there is much work to be done to address the problem of physician burnout nationally. The work was funded by the Mayo Clinic Program on Physician Well-Being. Mayo Clinic Proceedings is a monthly peer-reviewed medical journal that publishes original articles and reviews dealing with clinical and laboratory medicine, clinical research, basic science research and clinical epidemiology. Proceedings is sponsored by the Mayo Foundation for Medical Education and Research as part of its commitment to physician education. It publishes submissions from authors worldwide. The journal has been published for more than 80 years and has a circulation of 130,000. Articles are available at Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

News Article | November 2, 2016

ROCHESTER, Minn. -- Mayo Clinic nephrologists have uncovered a connection between first-time kidney stone formers and chronic kidney disease. In a paper published today in Mayo Clinic Proceedings, researchers announce a persistent decline in kidney functioning following an individual's first case of kidney stones. A Mayo Clinic team led by William Haley, M.D., and Andrew Rule, M.D., assessed a group of 384 stone formers three months after their first stone event to study the effect of kidney stones on their kidney function. Compared to the control group, kidney stone formers maintained higher levels of the blood marker cystatin C and higher levels of urine protein ? both of which are connected with higher risk of chronic kidney disease. "Even after adjusting for other risk factors, including urine chemistries, hypertension and obesity, we still found that those with a kidney stone episode had subsequent abnormal kidney function," says Dr. Rule. "This helps us better understand the long-term implications of kidney stones beyond recovery time." Kidney stones affect just over 7 percent of adults, and that number has been on the rise. Though previous studies have identified a long-term risk of chronic kidney disease in kidney stone formers, prior research has not assessed kidney function immediately after their first stone event. The small, hard mineral deposits that characterize kidney stones can cause severe pain, nausea and difficulty passing urine. An increased risk of chronic kidney disease, however, could make the condition one that has a more long-term impact on an individual's health. "This research shows that the implications of kidney stones may go beyond the discomfort they are so often associated with," says Dr. Rule. "Prevention of kidney stones may be beneficial for a person's overall kidney health." In addition to Drs. Haley and Rule, other authors are: Mayo Clinic Proceedings is a monthly peer-reviewed medical journal that publishes original articles and reviews dealing with clinical and laboratory medicine, clinical research, basic science research, and clinical epidemiology. Mayo Clinic Proceedings is sponsored by the Mayo Foundation for Medical Education and Research as part of its commitment to physician education. It publishes submissions from authors worldwide. The journal has been published for more than 80 years and has a circulation of 130,000. Articles are available at Mayo Clinic is a nonprofit organization committed to medical research and education, and providing expert, whole-person care to everyone who needs healing. For more information, visit or

News Article | November 28, 2016

ROCHESTER, Minn. -- Walking is a milestone in development for toddlers, but it's actually only one part of the complex cognitive task known as gait that includes everything from a person's stride length to the accompanying swing of each arm. A Mayo Clinic study recently published in the Journal of Alzheimer's Disease found that problems associated with gait can predict a significant decline in memory and thinking. Using the Rochester Epidemiology Project, Mayo Clinic researchers examined medical records of Olmsted County, Minnesota, residents, who were between ages 70 to 89 as of Oct. 1, 2004. The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging who had a complete gait and neuropsychological assessment. Alterations in several gait parameters were associated with decline in memory, thinking and language skills, and visual perception of the spatial relationship of objects. The study results also supported the role of computerized analysis because the computer tool detected modifications before impairment was detected with a standard neuropsychological test. "The presence of gait disturbances increases with advancing age and affects the independence of daily living, especially in the elderly," says neurologist Rodolfo Savica, M.D., lead author on the study. "Computerized gait analysis is a simple, noninvasive test that potentially could be used to identify patients at high risk for cognitive decline and to target appropriate therapies." Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit or

Miller D.V.,University of Utah | Maleszewski J.J.,Mayo Medical School
Clinical and Experimental Rheumatology | Year: 2011

Vasculitis affecting large elastic arteries, including the aorta and major proximal branches, encompasses various diseases including Takayasu arteritis, giant cell (or temporal) arteritis, and tertiary syphilis, but also may occur as a rare complication of Behçet's disease, rheumatoid arthritis, sarcoidosis, Cogan syndrome, Kawasaki disease, ankylosing spondylitis, systemic lupus erythematosus and Wegener's granulomatosis. Recent reports have also established a link between inflammatory abdominal aortic aneurysm as well as lymphoplasmacytic thoracic aortitis with an overabundance of IgG4-producing plasma cells and the burgeoning constellation of "Hyper-IgG4" syndromes. This review focuses on morphologic aspects of large-vessel vasculitis pathology associated with giant cell arteritis, Takayasu arteritis, idiopathic or isolated aortitis, lymphoplasmacytic thoracic and ascending aortitis, and the inflammatory aneurysm/retroperitoneal fibrosis syndrome. © Copyright Clinical and Experimental Rheumatology 2011.

Nemeth S.A.,Mayo Medical School | Lawrence N.,Cooper University Hospital
Journal of the American Academy of Dermatology | Year: 2012

Background: Previous single-institution studies have shown that patients and physicians struggle to identify biopsy sites requiring surgery on the day of treatment. To date no studies have been done to assess if this is a widespread challenge faced by many dermatologic surgeons. Objective: We sought to determine if site identification is an issue among Mohs surgeons, and to determine which practice environments have the best supplementary data available to surgeons for site localization. Methods: We conducted an online survey of 722 members of the American College of Mohs Surgery inquiring about site identification and documentation typically received from referring physicians. Results: Of 325 surveys completed (45% response rate), 71% reported that more than 5% of their patients have difficulty identifying their surgery site. The majority (89%) responded that a photograph is most useful for identifying biopsy sites. Surgeons in academic centers and multispecialty group practices were more likely to receive a photograph versus those in private practice. Limitations: Individual survey responses may be subject to recall bias. Conclusion: Difficulty identifying biopsy sites needing surgery is a common challenge faced by Mohs surgeons. The majority of Mohs surgeons surveyed find photographs the most useful documentation for decreasing the risk of wrong-site dermatologic surgery. © 2011 by the American Academy of Dermatology, Inc.

Sagar P.M.,General Infirmary at Leeds | Pemberton J.H.,Mayo Medical School
British Journal of Surgery | Year: 2012

Background: Proctocolectomy with ileal pouch-anal anastomosis (IPAA) has been developed and refined since its introduction in the late 1970s. Nonetheless, it is a procedure associated with significant morbidity. The aim of this review was to provide a structured approach to the challenges that surgeons and physicians encounter in the management of intraoperative, postoperative and reoperative problems associated with ileoanal pouches. Methods: The review was based on relevant studies identified from an electronic search of MEDLINE, Embase and PubMed databases from 1975 to April 2011. There were no language or publication year restrictions. Original references in published articles were reviewed. Results: Although the majority of patients experience long-term success with an ileoanal pouch, significant morbidity surrounds IPAA. Surgical intervention is often critical to achieve optimal control of the situation. Conclusion: A structured management plan will minimize the adverse consequences of the problems associated with pouches. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Desy N.M.,McGill University | Spinner R.J.,Mayo Medical School
Journal of Vascular Surgery | Year: 2014

Background Cystic adventitial disease (CAD) is a rare condition that affects arteries and veins. The etiology remains controversial and several treatment methods have been described. By understanding the pathogenesis of CAD, we can improve the surgical treatment, reduce recurrence rates, and improve patient outcomes. The objective of this study was to perform a systematic review of the world's literature. Methods We searched across multiple scientific databases and cross-referenced each article to collect the world's literature on CAD. Studies included were those that reported a case or case series of CAD. Each article was analyzed for site of CAD, patient demographic data, type of imaging, surgical management, presence of a joint connection on imaging or at surgery, and recurrences. A regression analysis was used to identify risk factors for cyst recurrence. Results We identified 503 reports (724 patients), which were included in our analysis. The most common vessel affected was the popliteal artery with 587 cysts. The mean age was 46 (range, 5-80) years with a male-to-female ratio of approximately 4:1. Magnetic resonance imaging (MRI) or angiography was performed for 182 cysts and conventional angiography was the most advanced imaging modality used in 355 patients who did not receive a MRI or computed tomography scan as part of their assessment. Multiple types of surgical interventions were reported with the most common being cyst resection and saphenous vein graft reconstruction (204 cases). There were 122 joint connections (17%) identified. Sixty-five patients (9%) developed at least one cyst recurrence or persistence. Percutaneous surgery (aspiration or angioplasty) was found to be a risk factor for cyst recurrence (odds ratio, 13.7; 95% confidence interval, 6.5-29.0; P <.0001). Because of the rarity of this condition, publications were limited to level IV evidence consisting of case series and case reports. Several reports had short or no follow-up and few patients had postoperative MRI. These limitations likely underestimate the true rate of cyst recurrence or persistence. Conclusions This article provides a comprehensive review of the world's literature on CAD, which can serve as a baseline for future studies. When analyzed in the context of the literature, this systematic review supplies further evidence that CAD adheres to the articular (synovial) theory. We believe that knowledge of these joint connections can simplify treatment, reduce recurrence rates, and improve patient outcomes.

