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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.


Jobst B.C.,Dartmouth Hitchcock Medical Center | Cascino G.D.,Mayo Medical School
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE: Epilepsy surgery is indicated for patients with focal seizures who do not respond to appropriate antiepileptic drug therapy consisting of 2 or more medications. OBJECTIVES: To review resective surgery outcomes for focal epilepsy, to identify which patients benefit the most, and to discuss why epilepsy surgerymay not be universally accepted. EVIDENCE REVIEW: Medline and Cochrane databases were searched between January 1993 and June 2014 for randomized clinical trials, meta-analyses, systematic reviews, and large retrospective case series (>300 patients) using Medical Subject Headings and indexed text terms. Fifty-five articles were included. Subpopulations and prognostic factors were identified. Systematic reviews for cognitive, psychiatric, quality-of-life, and psychosocial outcomes were included. FINDINGS: Two randomized clinical trials enrolling 118 patients with temporal lobe epilepsy found greater freedom from seizures with surgery when compared with continued medical treatment (58%vs 8%[n = 80] and 73%vs 0%[n = 38], P < .001). Nine systematic reviews and 2 large case series of medically refractory patients treated with surgery reported seizure-free outcomes in 34%to 74%of patients (median, 62.4%). The remainder of systematic reviews and meta-analyses examined subpopulations. Epilepsy surgery was less effective when there were extratemporal lesions, the epilepsy was not associated with a structural lesion, or both. Seizure-free outcomes were similar between children and adults. Hippocampal sclerosis and benign tumors were associated with better outcomes relative to other pathologies. Similar procedures such as selective amygdalohippocampectomy and temporal lobectomy for temporal lobe epilepsy were associated with subtle differences in seizure and neuropsychological outcome. There is low perioperative mortality (0.1%-0.5%) from epilepsy surgery. The most frequent neurologic complication is visual field defect occurring from temporal lobe resection. Quality of life improved after surgery but improved the most in patients who were seizure-free after surgery. CONCLUSIONS AND RELEVANCE: Epilepsy surgery reduced seizure activity in randomized clinical trials when compared with continued medical therapy. Long-term cognitive, psychiatric, psychosocial, and quality-of-life outcomes were less well defined. Despite good outcomes from high-quality clinical trials, referrals of patients with seizures refractory to medical treatment remain infrequent. Copyright 2015 American Medical Association. All rights reserved.


Fatourechi V.,Mayo Medical School
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2012

Graves' disease is an autoimmune condition commonly associated with thyroid dysfunction and with anti-thyroid antibodies, usually TSH receptor stimulating antibodies. Thyroid autoimmunity also may be associated with extra thyroidal manifestations. Most common extra thyroidal manifestation is ophthalmopathy. Less common is thyroid dermopathy, usually occurring in pretibial area. Dermopathy is almost always associated with ophthalmopathy and in severe cases with acropachy. A common antigen with thyroid in tissues of the skin and the eyes, most likely TSH receptor, is involved in pathogenesis of extra thyroidal manifestations. Presence of dermopathy and acropachy are predictors of severity of autoimmune process. Local corticosteroid application is the standard therapy for dermopathy. Response to therapy is good in mild cases and poor in severe cases. Immune modulators and biotherapies are undergoing randomized trials for ophthalmopathy component of Graves' disease. Any therapy proven to be effective for ophthalmopathy can be utilized in future for management of dermopathy. © 2011 Elsevier Ltd. All rights reserved.


Hung J.C.,Mayo Medical School
Theranostics | Year: 2013

The regulatory framework for radioactive drugs, in particular those used in positron emission tomography (PET) scans, has been gradually established since the release of the Food and Drug Administration Modernization Act in 1997. Various guidances specially tailored to accommodate special properties of PET drugs have been issued by the Food and Drug Administration (FDA) in order to ensure this valuable technology (i.e., PET molecular imaging) will continue to be available to patients and yet the safety and efficacy of PET drugs are well regulated so that public health will be protected. This article presents several key elements of this regulatory framework for PET drugs. New regulatory avenues proposed by the FDA to facilitate the research and development process to bring more new PET drugs to clinical practice, as well as to foster the opportunity of using "orphan" PET drugs in clinical practice are also discussed in this paper. © Ivyspring International Publisher.