Leissring M.A.,Mayo Medical School | Turner A.J.,University of Leeds
Alzheimer's Research and Therapy | Year: 2013

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder characterized by extracellular and intracellular deposition of the amyloid β-protein (Aβ). The study of rare, familial forms of AD has shown that sustained elevations in the production of Aβ (either all forms or specific pathogenic variants thereof) are sufficient to trigger the full spectrum of cognitive and histopathological features of the disease. Although the exact cause or causes remain unknown, emerging evidence suggests that impairments in the clearance of Aβ, after it is produced, may underlie the vast majority of sporadic AD cases. This review focuses on Aβ-degrading proteases (AβDPs), which have emerged as particularly important mediators of Aβ clearance. A wide variety of proteases that - by virtue of their particular regional and subcellular localization profiles - define distinct pools of Aβ have been identified. Different pools of Aβ, in turn, may contribute differentially to the pathogenesis of the disease. The study of individual AβDPs, therefore, promises to offer new insights into the mechanistic basis of AD pathogenesis and, ultimately, may facilitate the development of effective methods for its prevention or treatment or both. © 2013 BioMed Central Ltd.

Lobel D.A.,Cleveland Clinic | Lee K.H.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2014

Functional restoration of limb movement after traumatic spinal cord injury (SCI) remains the ultimate goal in SCI treatment and directs the focus of current research strategies. To date, most investigations in the treatment of SCI focus on repairing the injury site. Although offering some promise, these efforts have met with significant roadblocks because treatment measures that are successful in animal trials do not yield similar results in human trials. In contrast to biologic therapies, there are now emerging neural interface technologies, such as brain machine interface (BMI) and limb reanimation through electrical stimulators, to create a bypass around the site of the SCI. The BMI systems analyze brain signals to allow control of devices that are used to assist SCI patients. Such devices may include a computer, robotic arm, or exoskeleton. Limb reanimation technologies, which include functional electrical stimulation, epidural stimulation, and intraspinal microstimulation systems, activate neuronal pathways below the level of the SCI. We present a concise review of recent advances in the BMI and limb reanimation technologies that provides the foundation for the development of a bypass system to improve functional outcome after traumatic SCI. We also discuss challenges to the practical implementation of such a bypass system in both these developing fields. © 2014 Mayo Foundation for Medical Education and Research.

Singal A.K.,University of Alabama | Kamath P.S.,University of Alabama | Tefferi A.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2013

The prevalence of mesenteric venous thrombosis has increased over the past 2 decades with the routine use of contrast-enhanced computed tomography (CT) in patients presenting with abdominal pain and those with portal hypertension. Concurrent with increasing recognition, routine and frequent use of anticoagulation has reduced the need for surgical intervention and improved outcome in these patients. Acute thrombosis often presents with abdominal pain, whereas chronic disease manifests either as an incidental finding on CT or with features of portal hypertension. Contrast-enhanced CT diagnoses about 90% of cases. The presence of collateral circulation and cavernoma around a chronically thrombosed vein differentiates chronic from acute disease. The superior mesenteric vein is often involved, whereas involvement of the inferior mesenteric vein is rare. Associated portal venous thrombosis can be seen if the disease originates in the major veins instead of the small vena rectae. Thrombophilia and local abdominal inflammatory conditions are common causes. Management is aimed at preventing bowel infarction and recurrent thrombosis. Anticoagulation, the mainstay of management, has also been safely used in patients with cirrhosis and portal hypertension. This review discusses the pathogenesis of thrombosis of mesenteric veins, the diagnosis and differentiation from arterial ischemia, the emergence of the JAK2 (Janus kinase 2) sequence variation as a marker of thrombophilia and myelodysplastic neoplasms, and new anticoagulants. Algorithms for the management of acute and chronic mesenteric venous thrombosis are provided to help readers understand and remember the approach to the management of acute and chronic mesenteric venous thrombosis. © 2013 Mayo Foundation for Medical Education and Research.

Mackenzie I.R.A.,Vancouver General Hospital | Rademakers R.,Mayo Medical School | Neumann M.,University of Zürich
The Lancet Neurology | Year: 2010

Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies. © 2010 Elsevier Ltd.

Katzka D.A.,Mayo Medical School | Castell D.O.,Medical University of South Carolina
Alimentary Pharmacology and Therapeutics | Year: 2011

Background Pneumatic dilation has re-emerged as a first line treatment for achalasia, but conclusions are limited by the relatively small numbers of patients studied and the lack of long term follow-up. Aim To summarise and analyse 29 available studies evaluating pneumatic dilation for achalasia with focus on efficacy, rate or perforation and dilation technique. Methods A literature search for all studies, in which pneumatic dilation was performed for treatment of achalasia, was conducted. Studies, in which clear endpoints of efficacy of single dilation sessions over a period of years, were chosen. Results The response for a single dilation session was 66% at 1 year and 59, 53, 50 and 25% at 2, 3, 5 and 10 years respectively. Use of a Rigiflex dilator and multiple dilations during the initial treatment improved efficacy. Overall perforation rate was only 2% (24/1358) of which only 1% required surgery. Use of multiple dilations led to increased perforation risk. The method of dilation used with regard to balloon size, pressure used, dilation times and single or multiple dilations varied in almost every study. Conclusions Pneumatic dilation is safer than commonly thought and efficacious, although multiple dilations will be needed over a lifetime in most patients. Standardisation of the technique should be attempted. © 2011 Blackwell Publishing Ltd.

Rosado F.G.N.,Mayo Medical School | Kim A.S.,Vanderbilt University
American Journal of Clinical Pathology | Year: 2013

Hemophagocytic lymphohistiocytosis (HLH) is a frequently fatal and likely underdiagnosed disease involving a final common pathway of hypercytokinemia, which can result in end-organ damage and death. Although an early diagnosis is crucial to decrease mortality, the definitive diagnosis is often challenging because of the lack of specificity of currently accepted diagnostic criteria and the absence of confirmatory gold standards. Because of the wide range of laboratory assays involved in the diagnosis of HLH, practicing pathologists from a broad spectrum of clinical specialties need to be aware of the disease so that they may appropriately flag results and convey them to their clinical counterparts. Our article summarizes these new advances in the diagnosis of HLH and includes a review of clinical findings, updated understanding of the pathogenesis, and promising new testing methods. © American Society for Clinical Pathology.

Camilleri M.,Mayo Medical School | Parkman H.P.,Temple University | Shafi M.A.,University of Houston | Abell T.L.,University of Mississippi | Gerson L.,Stanford University
American Journal of Gastroenterology | Year: 2013

This guideline presents recommendations for the evaluation and management of patients with gastroparesis. Gastroparesis is identified in clinical practice through the recognition of the clinical symptoms and documentation of delayed gastric emptying. Symptoms from gastroparesis include nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain. Management of gastroparesis should include assessment and correction of nutritional state, relief of symptoms, improvement of gastric emptying and, in diabetics, glycemic control. Patient nutritional state should be managed by oral dietary modifications. If oral intake is not adequate, then enteral nutrition via jejunostomy tube needs to be considered. Parenteral nutrition is rarely required when hydration and nutritional state cannot be maintained. Medical treatment entails use of prokinetic and antiemetic therapies. Current approved treatment options, including metoclopramide and gastric electrical stimulation (GES, approved on a humanitarian device exemption), do not adequately address clinical need. Antiemetics have not been specifically tested in gastroparesis, but they may relieve nausea and vomiting. Other medications aimed at symptom relief include unapproved medications or off-label indications, and include domperidone, erythromycin (primarily over a short term), and centrally acting antidepressants used as symptom modulators. GES may relieve symptoms, including weekly vomiting frequency, and the need for nutritional supplementation, based on open-label studies. Second-line approaches include venting gastrostomy or feeding jejunostomy; intrapyloric botulinum toxin injection was not effective in randomized controlled trials. Most of these treatments are based on open-label treatment trials and small numbers. Partial gastrectomy and pyloroplasty should be used rarely, only in carefully selected patients. Attention should be given to the development of new effective therapies for symptomatic control. © 2013 by the American College of Gastroenterology.

Sagar S.,Mayo Medical School | Liu P.P.,University of Toronto | Cooper Jr. L.T.,Mayo Medical School
The Lancet | Year: 2012

Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression. © 2012 Elsevier Ltd.

Reed D.A.,Mayo Medical School | Fletcher K.E.,Milwaukee Veterans Affairs Medical Center | Arora V.M.,University of Chicago
Annals of Internal Medicine | Year: 2010

Background: The Accreditation Council for Graduate Medical Education's new duty-hour standards limit interns' shifts to 16 hours and night float to 6 consecutive nights. Protected sleep time (that is, "nap") is strongly encouraged. As duty-hour reforms are implemented, examination of the quality and outcomes of the relevant literature is important. Purpose: To systematically review the literature examining shift length, protected sleep time, and night float. Data Sources: MEDLINE, PREMEDLINE, and EMBASE from January 1989 through May 2010. Study Selection: Studies examined the associations of shift length, protected sleep time, or night float with patient care, resident health, and education outcomes among residents in practice settings. Data Extraction: Study quality was measured by using the validated Medical Education Research Study Quality Instrument and the U.S. Preventive Services Task Force criteria. Two investigators independently rated study quality, and interrater agreement was calculated. Data Synthesis: Sixty-four studies met inclusion criteria. Most studies used single-group cross-sectional (19 studies [29.7%]) or prepost (41 studies [64.1%]) designs, and 4 (6.3%) were randomized, controlled trials. Five studies (7.8%) were multi-institutional. Twenty-four of 33 (72.7%) studies examining shift length reported that shorter shifts were associated with decreased medical errors, motor vehicle crashes, and percutaneous injuries. Only 2 studies assessed protected sleep time and reported that residents' adherence to naps was poor. Night floats described in 33 studies involved 5 to 7 consecutive nights. Limitations: Most studies used single-institution, observational designs. Publication bias is likely but difficult to assess in this methodologically weak and heterogeneous body of evidence. Conclusion: For the limited outcomes measured, most studies supported reducing shift length but did not adequately address the optimal shift duration. Studies had numerous methodological limitations and unclear generalizability for most outcomes. Specific recommendations about shift length, protected sleep time, and night float should acknowledge the limitations of this evidence. Primary Funding Source: Accreditation Council for Graduate Medical Education. © 2010 American College of Physicians.

Hart P.A.,Ohio State University | Zen Y.,Kobe University | Chari S.T.,Mayo Medical School
Gastroenterology | Year: 2015

Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that is characterized clinically by frequent presentation with obstructive jaundice, histologically by a dense lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to corticosteroid therapy. Two distinct diseases, type 1 and type 2 AIP, share these features. However, these 2 diseases have unique pancreatic histopathologic patterns and differ significantly in their demographic profiles, clinical presentation, and natural history. Recognizing the popular and long-standing association of the term "AIP" with what is now called "type 1 AIP," we suggest using "AIP" solely for type 1 AIP and to acknowledge its own distinct disease status by using "idiopathic duct-centric chronic pancreatitis" (IDCP) for type 2 AIP. AIP is the pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). The etiopathogenesis of AIP and IgG4-RD is largely unknown. However, the remarkable effectiveness of B-cell depletion therapy with rituximab in patients with AIP and IgG4-RD highlights the crucial role of B cells in its pathogenesis. IDCP is less commonly recognized, and little is known about its pathogenesis. IDCP has no biomarker but is associated with inflammatory bowel disease in ∼25% of patients. Recently, the international consensus diagnostic criteria for AIP identified combinations of features that are diagnostic of both diseases. Both AIP and IDCP are corticosteroid responsive; however, relapses are common in AIP and rare in IDCP. Therefore, maintenance therapy with either an immunomodulator (eg, azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or rituximab is often necessary for patients with AIP. Long-term survival is excellent for both patients with AIP and patients with IDCP. © 2015 AGA Institute.

Baumgartner I.,University of Bern | Lerman L.O.,Mayo Medical School
European Heart Journal | Year: 2011

The diagnosis and management of patients with renovascular disease and hypertension continue to elude healthcare providers. The advent of novel imaging and interventional techniques, and increased understanding of the pathways leading to irreversible renal injury and renovascular hypertension, have ushered in commendable attempts to optimize and finetune strategies to preserve or restore renal function and control blood pressure. Large randomized clinical trials that compare different forms of therapy, and smaller trials that test novel experimental treatments, will hopefully help formulate innovative concepts and tools to manage the patient population with atherosclerotic renovascular disease. © 2011 The Author.

Landmesser U.,University of Zürich | Holmes D.R.,Mayo Medical School
European Heart Journal | Year: 2012

Atrial fibrillation is a frequent cause of stroke; in the elderly, more than 20 of strokes are attributed to this common arrhythmia. Anticoagulation with warfarin reduces the risk of stroke by ∼60; however, a large proportion of patients with atrial fibrillation do not receive this treatment because of relative/absolute contraindications. Moreover, patients often discontinue warfarin for a variety of reasons and chronic warfarin administration rates remain suboptimal. Although the compliance with anticoagulation may improve with novel anticoagulants and bleeding risk can be somewhat reduced when compared with warfarin, there is still a progressive increase in bleeding complications over time. Accordingly, new approaches for stroke prevention in these patients are being explored and tested. In transoesophageal echocardiographic (TEE) studies, more than 90 of thrombi were found in the left atrial appendage (LAA) in non-valvular atrial fibrillation, and transcatheter LAA closure is developed and examined as a novel approach to reduce the risk of stroke in these patients. The PROTECT-AF study provides first evidence from a randomized clinical trial that a strategy of LAA occlusion using the Watchman device can be non-inferior to anticoagulation with warfarin for a combined endpoint in patients with non-valvular atrial fibrillation (mean CHADS2 score 1.8). In successfully occluded patients fulfilling TEE criteria (86), warfarin was stopped after 45 days, followed by aspirin and clopidogrel for 6 months after randomization and subsequently aspirin. The PREVAIL trial is further evaluating this concept. Limited data are available for another LAA occlusion system, the Amplatzer Cardiac Plug (ACP) device, for which the ACP trial has been initiated. Left atrial appendage occlusion needs to be performed with meticulous care by experienced operators because periprocedural complications such as pericardial effusion or stroke have been documented. With increased operator experience and technical improvements of the device, these complications can be minimized. © 2011 The Author.

Lake D.F.,Life Clinic | Faigel D.O.,Mayo Medical School
Antioxidants and Redox Signaling | Year: 2014

Significance: Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme that oxidizes thiols during protein folding, reducing molecular oxygen to hydrogen peroxide. Tumor cells may take advantage of oxidative environments at different stages of tumorigenesis, but QSOX1 may also serve additional functions in tumors. Recent Advances: Several groups have reported the over-expression of QSOX1 in breast, pancreas, and prostate cancers. A consensus is building that QSOX1 over-expression is important during tumor cell invasion, facilitating tumor cell migration at the tumor-stroma interface. As such, QSOX1 may be considered a prognostic indicator of metastatic potential or even indicate that cancer is present in a host. Critical Issues: However, some controversy exists between QSOX1 as a marker of poor or favorable outcome in breast cancer. More studies are required to reveal what advantage QSOX1 provides to breast and other types of cancer. More specifically, it is critical to learn which tumor types over-express QSOX1 and use its enzymatic activity to their advantage. Future Directions: As interest increases in understanding the mechanisms of tumorigenesis within the extracellular matrix and how tumor cells influence fibroblasts and other stromal cells, QSOX1 may be revealed as an important player in cancer detection and prognosis. Defining the mechanism(s) of QSOX1 activity in tumors and in in vivo models will provide important insights into how to target QSOX1 with anti-neoplastic agents. Antioxid. Redox Signal. 21, 485-496. © Mary Ann Liebert, Inc.

She J.,Fudan University | Yang P.,Mayo Medical School | Hong Q.,Fudan University | Bai C.,Fudan University
Chest | Year: 2013

In 2008, lung cancer replaced liver cancer as the number one cause of death among people with malignant tumors in China. The registered lung cancer mortality rate increased by 464.84% in the past 3 decades, which imposes an enormous burden on patients, health-care professionals, and society. We performed a systematic review of the published data on lung cancer in China between 1990 and 2011 to analyze the incidence and mortality rates, economic burden, and risk factors of cancer and the effectiveness of interventions. Lung cancer incidence varies within China. People in eastern China, especially women, likely have a higher risk of developing lung cancer than those in western China. The crude mortality rates from lung cancer in 2008 were 47.51 per 100,000 men and 22.69 per 100,000 women. The crude mortality rate was highest in Shanghai (76.49 per 100,000 men and 35.82 per 100,000 women) and lowest in Tibet (25.14 per 100,000 men) and Ningxia (12.09 per 100,000 women). Smoking and environmental pollution are major risk factors for lung cancer in China. Continuous efforts should be concentrated on education of the general public regarding lung cancer to increase prevention and early detection. Specific interventions need to be implemented to reduce smoking rates and environmental risk factors. Standardized treatment protocols should be adapted in China. © 2013 American College of Chest Physicians.

Huang G.,University of Southern California | Schaff H.V.,Mayo Medical School | Sundt T.M.,Massachusetts General Hospital | Rahimtoola S.H.,University of Southern California
Journal of the American College of Cardiology | Year: 2013

Obstructive thrombosed prosthetic heart valve (OTPHV) is a serious complication of heart valve replacement. There are no generally accepted criteria for management of these patients. Therefore, in September 2012, a literature survey of studies published after 1995 was performed to analyze the data regarding clinical outcomes of patients with OTPHV treated with thrombolytic agents and with surgery since 1996. The search yielded appropriate and relevant studies, which included 17 studies comprising 756 patients who had received thrombolytic therapy and 13 studies comprising 662 patients who had received surgery. The data on these 2 groups was analyzed in detail relating to frequency of use of the diagnostic studies, baseline patient data, and on the rate of complete success, outcomes, and complications of the therapy they had received, and the limitations of the studies. We have then developed a strategy for therapy of OTPHV. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.

Melin B.,Umeå University | Jenkins R.,Mayo Medical School
Current Opinion in Neurology | Year: 2013

Summary The link of genetic loci to specific tumor subtypes may have relevance for understanding glioma biology, and for developing new diagnostic tools and targeted therapy for glioma. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Kantarjian H.,University of Houston | Rajkumar S.V.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2015

High cancer drug prices are a worsening trend in cancer care and are affecting patient care and our health care system. In the United States, the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000 to more than $100,000 by 2012, while the average household income has decreased by about 8% in the past decade. Further, although 85% of cancer basic research is funded through taxpayers' money, Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries. Bound by the Hippocratic Oath, oncologists have a moral obligation to advocate for affordable cancer drugs. In this article, we discuss the high cost of cancer drugs, the reasons for these high prices, the implications for patients and the health care system, and potential solutions to the problem. © 2015 Mayo Foundation for Medical Education and Research.