Boes C.J.,Mayo Medical School
Journal of neurology | Year: 2014

In the late 1800s, Wilhelm Erb, Joseph Babinski, William Gowers, and others helped develop the neurologic examination as we know it today. Erb was one of the first to emphasize a detailed and systematic neurologic exam and was co-discoverer of the muscle stretch reflex, Gowers began studying the knee jerk shortly after it was described, and Babinski focused on finding reliable signs that could differentiate organic from hysterical paralysis. These physicians and others emphasized the bedside examination of reflexes, which have been an important part of the neurologic examination ever since. This review will focus on the history of the examination of the following muscle stretch and superficial/cutaneous reflexes: knee jerk, jaw jerk, deep abdominal reflexes, superficial abdominal reflexes, plantar reflex/Babinski sign, and palmomental reflex. The history of reflex grading will also be discussed.


An antitumor T-cell response can lead to tumor control without clearing all tumor cells. As long as residual tumor cells remain, there is a constant risk of escape from that T-cell response. We previously showed that adoptive transfer of anti-ova OT-I T cells into B16ova-bearing mice led to tumor regression followed by escape of tumors that had lost the ova gene, rendering the OT-I T cells ineffective. In this study, we hypothesized that simultaneous transfer of cytotoxic T lymphocytes targeted against two independent antigens would reduce selection for single-antigen-loss cells, thereby limiting tumor escape. Using OT-I and Pmel T cells to treat B16ova tumors, we found that early cotransfer could prevent tumor emergence in most mice, whereas neither T-cell specificity alone was able to do so. When combined with total body irradiation for the treatment of larger 7-day tumors, cotransfer was also better at limiting tumor recurrence, and the tumors that did escape combination therapy continued to express both target antigens. As adoptively transferred T cells also persisted in vivo, even in mice with recurrent tumors, we hypothesized that restimulation of these antitumor T cells would prolong survival of mice with recurrent tumors. Consistent with this hypothesis, administration of a low-dose regimen of cyclophosphamide following tumor escape slowed tumor growth in mice that had previously received T-cell therapy, but not in control-treated mice, an effect that was associated with increased activation of T cells in vitro by low- but not high-dose cyclophosphamide.


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.


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.


Farrugia G.,Mayo Medical School
Gastroenterology Clinics of North America | Year: 2015

The cellular abnormalities that lead to diabetic gastroparesis are increasingly being understood. Several key cell types are affected by diabetes, leading to gastroparesis. These changes include abnormalities in the extrinsic innervation to the stomach, loss of key neurotransmitters at the level of the enteric nervous system, smooth muscle abnormalities, loss of interstitial cells of Cajal, and changes in the macrophage population resident in the muscle wall. This article reviews the current understanding with a focus on data from human studies when available. © 2015 Elsevier Inc.


Bharucha A.E.,Mayo Medical School
Gastroenterology Clinics of North America | Year: 2015

Gastroparesis is characterized by delayed gastric emptying and symptoms thereof in the absence of gastric outlet obstruction. Most studies on the epidemiology of gastroparesis have been conducted in selected case series rather than in the population at large. In the only community-based study of gastroparesis in diabetes mellitus (DM), the average cumulative incidence of symptoms and delayed gastric emptying over 10 years was higher in type 1 DM (5%) than in type 2 DM (1%) and controls (1%). In the United States, the incidence of hospitalizations related to gastroparesis increased substantially between 1995 and 2004, and particularly after 2000. © 2015 Elsevier Inc.