Miller A.J.,Mayo Medical School | Tsao H.,Massachusetts General Hospital
British Journal of Dermatology | Year: 2010

The ability of cells to respond to and to mitigate environmental stress is crucial for their survival. Constitutive and facultative pigmentation have evolved in order for human skin to contend with high levels of terrestrial ultraviolet radiation (UVR). When this melanin 'shield' is compromised, individuals are exposed to increased skin cancer risk. The purpose of this review is to discuss new insights into the genetic basis of phenotypic risk factors for skin cancer, their connection to pigmentation and tanning, the precise molecular connections linking UVR to the tanning response, and potential methods of modulating pigmentation that avoid genotoxic damage. Highly translational implications of this research include a scientific basis on which to counsel patients regarding the carcinogenicity of UVR exposure related to tanning and potential new tanning agents that may actually protect against skin cancer by circumventing the need for UVR exposure. © 2009 British Association of Dermatologists.

Bosch J.,University of Barcelona | Groszmann R.J.,Yale University | Shah V.H.,Mayo Medical School
Journal of Hepatology | Year: 2015

Among the common complication of cirrhosis portal hypertension witnessed a major improvement of prognosis during the past decades. Principally due to the introduction of rational treatments based on new pathophysiological paradigms (concepts of thought) developed in the 1980s. The best example being the use of non-selective beta-blockers and of vasopressin analogs, somatostatin, and its analogs. Further refinement in the knowledge of the molecular mechanisms involved in the regulation of both the splanchnic and hepatic circulation has led to the emergence of new treatments, which are based on evidence that show not only structural but also vasoactive components increase the hepatic vascular resistance, as well as of angiogenesis. This knowledge and future improvements will most likely result in more effective treatment of portal hypertension and effective prevention of its complications in early stages. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Rank M.A.,Mayo Medical School | Peters S.P.,Center for Genomics and Personalized Medicine Research
Journal of Allergy and Clinical Immunology: In Practice | Year: 2014

Stepwise adjustments have been suggested as a framework to manage chronic asthma over time. In this framework, individuals with good asthma control and a low risk for future asthma exacerbations may be considered for a reduction or "step down" of their chronic asthma medications. In this article, we discuss how patients may benefit or be harmed by stepping down asthma medications. Based on the literature presented in this article, we recommend that clinicians discuss the option of stepping down with patients when symptoms are stable, lung function is near normal, and biomarkers (if measured) are near normal. Other factors that should be considered in the decision to step down include the length of asthma stability, age of the patient, time of year, and patient preferences. Reducing the dose of inhaled corticosteroid by 25% to 50% appears to be the safest method of stepping down. A clear plan of care and follow-up is needed when stepping down asthma medications because many patients are likely to have recurrent exacerbations. © 2014 American Academy of Allergy, Asthma & Immunology.

Naqvi T.Z.,Mayo Medical School | Naqvi T.Z.,University of Southern California | Lee M.-S.,University of Southern California
JACC: Cardiovascular Imaging | Year: 2014

Carotid intima-media thickness (CIMT) has been shown to predict cardiovascular (CV) risk in multiple large studies. Careful evaluation of CIMT studies reveals discrepancies in the comprehensiveness with which CIMT is assessed - the number of carotid segments evaluated (common carotid artery [CCA], internal carotid artery [ICA], or the carotid bulb), the type of measurements made (mean or maximum of single measurements, mean of the mean, or mean of the maximum for multiple measurements), the number of imaging angles used, whether plaques were included in the intima-media thickness (IMT) measurement, the report of adjusted or unadjusted models, risk association versus risk prediction, and the arbitrary cutoff points for CIMT and for plaque to predict risk. Measuring the far wall of the CCA was shown to be the least variable method for assessing IMT. However, meta-analyses suggest that CCA-IMT alone only minimally improves predictive power beyond traditional risk factors, whereas inclusion of the carotid bulb and ICA-IMT improves prediction of both cardiac risk and stroke risk. Carotid plaque appears to be a more powerful predictor of CV risk compared with CIMT alone. Quantitative measures of plaques such as plaque number, plaque thickness, plaque area, and 3-dimensional assessment of plaque volume appear to be progressively more sensitive in predicting CV risk than mere assessment of plaque presence. Limited data show that plaque characteristics including plaque vascularity may improve CV disease risk stratification further. IMT measurement at the CCA, carotid bulb, and ICA that allows inclusion of plaque in the IMT measurement or CCA-IMT measurement along with plaque assessment in all carotid segments is emerging as the focus of carotid artery ultrasound imaging for CV risk prediction. © 2014 American College of Cardiology Foundation.

Rosenthal D.,Massachusetts General Hospital | Callstrom M.R.,Mayo Medical School
Radiology | Year: 2012

Image-guided percutaneous ablation methods have proved effective for treatment of benign bone tumors and for palliation of metastases involving bone and soft-tissue sites beyond the liver and lung. Image-guided radiofrequency ablation is now the standard treatment for osteoid osteoma, as the procedure can be performed with higher rates of technical success, decreased morbidity, and lower cost than those obtained with open surgery. Several ablation methods have been used to effectively palliate focal painful metastatic disease involving bone and soft-tissue sites beyond the liver and lung. Substantial pain reduction is possible in patients who have failed to achieve benefit from conventional therapies, including chemotherapy and external-beam radiation. Importantly, the pain reduction that is achieved is durable over many months of observation. © RSNA, 2012.

Logsdon C.D.,University of Houston | Ji B.,Mayo Medical School
Nature Reviews Gastroenterology and Hepatology | Year: 2013

The exocrine pancreas is the organ with the highest level of protein synthesis in the adult - each day the pancreas produces litres of fluid filled with enzymes that are capable of breaking down nearly all organic substances. For optimal health, the pancreas must produce sufficient enzymes of the right character to match the dietary intake. Disruption of normal pancreatic function occurs primarily as a result of dysfunction of the acinar cells that produce these digestive enzymes, and can lead to acute or chronic diseases. For many years, the prevailing dogma has been that inappropriate intracellular activation of the digestive enzymes produced by acinar cells was the key to pancreatic inflammatory diseases, as digestive enzymes themselves are potentially harmful to the cells that secrete them. However, we now know that many stressors can affect pancreatic acinar cells, and that these stressors can independently trigger pancreatic pathology through various mechanisms. This Review focuses on protein synthesis and active digestive enzymes - two key stressors faced by the acinar cell that are likely to be the major drivers of pathology encountered in the pancreas. © 2013 Macmillan Publishers Limited. All rights reserved.

Katz S.,Long Island University | Pardi D.S.,Mayo Medical School
American Journal of Gastroenterology | Year: 2011

The growing recognition of the older inflammatory bowel disease (IBD) patient is heightened by the entry of the 77.2 million baby boomers who will turn 65 beginning of 2011. It is anticipated that this will occur at a rate of 10,000 per day or 4 million per year for the next 19 years. The management of IBD in this population is complex because of problems with co-morbidities, polypharmacy, impaired mobility, and cognition, as well as difficult social and financial issues. This review focuses on the older IBD patient's unique concerns and provides guidance in their diagnosis and management. © 2011 by the American College of Gastroenterology.

Salvarani C.,Unit of Rheumatology | Brown Jr. R.D.,Mayo Medical School | Hunder G.G.,Rochester College
The Lancet | Year: 2012

Primary CNS vasculitis is an uncommon disorder of unknown cause that is restricted to brain and spinal cord. The median age of onset is 50 years. The neurological manifestations are diverse, but generally consist of headache, altered cognition, focal weakness, or stroke. Serological markers of inflammation are usually normal. Cerebrospinal fluid is abnormal in about 80-90% of patients. Diagnosis is unlikely in the presence of a normal MRI of the brain. Biopsy of CNS tissue showing vasculitis is the only definitive test; however, angiography has often been used for diagnosis even though it has only moderate sensitivity and specificity. The size of the affected vessels varies and determines outcome and response to treatment. Early recognition is important because treatment with corticosteroids with or without cytotoxic drugs can often prevent serious outcomes. The differential diagnosis includes reversible cerebral vasoconstriction syndromes and secondary cerebral vasculitis.

Everett B.M.,Harvard University | Brooks M.M.,University of Pittsburgh | Vlachos H.E.A.,University of Pittsburgh | Chaitman B.R.,Saint Louis University | And 2 more authors.
New England Journal of Medicine | Year: 2015

Background: Cardiac troponin concentrations are used to identify patients who would benefit from urgent revascularization for acute coronary syndromes. We hypothesized that they might be used in patients with stable ischemic heart disease to identify those at high risk for cardiovascular events who might also benefit from prompt coronary revascularization. Methods: We measured the cardiac troponin T concentration at baseline with a high-sensitivity assay in 2285 patients who had both type 2 diabetes and stable ischemic heart disease and were enrolled in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes trial. We tested for an association between the troponin T concentration and a composite end point of death from cardiovascular causes, myocardial infarction, or stroke; we then evaluated whether random assignment to prompt revascularization reduced the rate of the composite end point in patients with an abnormal troponin T concentration (≥14 ng per liter) as compared with those with a normal troponin T concentration (<14 ng per liter). Results: Of the 2285 patients, 2277 (99.6%) had detectable (≥3 ng per liter) troponin T concentrations and 897 (39.3%) had abnormal troponin T concentrations at baseline. The 5-year rate of the composite end point was 27.1% among the patients who had had abnormal troponin T concentrations at baseline, as compared with 12.9% among those who had had normal baseline troponin T concentrations. In models that were adjusted for cardiovascular risk factors, severity of diabetes, electrocardiographic abnormalities, and coronary anatomy, the hazard ratio for the composite end point among patients with abnormal troponin T concentrations was 1.85 (95% confidence interval [CI], 1.48 to 2.32; P<0.001). Among patients with abnormal troponin T concentrations, random assignment to prompt revascularization, as compared with medical therapy alone, did not result in a significant reduction in the rate of the composite end point (hazard ratio, 0.96; 95% CI, 0.74 to 1.25). Conclusions: The cardiac troponin T concentration was an independent predictor of death from cardiovascular causes, myocardial infarction, or stroke in patients who had both type 2 diabetes and stable ischemic heart disease. An abnormal troponin T value of 14 ng per liter or higher did not identify a subgroup of patients who benefited from random assignment to prompt coronary revascularization. Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Syed F.F.,Mayo Medical School | Sani M.U.,Bayero University
Heart | Year: 2013

The last decade has witnessed major advances in our understanding of the epidemiology and pathophysiology of HIV-related cardiovascular disease in sub-Saharan Africa. In this review, we summarise these and discuss clinically relevant advances in diagnosis and treatment. In the Heart of Soweto Study, 10% of patients with newly diagnosed cardiovascular disease were HIV positive, and the most common HIV-related presentations were cardiomyopathy (38%), pericardial disease (13%) and pulmonary arterial hypertension (8%). HIV-related cardiomyopathy is more common with increased immunosuppression and HIV viraemia. With adequate antiretroviral therapy, the prevalence is low. Contributing factors such as malnutrition and genetic predisposition are under investigation. In other settings, pericardial disease is the most common presentation of HIV-related cardiovascular disease (over 40%), and over 90% of pericardial effusions are due to Mycobacterium tuberculosis (TB) pericarditis. HIV-associated TB pericarditis is associated with a greater prevalence of myopericarditis, a lower rate of progression to constriction, and markedly increased mortality. The role of steroids is currently under investigation in the form of a randomised controlled trial. HIV-associated pulmonary hypertension is significantly more common in sub- Saharan Africa than in developed countries, possibly as a result of interactions between HIV and other infectious agents, with very limited treatment options. It has recently been recognised that patients with HIV are at increased risk of sudden death. Infection with HIV is independently associated with QT prolongation, which is more marked with hepatitis C co-infection and associated with a 4.5-fold higher than expected rate of sudden death. The contribution of coronary disease to the overall burden of HIV-associated cardiovascular disease is still low in sub-Saharan Africa.

Kashani K.,Mayo Medical School | Kellum J.A.,University of Pittsburgh
Current Opinion in Nephrology and Hypertension | Year: 2015

Purpose of review Although recovery of kidney function following acute kidney injury (AKI) is not uncommon, it is often incomplete and associated with the development of chronic kidney disease (CKD). In order to improve AKI management, there is a critical need to develop a series of tests and biomarkers to detect renal function recovery and identify patients with progressive kidney disease. This article examines the current body of literature in the field. Recent findings The recently established consensus definition for AKI has resulted in significant advances in pathophysiologic understanding, patient identification, and disease prognostication. Unfortunately, the definition for renal recovery following AKI remains inconsistent. Proteinuria and microalbuminuria - classical markers of CKD progression - have been used and validated for the progression of AKI to CKD. Data on the performance of other biomarkers of kidney repair and the progression toward CKD are very limited. Specifically, the role of novel biomarkers including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephronectin (NPNT) in the recovery process has been studied, but it has not reached the point of widespread clinical implementation. Summary There is a critical need for translational and clinical investigations to verify the performance of potential kidney injury repair and progression biomarker candidates in the clinical setting. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Hofstra J.M.,Radboud University Nijmegen | Fervenza F.C.,Mayo Medical School | Wetzels J.F.M.,Radboud University Nijmegen
Nature Reviews Nephrology | Year: 2013

Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease - spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN. © 2013 Macmillan Publishers Limited. All rights reserved.

Novak C.M.,Kent State University | Burghardt P.R.,University of Michigan | Levine J.A.,Mayo Medical School
Neuroscience and Biobehavioral Reviews | Year: 2012

Running wheels are commonly employed to measure rodent physical activity in a variety of contexts, including studies of energy balance and obesity. There is no consensus on the nature of wheel-running activity or its underlying causes, however. Here, we will begin by systematically reviewing how running wheel availability affects physical activity and other aspects of energy balance in laboratory rodents. While wheel running and physical activity in the absence of a wheel commonly correlate in a general sense, in many specific aspects the two do not correspond. In fact, the presence of running wheels alters several aspects of energy balance, including body weight and composition, food intake, and energy expenditure of activity. We contend that wheel-running activity should be considered a behavior in and of itself, reflecting several underlying behavioral processes in addition to a rodent's general, spontaneous activity. These behavioral processes include defensive behavior, predatory aggression, and depression- and anxiety-like behaviors. As it relates to energy balance, wheel running engages several brain systems-including those related to the stress response, mood, and reward, and those responsive to growth factors-that influence energy balance indirectly. We contend that wheel-running behavior represents factors in addition to rodents' tendency to be physically active, engaging additional neural and physiological mechanisms which can then independently alter energy balance and behavior. Given the impact of wheel-running behavior on numerous overlapping systems that influence behavior and physiology, this review outlines the need for careful design and interpretation of studies that utilize running wheels as a means for exercise or as a measurement of general physical activity. © 2012 Elsevier Ltd.

Dedania V.S.,Lions Eye Institute | Bakri S.J.,Mayo Medical School
Retina | Year: 2015

Purpose: To summarize the literature addressing sustained and delayed elevation of intraocular pressure (IOP) in patients with neovascular age-related macular degeneration being treated with intravitreal vascular endothelial growth factor (VEGF) inhibitors and to present possible mechanisms of effect. Methods: Analysis of current literature evaluating sustained and delayed elevation of IOP in patients receiving intravitreal anti-VEGF therapy for neovascular age-related macular degeneration. Results: Studies have demonstrated that patients undergoing treatment with intravitreal anti-VEGF agents may experience sustained and delayed elevation of IOP. The incidence of sustained elevation of IOP in patients with neovascular age-related macular degeneration varied from 3.45% to 11.6%, and few patients required surgical management to control IOP. Possible risk factors associated with sustained and delayed elevation of IOP include, but are not limited to, history of glaucoma, phakia, history of glucocorticoid use, and/or extended treatment duration. There are multiple theories explaining the pathogenesis of sustained elevation of IOP, including microparticle obstruction of the trabecular meshwork, intraocular inflammation, and transient elevation of IOP. Conclusion: Sustained and delayed elevation of IOP in patients undergoing treatment of neovascular age-related macular degeneration with intravitreal anti-VEGF agents is likely a multifactorial process. Further studies to prospectively investigate sustained elevation of IOP in large, randomized, controlled trials might lead to a better understanding of the long-term adverse events associated with intravitreal anti-VEGF therapy. Copyright © by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.

Comin J.,St Vincents Hospital Melbourne | Kallmes D.F.,Mayo Medical School
American Journal of Neuroradiology | Year: 2013

In the context of neurointerventional procedures, clopidogrel hyper-responsiveness has been associated with hemorrhage; on the other hand, clopidogrel resistance has been associated with thromboembolism. This might seem to make a compelling argument in favor of routine platelet testing. Our reading of the literature leads us to conclude that routine platelet testing in neurointerventional procedures is not, unfortunately, ready for prime time.

News Article | December 23, 2016

PHOENIX - How do medical professionals determine whether or not a patient has experienced a post-operative complication? A team of Mayo Clinic physicians and researchers has published results of a three-year study examining mechanisms for measuring and reporting postoperative infection complications. The study analyzed patient admissions between 2012 and 2014 at the four teaching hospitals across Mayo Clinic's campuses in Arizona, Florida and Minnesota. The results are published online in the Annals of Surgery. In their analysis, the research team examined four common postoperative complications: pneumonia, sepsis, surgical site infections, and urinary tract infections. The goal of their study was to compare and contrast the different ways used to determine whether one of these complications occurred. Administrative data are gathered by hospitals and providers for financial purposes. Complications that occur in the postoperative context are reported as part of these data, and they affect hospital-based reimbursement. These data are widely used, especially by the Centers for Medicare & Medicaid Services, to assess quality of care. While widely available, these data often are criticized for not being accurate because of an absence of clear standards. According to David Etzioni, M.D., chair of the Division of Colorectal Surgery on Mayo Clinic's Arizona campus, registry data, on the other hand, are gathered by trained staff using strictly defined clinical criteria. While these types of data are considered to be more accurate and consistent, the process of gathering and reporting registry data is expensive, he says. Dr. Etzioni notes that the National Surgical Quality Improvement Program is the most commonly reported source of postoperative registry data. "These two systems give very different assessments of postoperative complications, even for the same patient," explains Dr. Etzioni, who is lead author of the study. He and a group of researchers examined situations where these two data sources disagreed. "Every discordant complication was examined by two independent reviewers -- at least one of whom is a practicing surgeon," says Dr. Etzioni. "What we find is that these two types of databases -- even when looking at the same patient -- report very different answers as to whether or not a complication occurred," Dr. Etzioni adds. "The rates of complications seen in these two databases can vary quite widely -- up to fivefold." What Dr. Etzioni finds most interesting, however, is why the two approaches differ so greatly. "It's tempting to think of registry data as right and administrative data as wrong, when it comes to assessing whether or not a complication occurred, he says. "The most important reason for the differences is that these two approaches use different approaches and different criteria." The question raised by this study is, "How should we be assessing postoperative outcomes?" Dr. Etzioni concludes. "Given the impact of this question on every aspect of the health policy as it pertains to surgical care, the ramifications of this study are wide-reaching." Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .

West C.P.,Mayo Medical School | Shanafelt T.D.,Mayo Medical School | Kolars J.C.,University of Michigan
JAMA - Journal of the American Medical Association | Year: 2011

Context: Physician distress is common and has been associated with negative effects on patient care. However, factors associated with resident distress and wellbeing have not been well described at a national level. Objectives: To measure well-being in a national sample of internal medicine residents and to evaluate relationships with demographics, educational debt, and medical knowledge. Design, Setting, and Participants: Study of internal medicine residents using data collected on 2008 and 2009 Internal Medicine In-Training Examination (IM-ITE) scores and the 2008 IM-ITE survey. Participants were 16 394 residents, representing 74.1% of all eligible US internal medicine residents in the 2008-2009 academic year. This total included 7743 US medical graduates and 8571 international medical graduates. Main Outcome Measures: Quality of life (QOL) and symptoms of burnout were assessed, as were year of training, sex, medical school location, educational debt, and IM-ITE score reported as percentage of correct responses. Results: Quality of life was rated "as bad as it can be" or "somewhat bad" by 2402 of 16 187 responding residents (14.8%). Overall burnout and high levels of emotional exhaustion and depersonalization were reported by 8343 of 16 192 (51.5%), 7394 of 16 154 (45.8%), and 4541 of 15 737 (28.9%) responding residents, respectively. In multivariable models, burnout was lesscommonamong international medical graduates than among US medical graduates (45.1% vs 58.7%; odds ratio, 0.70 [99% CI, 0.63-0.77]; P<.001). Greater educational debt was associated with the presence of at least 1 symptom of burnout (61.5% vs 43.7%; odds ratio, 1.72 [99% CI, 1.49-1.99]; P<.001 for debt >$200 000 relative to no debt). Residents reporting QOL "as bad as it can be" and emotional exhaustion symptoms daily had mean IM-ITE scores 2.7 points (99% CI, 1.2-4.3; P<.001) and 4.2 points (99% CI, 2.5-5.9; P<.001) lower than those with QOL "as good as it can be" and no emotional exhaustion symptoms, respectively. Residents reporting debt greater than $200 000 had mean IM-ITE scores 5.0 points (99% CI, 4.4-5.6; P<.001) lower than those with no debt. These differences were similar in magnitude to the 4.1-point (99% CI, 3.9-4.3) and 2.6-point (99% CI, 2.4-2.8) mean differences associated with progressing from first to second and second to third years of training, respectively. Conclusions: In this national study of internal medicine residents, suboptimal QOL and symptoms of burnout were common. Symptoms of burnout were associated with higher debt and were less frequent among international medical graduates. Low QOL, emotional exhaustion, and educational debt were associated with lower IM-ITE scores. ©2011 American Medical Association. All rights reserved.

Nielsen O.H.,Copenhagen University | Loftus E.V.,Mayo Medical School | Jess T.,Statens Serum Institute
BMC Medicine | Year: 2013

Background: Tumor necrosis factor (TNF)-α inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome.Methods: We performed a systematic review of the English-language literature to investigate if treatment with TNF-α blockers during pregnancy in women with IBD increases the risk of spontaneous abortions, preterm delivery, stillbirth, low birth weight, congenital malformations, or risk of infections in the offspring. Of 552 articles and abstracts reviewed, 58 articles or abstracts with unique content were identified and included in this systematic review. However, most presentations were case reports or case series supplied by a limited number of observational studies. No randomized controlled studies were available.Results: TNF-α inhibitors do not seem to affect either outcome of pregnancy in mothers with IBD, or the outcome in the offspring (congenital malformations and immunosuppression). Further, recent data have not identified any increased risk of infections in the first year of life in the offspring of mothers who received biologics, even in combination with immunomodulators (thiopurines).Conclusions: From the present systematic review, no association was found between administration of TNF inhibitors for IBD during pregnancy and adverse pregnancy outcome or congenital abnormalities. Further, no increased relative risk of infections has been reported in the first year of life in offspring of mothers who received biologics. Biologics should be discontinued during pregnancy solely if the IBD is in remission using the same stopping criteria as for patients with IBD in general, as uncontrolled activity of IBD may expose the mother and child to a risk greater than those only potentially coming from the use of TNF-α inhibitors. In such cases, inoculation of the offspring with live vaccines is contraindicated until the biologic agent is no longer detectable in the child's circulation. © 2013 Nielsen et al.; licensee BioMed Central Ltd.

Joyner M.J.,Mayo Medical School | Pedersen B.K.,Copenhagen University
Journal of Physiology | Year: 2011

In this paper we raise 'ten questions' broadly related to 'omics', the term systems biology, and why the new biology has failed to deliver major therapeutic advances for many common diseases, especially diabetes and cardiovascular disease. We argue that a fundamentally narrow and reductionist perspective about the contribution of genes and genetic variants to disease is a key reason 'omics' has failed to deliver the anticipated breakthroughs. We then point out the critical utility of key concepts from physiology like homeostasis, regulated systems and redundancy as major intellectual tools to understand how whole animals adapt to the real world. We argue that a lack of fluency in these concepts is a major stumbling block for what has been narrowly defined as 'systems biology' by some of its leading advocates. We also point out that it is a failure of regulation at multiple levels that causes many common diseases. Finally, we attempt to integrate our critique of reductionism into a broader social framework about so-called translational research in specific and the root causes of common diseases in general. Throughout we offer ideas and suggestions that might be incorporated into the current biomedical environment to advance the understanding of disease through the perspective of physiology in conjunction with epidemiology as opposed to bottom-up reductionism alone. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.

Jett J.R.,National Jewish Health | Schild S.E.,Mayo Medical School | Kesler K.A.,Indiana University | Kalemkerian G.P.,University of Michigan
Chest | Year: 2013

Background: Small cell lung cancer (SCLC) is a lethal disease for which there have been only small advances in diagnosis and treatment in the past decade. Our goal was to revise the evidence-based guidelines on staging and best available treatment options. Methods: A comprehensive literature search covering 2004 to 2011 was conducted in MEDLINE, Embase, and five Cochrane databases using SCLC terms. This was cross-checked with the authors' own literature searches and knowledge of the literature. Results were limited to research in humans and articles written in English. Results: The staging classification should include both the old Veterans Administration staging classification of limited stage (LS) and extensive stage (ES), as well as the new seventh edition American Joint Committee on Cancer/International Union Against Cancer staging by TNM. The use of PET scanning is likely to improve the accuracy of staging. Surgery is indicated for carefully selected stage I SCLC. LS disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle 1 or 2 of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. ES disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in those individuals with both LS and ES disease who achieve a complete or partial response to initial therapy. To date, no molecularly targeted therapy agent has demonstrated proven efficacy against SCLC. Conclusion: Evidence-based guidelines are provided for the staging and treatment of SCLC. LS-SCLC is treated with curative intent with 20% to 25% 5-year survival. ES-SCLC is initially responsive to standard treatment, but almost always relapses, with virtually no patients surviving for 5 years. Targeted therapies have no proven efficacy against SCLC. Copyright © by the American College of Chest Physicians 2013.

Acosta A.,Clinical Enteric Neuroscience Translational And Epidemiological Research Center | Dayyeh B.K.A.,Clinical Enteric Neuroscience Translational And Epidemiological Research Center | Port J.D.,Mayo Medical School | Camilleri M.,Clinical Enteric Neuroscience Translational And Epidemiological Research Center
Gut | Year: 2014

Despite advances in understanding the roles of adiposity, food intake, GI and adipocyte-related hormones, inflammatory mediators, the gut-brain axis and the hypothalamic nervous system in the pathophysiology of obesity, the effects of different therapeutic interventions on those pathophysiological mechanisms are controversial. There are still no low-cost, safe, effective treatments for obesity and its complications. Currently, bariatric surgical approaches targeting the GI tract are more effective than non-surgical approaches in inducing weight reduction and resolving obesity-related comorbidities. However, current guidelines emphasise non-surgical approaches through lifestyle modification and medications to achieve slow weight loss, which is not usually sustained and may be associated with medication-related side effects. This review analyses current central, peripheral or hormonal targets to treat obesity and addresses challenges and opportunities to develop novel approaches for obesity.

Huebert R.C.,Gastroenterology Research Unit | Rakela J.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2014

Regenerative medicine is energizing and empowering basic science and has the potential to dramatically transform health care in the future. Given the remarkable intrinsic regenerative properties of the liver, as well as widespread adoption of regenerative strategies for liver disease (eg, liver transplant, partial hepatectomy, living donor transplant), hepatology has always been at the forefront of clinical regenerative medicine. However, an expanding pool of patients awaiting liver transplant, a limited pool of donor organs, and finite applicability of the current surgical approaches have created a need for more refined and widely available regenerative medicine strategies. Although cell-based therapies have been used extensively for hematologic malignant diseases and other conditions, the potential application of cellular therapy for acute and chronic liver diseases has only more recently been explored. New understanding of the mechanisms of liver regeneration and repair, including activation of local stem/progenitor cells and contributions from circulating bone marrowederived stem cells, provide the theoretical underpinnings for the rational use of cell-based therapies in clinical trials. In this review, we dissect the scientific rationale for various modalities of cell therapy for liver diseases being explored in animal models and review those tested in human clinical trials. We also attempt to clarify some of the important ongoing questions that need to be addressed in order to bring these powerful therapies to clinical translation. Discussions will cover transplant of hepatocytes and liver stem/progenitor cells as well as infusion or stimulation of bone marrowederived stem cells. We also highlight tremendous scientific advances on the horizon, including the potential use of induced pluripotent stem cells and their derivatives as individualized regenerative therapy for liver disease. © 2014 Mayo Foundation for Medical Education and Research.