Watson J.C.,Mayo Medical School
Neurologic Clinics | Year: 2012

CTS is a clinically defined syndrome; however, there is value added by an evidence-based electrodiagnostic approach to (1) efficiently confirm the diagnosis (particularly before invasive interventions), (2) to identify neurogenic mimickers or superimposed processes that may influence the response to treatment, and (3) to stratify the degree of neurogenic injury to help the clinician make management decisions in conjunction with the severity of the clinical symptoms. The literature on the electrodiagnostic diagnosis of CTS is reviewed and an evidence based diagnostic algorithm is proposed. Confounders to CTS electrodiagnostic diagnosis are discussed (crossovers, peripheral neuropathy, and recurrent symptoms after surgical release). © 2012 Elsevier Inc.


Chandok N.,University of Western Ontario | Watt K.D.,Mayo Medical School
Liver Transplantation | Year: 2012

Recipients of liver transplantation (LT) have a higher overall risk (2-3 times on average) of developing de novo malignancies than the general population, with standardized incidence ratios ranging from 1.0 for breast and prostate cancers to 3-4 for colon cancer and up to 12 for esophageal and oropharyngeal cancers. Aside from immunosuppression, other identified risk factors for de novo malignancies include the patient's age, a history of alcoholic liver disease or primary sclerosing cholangitis, smoking, and viral infections with oncogenic potential. Despite outcome studies showing that de novo malignancies are major causes of mortality and morbidity after LT, there are no guidelines for cancer surveillance protocols or immunosuppression protocols to lower the incidence of de novo cancers. Patient education, particularly for smoking cessation and excess sun avoidance, and regular clinical follow-up remain the standard of care. Further research in epidemiology, risk factors, and the effectiveness of screening and management protocols is needed to develop evidence-based guidelines for the prevention and treatment of de novo malignancies. © 2012 AASLD.


Huskins W.C.,Mayo Medical School
Current Opinion in Pediatrics | Year: 2012

Purpose of review: Healthcare-associated infections cause substantial harm to hospitalized neonates and children. Efforts that prevent these infections are a major focus of current patient safety initiatives. This review focuses on the reports of quality improvement interventions to prevent central line-associated bloodstream infections (CLABSIs) in neonates and children. Recent findings: Single-center and multicenter collaborative studies have examined the effect of quality improvement interventions to reliably implement central line insertion and maintenance bundles on CLABSI rates in neonatal and pediatric intensive care units. Quality improvement interventions were associated with reductions in CLABSI rates in neonates and children by a half or more, although many of the studies have important methodologic limitations. Studies that utilized improvement science methodologies demonstrated larger improvement effects, but required a sizable investment of institutional support and personnel time. Summary: Quality improvement interventions to reduce CLABSI are an important component of patient safety initiatives. Future studies of quality improvement interventions to reduce HAI among hospitalized neonates and children will benefit from further investigation of methods to enhance reliable implementation of evidence-based practices, factors that enable multicenter collaboratives to be more successful, and better understanding of the causes of heterogeneity in the results at different centers. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


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.


Young Jr. W.F.,Mayo Medical School
Endocrine Practice | Year: 2010

Objective: To review the first reported cases of successfully treated pheochromocytoma and primary aldosteronism and to document the diagnostic and therapeutic advances that have occurred since the initial descriptions. Methods: The original case descriptions and the subsequent pertinent literature were reviewed. Results: The successful management of the initial cases of pheochromocytoma in 1926 and primary aldosteronism in 1954 was highlighted by keen clinical observation, clinical intuition, and application of scientific principles. Since those prismatic case descriptions, the technological advances in laboratory-based diagnosis, radiology-based tumor localization, and surgical approaches to the adrenal glands have been truly remarkable. Conclusions: The evolution in the diagnosis and treatment of pheochromocytoma will continue to progress as we identify more genetic causes, develop biochemical markers for "preclinical" pheochromocytoma, identify better markers for malignant disease, and develop more effective treatment options for malignant pheochromocytoma. Over the next decade, we hope to determine the pathophysiology for bilateral idiopathic hyperaldosteronism, develop less invasive and less technically demanding tests to distinguish between unilateral aldosterone-producing adenoma and bilateral idiopathic hyperaldosteronism, determine where low renin hypertension stops and primary aldosteronism starts, and determine the impact of genetic and environmental factors on aldosterone secretion in patients with and without primary aldosteronism. Copyright © 2010 AACE.


Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straightforward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail. © 2009 New York Academy of Sciences.


Wirrell E.C.,Mayo Medical School
Journal of Clinical Neurophysiology | Year: 2010

EEGs performed for new-onset seizures show epileptiform discharge in approximately 18% to 56% of children and 12% to 50% of adults. An EEG after sleep deprivation improves detection of epileptiform abnormalities, showing discharge in 13% to 35% of patients whose standard EEG findings were normal. Some studies have also shown a higher yield with EEG performed within 24 hours after the seizure. The EEG is a useful diagnostic study in this clinical setting for a number of reasons. First, specific EEG abnormalities help characterize the seizure type and epilepsy syndrome, which allows more informed decisions regarding therapy and more accurate prediction of seizure control and ultimate remission. Second, in certain cases, the EEG may detect more subtle seizures, including absence, myoclonic, or partial seizures. Third, specific EEG patterns may alert the clinician to the presence of a focal cerebral lesion. Fourth, most studies have shown that an epileptiform discharge is predictive of seizure recurrence, particularly in patients with idiopathic epilepsy. In the presence of epileptiform discharge, the recurrence risk is approximately double what would be predicted after a normal EEG. The predictive value of nonepileptiform abnormalities is not clearly established. Copyright © 2010 by the American Clinical Neurophysiology Society.


Sridhara R.,U.S. Food and Drug Administration | Mandrekar S.J.,Mayo Medical School | Dodd L.E.,U.S. National Institutes of Health
Clinical Cancer Research | Year: 2013

Progression-free survival (PFS) is frequently used as the primary efficacy endpoint in the evaluation of cancer treatment that is considered for marketing approval. Missing or incomplete data problems become more acute with a PFS endpoint (compared with overall survival). In a given clinical trial, it is common to observe incomplete data due to premature treatment discontinuation, missed or flawed assessments, change of treatment, lack of follow-up, and unevaluable data. When incomplete data issues are substantial, interpretation of the data becomes tenuous. Plans to prevent, minimize, or properly analyze incomplete data are critical for generalizability of results from the clinical trial. Variability in progressive disease measurement between radiologists further contributes to data problems with a PFS endpoint. The repercussions of this on phase III clinical trials are complex and depend on several factors, including the magnitude of the variability and whether there is a systematic reader evaluation bias favoring one treatment arm particularly in open-label trials. © 2013 AACR.


Pang Y.-P.,Mayo Medical School
Biochemical and Biophysical Research Communications | Year: 2014

CLN025 is one of the smallest fast-folding proteins. Until now it has not been reported that CLN025 can autonomously fold to its native conformation in a classical, all-atom, and isothermal-isobaric molecular dynamics (MD) simulation. This article reports the autonomous and repeated folding of CLN025 from a fully extended backbone conformation to its native conformation in explicit solvent in multiple 500-ns MD simulations at 277 K and 1 atm with the first folding event occurring as early as 66.1 ns. These simulations were accomplished by using AMBER forcefield derivatives with atomic masses reduced by 10-fold on Apple Mac Pros. By contrast, no folding event was observed when the simulations were repeated using the original AMBER forcefields of FF12SB and FF14SB. The results demonstrate that low-mass MD simulation is a simple and generic technique to enhance configurational sampling. This technique may propel autonomous folding of a wide range of miniature proteins in classical, all-atom, and isothermal-isobaric MD simulations performed on commodity computers - an important step forward in quantitative biology. © 2014 The Author. Published by Elsevier Inc.


Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are 99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17%; these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation. © 2010 Macmillan Publishers Limited All rights reserved.


The obesity epidemic is one of the greatest health challenges currently facing the general population, and it will have a major impact on LT because of the associated rise in the incidence of NASH and NASH-related HCC. There is already a severe shortage of available liver allografts, which will be exacerbated by an increased demand for LT with the rising incidence of obesity-related liver disease. Because the obesity crisis also impacts the availability of suitable living and deceased organ donors, the impact will be far more significant. Research and public health initiatives aimed at further elucidating and counteracting obesity in both adults and especially children is paramount. © 2014 American Association for the Study of Liver Diseases.


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.


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.


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.


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.


Textor S.C.,Mayo Medical School
Current Opinion in Nephrology and Hypertension | Year: 2011

Purpose: Whereas atherosclerotic renal artery stenosis is recognized to accelerate hypertension and threaten kidney function, recent trials indicate that many patients can be managed primarily with antihypertensive drug therapy without renal revascularization. These trials have been criticized for many reasons, including inclusion of large groups with only minor vascular occlusive disease. Recent findings: Although moderate stenosis is associated with preserved oxygenation within both cortex and medulla, severe disease is demonstrably associated with reduced oxygenation that can be identified using blood oxygen level-dependent magnetic resonance. Fewer clinical procedures to revascularize stenotic kidneys likely will be followed by advanced occlusion with loss of function. Experimental studies confirm that poststenotic microvascular injury is magnified in the presence of atherosclerosis, activating local inflammatory and fibrogenic pathways in the kidney. Even without restoring renal blood flow, experimental studies with endothelial progenitor cells indicate that recovery of renal vascular structures and function may be possible. Summary: The short-term prospective trials to date remain at odds with observational studies indicating improved blood pressure, stabilization of renal function, and improved management of some patients with congestive heart failure. Nephrologists will need to balance optimizing medical therapy for complex patients with renovascular disease and identifying those most likely to benefit from renal revascularization on an individualized basis. © 2011 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Yu L.,Mayo Medical School
AJR. American journal of roentgenology | Year: 2012

OBJECTIVE: We summarize how virtual monochromatic images are synthesized from dual-energy CT using image-domain and projection-domain methods. The quality of virtual monochromatic images is compared with that of polychromatic single-energy images acquired at different tube potentials and the same radiation dose. Clinical applications of dual-energy CT-based virtual monochromatic imaging are reviewed, including beam-hardening correction, contrast and noise optimization, metal artifact reduction, and material differentiation. CONCLUSION: Virtual monochromatic images synthesized from dual-energy CT data have the potential to reduce beam-hardening artifacts and to provide quantitative measurements. If there is no desire to obtain material-specific information or to correct for metal or beam-hardening artifacts from the dual-energy data, however, it is better to perform a conventional single-energy scan at the optimal tube potential.


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.


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.


Gay P.C.,Mayo Medical School
Respiratory Care | Year: 2010

Clinicians are becoming more aware of the risks of sleep deprivation and unrecognized sleep-disordered breathing in hospitalized patients, most importantly in those patients planning to undergo surgical procedures. Polysomnography is difficult to perform in the hospital setting, such that actigraphy or urinary metabolites of melatonin are often used as surrogate measures, and show that sleep is markedly impaired. Patients in the medical intensive care unit with sepsis or requiring mechanical ventilation may show complete absence of the normal circadian rhythm pattern, and many centers have initiated sleep-enhancement protocols. In postoperative patients, rapid-eye movement sleep is nearly obliterated, especially in the first 1-2 days after surgery, and this appears closely related to the use of high-dose opioids. Sleep-disordered breathing is common in postoperative patients, and tools such as the Sleep Apnea Clinical Score or the STOP-BANG (Snoring, Tiredness, Observed apnea, and high blood Pressure - Body mass index, Age, Neck circumference, and Gender) questionnaires have been utilized to predict the possibility of obstructive sleep apnea (OSA) and postoperative respiratory complications. Protocols to evaluate patients that determine the need and process for positive-airway-pressure treatment in the hospital patient with OSA are being developed. An obstructive apnea systematic intervention strategy protocol to deal with patients with suspected OSA can help guide diagnostic and therapeutic decision making. Hospitals that are proactive in the development of protocols for identification and management of patients with sleep-disordered breathing are likely to be rewarded with reduced complications and costs, and the issue is sure to be incorporated in future pay-for-performance evaluations. © 2010 Daedalus Enterprises.