Rose P.S.,Mayo Medical School | Buchowski J.M.,Washington University in St. Louis
Journal of the American Academy of Orthopaedic Surgeons | Year: 2011

Spinal metastases are found in most patients who die of cancer. The number of patients with symptomatic spinal metastases likely will increase as therapy for the primary disease improves and as cardiovascular mortality decreases. Understanding the epidemiology of metastatic spine disease and its presentation is essential to developing a diagnostic strategy. Treatment may involve chemotherapy, corticosteroids, radiotherapy, surgery, and/or percutaneous procedures (eg, vertebroplasty, kyphoplasty). A rational treatment plan can help improve quality of life, preserve neurologic function, and prolong survival. © 2011 by the American Academy of Orthopaedic Surgeons.

Nasr S.H.,Mayo Medical School | Radhakrishnan J.,Columbia University | D'Agati V.D.,Columbia University
Kidney International | Year: 2013

In the past, most cases of bacterial infection-related glomerulonephritis (IRGN) occurred in children following streptococcal upper respiratory tract or skin infections and were called postinfectious GN. Over the past 3 decades, there has been an important shift in epidemiology, bacteriology, and outcome of IRGN. A significant percentage of cases now target adults, particularly the elderly or immunocompromised. Because adult infections are often ongoing at the time of diagnosis, the term IRGN appears more appropriate. The sites of infection in adult IRGN are more heterogeneous than in children, and include the upper respiratory tract, skin, lung, heart, urinary tract, teeth/oral mucosa, and bone. In adults, the disease is more likely to be secondary to non-streptococcal infections, particularly staphylococcal infection. In contrast to the favorable course in children, a significant proportion of adults with IRGN, especially the elderly and diabetics, do not recover renal function. Whereas the pathogenesis of post-streptococcal glomerulonephritis has been studied extensively, leading to the identification of two candidate nephritogenic streptococcal antigens, glyceraldehyde-3-phosphate dehydrogenase and pyrogenic exotoxin B, few investigations have focused on IRGN caused by other bacteria. This review will address the current status of sporadic bacterial IRGN in adults. © 2013 International Society of Nephrology.

Kaeser P.-F.,University of Lausanne | Brodsky M.C.,Mayo Medical School
Current Neurology and Neuroscience Reports | Year: 2013

Based on neuroimaging data showing absence of the trochlear nerve, congenital superior oblique palsy is now classified as a congenital cranial dysinnervation disorder. A similar absence of the abducens nerve is accompanied by misinnervation to the lateral rectus muscle from a branch of oculomotor nerve in the Duane retraction syndrome. This similarity raises the question of whether some cases of Brown syndrome could arise from a similar synkinesis between the inferior and superior oblique muscles in the setting of congenital superior oblique palsy. This hypothesis has gained support from the confluence of evidence from a number of independent studies. Using Duane syndrome as a model, we critically review the accumulating evidence that some cases of Brown syndrome are ultimately attributable to dysgenesis of the trochlear nerve. © 2013 Springer Science+Business Media New York.

Chakkera H.A.,Mayo Clinic Hospital | Mandarino L.J.,Mayo Medical School
Transplantation | Year: 2013

New-onset diabetes after transplantation independently increases the risk of cardiovascular disease, infections, and graft loss and decreases patient survival. The required balance between insulin sensitivity/resistance and insulin secretion is necessary to maintain normal glucose metabolism. Calcineurin inhibitors are standard immunosuppression drugs used after transplantation and have been implicated in the development of new-onset diabetes after transplantation partially by pancreatic A-cell apoptosis and resultant decrease in insulin secretion. The ability of muscle to take up glucose is critical to blood glucose homeostasis. Skeletal muscle is quantitatively the most important tissue in the body for insulin-stimulated glucose disposal and is composed of diverse myofibers that vary in their properties between healthy and insulin-resistant muscle. Various signaling pathways are responsible for remodeling of skeletal muscle, and among these is the calcineurin/nuclear factor of activated T-cell pathway. The mechanism of action of the calcineurin inhibitors is to bind in a complex with a binding protein to calcineurin and inhibit its dephosphorylation and activation of nuclear factor of activated T cells. In this review, we will provide a detailed discussion of the hypothesis that inhibition of calcineurin in tissues involved in insulin sensitivity/resistance could be at least partially responsible for the diabetogenicity seen with the use of calcineurin inhibitors. Copyright © 2013 by Lippincott Williams & Wilkins.

Larson N.B.,Mayo Medical School | Fridley B.L.,University of Kansas Medical Center
Bioinformatics | Year: 2013

We have developed a novel Bayesian method, PurBayes, to estimate tumor purity and detect intratumor heterogeneity based on next-generation sequencing data of paired tumor-normal tissue samples, which uses finite mixture modeling methods. We demonstrate our approach using simulated data and discuss its performance under varying conditions.Availability: PurBayes is implemented as an R package, and source code is available for download through CRAN at Supplementary information: Supplementary data are available online at Bioinformatics online. © 2013 The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:

Trost L.W.,Mayo Medical School | Brannigan R.E.,Northwestern University
Current Treatment Options in Oncology | Year: 2012

Oncofertility as a discipline plays an important, adjunctive role in the treatment of male patients with cancer. Despite recommendations by the American Society of Clinical Oncology, many clinicians managing malignancies in males fail to consistently incorporate fertility preservation as a routine aspect of health care. Providers involved in the treatment of oncologic patients should have an awareness of the impact of their prescribed treatments on reproductive potential, just as they would be knowledgeable of the potential deleterious effects of cancer therapies on vital organs such as the kidneys, lungs, and liver. Providers should then have a discussion with their patients regarding these potential adverse therapeutic effects or consult a fertility preservation specialist to discuss these matters and fertility preservation options with the patient. Cryopreservation of sperm remains an excellent option for male fertility preservation as it is readily available and results in storage of viable gametes for future use in the event of post treatment infertility. With the use of assisted reproductive techniques (ART), cryopreserved sperm may ultimately result in successful paternity, even in the setting of very low numbers of stored sperm. While sperm cryopreservation is usually an option for adolescent and adult males, fertility preservation in pre-pubertal males presents a more challenging problem. To date, no clinically proven methods are available to preserve fertility in these males. However, some centers do offer experimental protocols under the oversight of an IRB, such as testicular tissue cryopreservation in these males. The hope is that one day science will provide a mechanism for immature germ cells from the testicular tissue of these patients to be used in vivo or in vitro to facilitate reproduction. In closing, studies have shown that the patient's regard for his provider is enhanced when the issue fertility preservation is raised. While oncologic care is often fraught with time constraints and acute medical concerns, fertility preservation care in the male can typically be administered quickly and without disruption of the overall plan of care. © Springer Science+Business Media, LLC 2012.

Freeze H.H.,Sanford Burnham Institute for Medical Research | Eklund E.A.,Lund University | Ng B.G.,Sanford Burnham Institute for Medical Research | Patterson M.C.,Mayo Medical School
The Lancet Neurology | Year: 2012

Congenital disorders of glycosylation comprise most of the nearly 70 genetic disorders known to be caused by impaired synthesis of glycoconjugates. The effects are expressed in most organ systems, and most involve the nervous system. Typical manifestations include structural abnormalities (eg, rapidly progressive cerebellar atrophy), myopathies (including congenital muscular dystrophies and limb-girdle dystrophies), strokes and stroke-like episodes, epileptic seizures, developmental delay, and demyelinating neuropathy. Patients can also have neurological symptoms associated with coagulopathies, immune dysfunction with or without infections, and cardiac, renal, or hepatic failure, which are common features of glycosylation disorders. The diagnosis of congenital disorder of glycosylation should be considered for any patient with multisystem disease and in those with more specific phenotypic features. Measurement of concentrations of selected glycoconjugates can be used to screen for many of these disorders, and molecular diagnosis is becoming more widely available in clinical practice. Disease-modifying treatments are available for only a few disorders, but all affected individuals benefit from early diagnosis and aggressive management. © 2012 Elsevier Ltd.

Grisold W.,Kaiser Franz Josef Hospital | Cavaletti G.,University of Milan Bicocca | Windebank A.J.,Mayo Medical School
Neuro-Oncology | Year: 2012

Peripheral neuropathies induced by chemotherapy (CIPN) are an increasingly frequent problem. Contrary to hematologic adverse effects, which can be treated with hematopoetic growth factors, neither prophylaxis nor specific treatment is available, and only symptomatic treatment can be offered. Neurotoxic drugs are becoming a major dose-limiting factor. The epidemiology is still unclear. Several drug-dependent pathogenetic mechanisms exist. CIPN are predominately sensory, length-dependent neuropathies that develop after a typical cumulative dose. Usually, the appearance of CIPN is dose dependent, although in at least 2 drugs (oxaliplatin and taxanes), immediate toxic effects occur. The most frequent substances causing CIPN are platin compounds, vinka alkaloids, taxanes, and bortezomib and thalidomide. The role of synergistic neurotoxicity caused by previously given chemotherapies and concomitant chemotherapies and the role pre-existent neuropathy on the development of a CIPN is not clear. As the number of long-term cancer survivors increases and a new focus on long-term effects of chemotherapy-induced neuropathies emerge, concepts of rehabilitation need to be implemented to improve the patients' functions and quality of life. © 2012 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Tabibian J.H.,Mayo Medical School | Lindor K.D.,Arizona State University
Expert Review of Gastroenterology and Hepatology | Year: 2013

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease characterized by fibro-obliterative inflammation of the hepatic bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and in some cases, cholangiocarcinoma. Despite clinical trials of nearly 20 different pharmacotherapies over several decades, safe and effective medical therapy, albeit critically needed, remains to be established. PSC is pathogenically complex, with genetic, immune, enteric microbial, environmental and other factors being potentially involved and, thus, not surprisingly, it manifests as a clinically heterogeneous disease with a relatively unpredictable course. It is likely that this complexity and clinical heterogeneity are responsible for the negative results of clinical trials, but novel insights about and approaches to PSC may shift this trend. The authors herein provide a review of previously tested pharmacologic agents, discuss emerging fundamental concepts and present viewpoints regarding how identifying therapies for PSC may evolve over the next several years. © 2013 2013 Expert Reviews Ltd.