Kurup A.N.,Mayo Medical School
Seminars in Interventional Radiology | Year: 2014

Although percutaneous ablation of small renal masses is generally safe, interventional radiologists should be aware of the various complications that may arise from the procedure. Renal hemorrhage is the most common significant complication. Additional less common but serious complications include injury to or stenosis of the ureter or ureteropelvic junction, infection/abscess, sensory or motor nerve injury, pneumothorax, needle tract seeding, and skin burn. Most complications may be treated conservatively or with minimal therapy. Several techniques are available to minimize the risk of these complications, and patients should be appropriately monitored for early detection of complications. In the event of a serious complication, prompt treatment should be provided. This article reviews the most common and most important complications associated with percutaneous ablation of small renal masses.©2014 by Thieme Medical Publishers, Inc.


Binnicker M.J.,Mayo Medical School
Current Opinion in Infectious Diseases | Year: 2012

PURPOSE OF REVIEW: A growing number of laboratories have implemented a reverse screening algorithm for syphilis testing, which has created confusion among many healthcare providers. This review focuses on recent data addressing the clinical and economical impact of reverse screening and discusses the advantages and limitations of the traditional and contemporary algorithms. RECENT FINDINGS: Screening for syphilis using a treponemal assay detects a higher number of patients with reactive results compared to traditional screening by rapid plasma reagin (RPR). Furthermore, a significant percentage of patients who are reactive by a treponemal screening assay are nonreactive by RPR. These discordant results may occur in patients with past, treated or untreated syphilis; early syphilis; or no syphilis. Recent reports suggest that the reverse screening algorithm may result in increased patient follow-ups, overtreatment, and potentially higher cost. However, other data suggest that reverse screening facilitates the detection of latent and early syphilis, while offering an objective and automated screening approach. SUMMARY: The Centers for Disease Control and Prevention currently recommends syphilis screening with a nontreponemal test. However, as laboratories continue to implement the reverse screening algorithm, it is important that samples with discordant screen-reactive, RPR-nonreactive results be tested by a second treponemal assay to assist in the interpretation of results. Copyright © Lippincott Williams & Wilkins.


Sierra R.J.,Mayo Medical School
The bone & joint journal | Year: 2013

Total hip replacement (THR) after acetabular fracture presents unique challenges to the orthopaedic surgeon. The majority of patients can be treated with a standard THR, resulting in a very reasonable outcome. Technical challenges however include infection, residual pelvic deformity, acetabular bone loss with ununited fractures, osteonecrosis of bone fragments, retained metalwork, heterotopic ossification, dealing with the sciatic nerve, and the difficulties of obtaining long-term acetabular component fixation. Indications for an acute THR include young patients with both femoral head and acetabular involvement with severe comminution that cannot be reconstructed, and the elderly, with severe bony comminution. The outcomes of THR for established post-traumatic arthritis include excellent pain relief and functional improvements. The use of modern implants and alternative bearing surfaces should improve outcomes further.


Melin B.,Umea 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.


Finn L.,Mayo Clinic Florida | Markovic S.N.,Mayo Medical School | Joseph R.W.,Mayo Clinic Florida
BMC Medicine | Year: 2012

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise. © 2012 Finn et al; licensee BioMed Central Ltd.