Gossard A.A.,Mayo Medical School | Lindor K.D.,Arizona State University
Journal of Gastroenterology | Year: 2012

Autoimmune hepatitis (AIH) is an inflammatory liver disease that predominantly affects females. The disease is characterized histologically by interface hepatitis, biochemically by increased aspartate and alanine aminotransferase levels, and serologically by the presence of autoantibodies and elevated levels of immunoglobulin G. AIH affects both adults and children, and is particularly aggressive in the latter group. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Treatment is often successful at inducing remission of disease, and this can lead to a normal life expectancy. However, progression to cirrhosis can and does occur in some. For those with advanced-stage disease and complications, consideration of liver transplantation is appropriate. © 2012 Springer.

Bordner A.J.,Mayo Medical School | Mittelmann H.D.,Arizona State University
Molecular Biology and Evolution | Year: 2014

Despite the importance of a thermodynamically stable structure with a conserved fold for protein function, almost all evolutionary models neglect site-site correlations that arise from physical interactions between neighboring amino acid sites. This is mainly due to the difficulty in formulating a computationally tractable model since rate matrices can no longer be used. Here, we introduce a general framework, based on factor graphs, for constructing probabilistic models of protein evolution with site interdependence. Conveniently, efficient approximate inference algorithms, such as Belief Propagation, can be used to calculate likelihoods for these models. We fit an amino acid substitution model of this type that accounts for both solvent accessibility and site-site correlations. Comparisons of the new model with rate matrix models and alternative structure-dependent models demonstrate that it better fits the sequence data. We also examine evolution within a family of homohexameric enzymes and find that site-site correlations between most contacting subunits contribute to a higher likelihood. In addition, we show that the new substitution model has a similar mathematical form to the one introduced in Rodrigue et al. (Rodrigue N, Lartillot N, Bryant D, Philippe H. 2005. Site interdependence attributed to tertiary structure in amino acid sequence evolution. Gene 347:207-217), although with different parameter interpretations and values. We also perform a statistical analysis of the effects of amino acids at neighboring sites on substitution probabilities and find a significant perturbation of most probabilities, further supporting the significant role of site-site interactions in protein evolution and motivating the development of new evolutionary models similar to the one described here. Finally, we discuss possible extensions and applications of the new substitution model. © 2013 The Author 2013. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.

Peng Y.,Stanford University | Peng Y.,Mayo Medical School | Han C.,Howard Hughes Medical Institute | Axelrod J.D.,Stanford University
Developmental Cell | Year: 2012

Secreted signaling molecules typically float in the outer leaflet of the plasma membrane or freely diffuse away from the signaling cell, suggesting that a signal should be sensed equally by all neighboring cells. However, we demonstrate that Spitz (Spi)-mediated epidermal growth factor receptor (EGFR) signaling is spatially biased to selectively determine the induction of a single bract cell on the proximal side of each mechanosensory organ on the Drosophila leg. Dynamic and oriented cellular protrusions emanating from the socket cell, the source of Spi, robustly favor the Spi/EGFR signaling response in a particular cell among equally competent neighbors. We propose that these protrusive structures enhance signaling by increasing contact between the signaling and responding cells. The planar polarized direction of the protrusions determines the direction of the signaling outcome. This asymmetric cell signaling serves as a developmental mechanism to generate spatially patterned cell fates.

Oliveira A.M.,Mayo Medical School | Chou M.M.,Children's Hospital of Philadelphia
Human Pathology | Year: 2014

Summary USP6 (also known as TRE17) is a ubiquitin-specific protease that was identified as an oncogene in transfection experiments with Ewing sarcoma DNA 2 decades ago. Until recently, little was known about USP6 function and mechanisms of oncogenic activation. The identification of USP6 fusion genes in aneurysmal bone cyst (ABC) and, more recently, in nodular fasciitis led to a better understanding of the pathogenesis of these lesions. Furthermore, the detection of USP6 genomic rearrangements or USP6 fusion genes may be used as a diagnostic tool for these lesions. In this review, we discuss the clinicopathologic features, molecular pathology, and pathogenesis of ABC and nodular fasciitis. We also discuss the possible line of differentiation of ABC and its relationship to nodular fasciitis and other lesions. © 2014 Elsevier Inc.

Carey E.J.,Mayo Medical School | Ali A.H.,Mayo Medical School | Lindor K.D.,Mayo Medical School | Lindor K.D.,Arizona State University
The Lancet | Year: 2015

Summary Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options. © 2015 Elsevier Ltd.

Husby S.,University of Southern Denmark | Murray J.A.,Mayo Medical School
Nature Reviews Gastroenterology and Hepatology | Year: 2014

The diagnosis of coeliac disease has advanced in the past decade owing to increased clinical awareness and improved tests. Coeliac disease is now regarded as a common disease presenting at any age with a broad spectrum of symptoms. Previous guidelines on diagnosis relied on the histological analysis of duodenal biopsy samples. However, contemporary antibody analysis is a diagnostic tool with a comparatively high accuracy that has reduced reliance on performing biopsies. Furthermore, determination of HLA-based genetic susceptibility to coeliac disease has become routine. European and North American guidelines utilize symptoms, coeliac antibodies (primarily tissue transglutaminase 2 IgA and endomysial IgA antibodies), HLA determination and histological analysis of biopsy tissue for diagnosis. Some guidelines conclude that the diagnostic accuracy of tissue transglutaminase 2 IgA antibodies is sufficient to omit duodenal biopsies in selected children with very high antibody levels, in the presence of clear symptom response as well as a positive endomysial antibody test and confirmation of genetic susceptibility. This Review discusses if such a strategy is appropriate for children and adults in all populations. The performance characteristics of antibody tests (particularly of the tissue transglutaminase 2 IgA test) including quality control and characterisation of the population in whom testing is performed are also discussed. © 2014 Macmillan Publishers Limited. All rights reserved.

Walker M.M.,Imperial College London | Murray J.A.,Mayo Medical School
Histopathology | Year: 2011

Coeliac disease is increasing in prevalence, which is currently estimated at one in 100 of the population and may occur de novo in adults. The diagnosis requires a joint clinicopathological approach; the recommended first-line test is serology with immunoglobulin A (IgA) tissue transglutaminase and IgA endomysial antibodies. These serological tests show high levels of sensitivity and specificity, but biopsy is the gold standard to confirm the diagnosis. It is important that both tests are performed before the introduction of a gluten-free diet. Although the classical histopathology changes of coeliac disease with partial or total villous atrophy are well recognized, the pathology classification of coeliac disease is changing, with recognition that coeliac disease may show minimal pathology (normal architecture and an intraepithelial lymphocyte count/100 enterocytes≥25). This entity is also described as lymphocytic duodenosis, and recommendation of follow-up serology testing is paramount in this condition. Follow-up of patients with coeliac disease is warranted, as normal serology does not predict mucosal recovery. Failure to heal predicts risk of progression to refractory coeliac disease and malignancies. Refractory coeliac disease occurs in 1-2% of patients and this diagnosis requires a combined clinical and histopathology approach with immunocytochemistry. © 2010 Blackwell Publishing Limited.

Peden D.,University of North Carolina at Chapel Hill | Reed C.E.,Mayo Medical School
Journal of Allergy and Clinical Immunology | Year: 2010

Airborne allergens are the major cause of allergic rhinitis and asthma. Daily exposure comes from indoor sources, chiefly at home but occasionally at schools or offices. Seasonal exposure to outdoor allergens, pollens, and molds is another important source. Exposure to unusual substances at work causes occupational asthma, accounting for about 5% of asthma in adults. Indoor and outdoor air pollutants trigger airway inflammation and increase the severity of asthma. Diesel exhaust particles increase the production of IgE antibodies. Identification and reduction of exposure to allergens is a very important part of the management of respiratory allergic diseases. The first section of this chapter discusses domestic allergens, arthropods (mites and cockroaches), molds, and mammals (pets and mice). Indoor humidity and water damage are important factors in the production of mite and mold allergens, and discarded human food items are important sources of proliferation of cockroaches and mice. Means of identifying and reducing exposure are presented. The second section discusses outdoor allergens: pollens and molds. The particular plants or molds and the amount of exposure to these allergens is determined by the local climate, and local pollen and mold counts are available to determine the time and amount of exposure. Climate change is already having an important effect on the distribution and amount of outdoor allergens. The third section discusses indoor and outdoor air pollution and methods that individuals can take to reduce indoor pollution in addition to eliminating cigarette smoking. The fourth section discusses the diagnosis and management of occupational asthma. © 2010 American Academ