Hillestad M.L.,Mayo Medical School
Human gene therapy | Year: 2012

Reporter genes are important tools for assessing vector pharmacology in vivo. Although useful, current systems are limited by (1) the need to generate a new vector for each different reporter, (2) the inability to package reporter genes in small vectors, and (3) variations in reporter gene feedback due to variations in cell-to-cell vector copy number. To circumvent these problems, we have used Cre recombinase as a "cat's paw" to activate reporter genes embedded in transgenic mice. The small Cre gene was introduced into self-complementary adeno-associated viral (scAAV) vectors with limited packaging capacity. Injection of scAAV-Cre vectors into mice with loxP-inactivated luciferase enabled in vivo imaging distributions comparable to the signal observed after AAV-luciferase injection. When injected into mT/mG mice, AAV-Cre converted ubiquitous expression of red fluorescent protein (RFP) to green fluorescent protein (GFP) expression only where the vectors transduced cells. Injection into F(1) hybrid luciferase and mT/mG mice enabled simultaneous three-reporter tracking. This system was able to discriminate cell-specific transduction in all organs tested, with particular usefulness for detecting AAV serotype-specific transduction in the liver, kidney, and muscle. Given that F(1) mice bear exactly one copy of luciferase and one copy of RFP-GFP, each reporter gene is either "on" or "off" in a cell. The Cre system therefore provides a unique quantum method to quantify vector delivery that can be applied when vector capacity is limited.


Benarroch E.E.,Mayo Medical School
Neurology | Year: 2016

The transmission of pain involves several types of primary unmyelinated Aδ- and unmyelinated C afferents from neurons in in the dorsal root (or trigeminal) ganglion; these afferents activate second-order spinothalamic and spinobulbar projection neurons in the dorsal horn (or trigeminal nucleus caudalis). The dorsal horn is not a simple relay station but rather a site of complex processing and gating of nociceptive information via circuits involving different subtypes of excitatory or inhibitory interneurons. These neurons are the target of descending pain-modulatory influences from the rostral ventromedial medulla and other regions. Pain circuits also participate in the relay and processing of the sensation of itch. Specific molecular markers, such as transient receptor potential (TRP) channels and Mas-related G-protein-coupled receptor (Mrgpr) subtypes, have allowed the identification of different subtypes of primary afferents transmitting pain and itch sensations. The application of transgenic and ablation techniques has provided insight into the heterogeneity of excitatory or inhibitory interneurons and their involvement in dorsal horn circuits regulating transmission and gating of pain and itch. Excitatory interneurons have a major role in both normal and abnormal transmission of sensory input to the projection neurons; inhibitory interneurons are critically involved in gating these inputs. These findings provide new insights into the pathophysiology of the manifestations of neuropathic pain, including spontaneous pain, hyperalgesia, and mechanical allodynia, as well as neuropathic itch. There are several reviews on all these topics. 1-19 This review is focused on the spinal dorsal horn, although similar processes likely underlie facial trigeminal-mediated pain. © 2016 American Academy of Neurology.


Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute leukemia or myelofibrosis. Diagnosis: Diagnosis is based on JAK2 mutation status (PV and ET), serum erythropoietin (Epo) level (PV), and bone marrow histopathology (ET). The presence of a JAK2 mutation and subnormal serum Epo level confirm a diagnosis of PV. Differential diagnosis in ET should include chronic myelogenous leukemia and prefibrotic myelofibrosis. Risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications: high-risk-age >60 years or presence of thrombosis history; low-risk-absence of both of these two risk factors. Presence of extreme thrombocytosis (platelet count >1,000 × 109/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include age >60 years, leukocytosis, history of thrombosis, and anemia. Risk-adapted therapy: Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is <1%/1% in ET and <5%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications and this is effectively and safely accomplished by the use of low-dose aspirin (PV and ET), phlebotomy (PV), and hydroxyurea (high risk PV and ET). Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures. © 2011 Wiley-Liss, Inc.


Streubel P.N.,Mayo Medical School
The journal of knee surgery | Year: 2013

Periprosthetic femur fractures are becoming more frequent, as the prevalence of hip and knee arthroplasties keeps increasing and our population continues to age. Although the vast majority of literature on periprosthetic fractures has centered on radiographic and functional outcomes, only limited information is available on mortality. Patients with periprosthetic femur fractures are at a similar or higher mortality risk than hip fracture patients. Furthermore, periprosthetic femur fractures carry a significantly higher mortality risk than hip or knee arthroplasty or operative fixation of native distal femur fractures. Advanced patient age and underlying comorbidities increase the risk of mortality. Factors related to the injury itself and treatment method may play an additional role, especially during the short postoperative period. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.


A fixed-dose co-formulated antiretroviral drug containing elvitegravir, a new integrase strand transfer inhibitor, boosted by a novel pharmacokinetic enhancer cobicistat, and further containing the nucleoside pair of tenofovir and emtricitabine was recently approved by the U.S. Food and Drug Administration as a single-tablet, once-a-day treatment of HIV-1 infection in antiretroviral therapy-naive adults. This drug was found to be noninferior to two currently preferred antiretroviral regimens in clinical practice in two large, 48-week, phase III studies. Renal adverse effects limit its use to those with creatinine clearance > 70 mL/min; its considerable drug interaction potential requires care and attention when used. Nevertheless, the availability of this fixed-dose combination product is an important progress in the management of HIV infection for a number of reasons: It provides a third option for a onepill, once-a-day antiretroviral regimen; it is the first such regimen that is not based on a non-nucleoside reverse transcriptase inhibitor; and it provides an alternative to ritonavir for the pharmaco-enhancement of other antiretroviral drugs. Copyright © 2012 Prous Science, S.A.U. or its licensors. All rights reserved.


Baron T.H.,Mayo Medical School
Current Opinion in Gastroenterology | Year: 2011

Purpose of review: Benign biliary diseases are often managed endoscopically using plastic stents. Benign biliary strictures (BBS) respond to placement of multiple large-bore plastic stents, though requiring multiple procedures to place stents, and to exchange stents to prevent and/or treat stent occlusion. Bile leaks close using plastic stents, which divert bile away from the leak into the duodenum. Covered self-expandable metal stents (CSEMS), intended for palliation of malignant biliary obstruction, have been used to treat benign biliary diseases. Advantages include small predeployment and large postexpansion diameters. Lack of imbedding of the metal into the bile duct wall enables removability. Recent findings: For strictures, one CSEMS is inserted without need for dilation and remains in place for up to 6 months. Successful removal has been reported in all cases. Long-term stricture resolution is achieved in up to 92%. Adverse events include migration and new stricture formation. For treatment of complex bile leaks, the covering and large diameter allow successful closure in nearly all cases. Other uses of CSEMS include treatment of postsphincterotomy bleeding and closure of perforations. Summary: CSEMS show promise for treatment of BBS and complex biliary leaks. Successful resolution can be achieved in the majority of patients with the advantage of fewer procedures, which offsets their higher cost. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Wingerchuk D.M.,Mayo Medical School
Mount Sinai Journal of Medicine | Year: 2011

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although its cause is not known, genetic and environmental factors both influence susceptibility to the disease. From the large array of environmental risk factors that have been examined over the past century, infection with Epstein-Barr virus, ultraviolet light exposure/vitamin D status, and cigarette smoking stand out because of the strength of supporting evidence. Epstein-Barr virus infection early in life appears to be necessary permissive step for disease development and probably acts in adolescence and early adulthood. Vitamin D-related mechanisms and cigarette smoking probably modify baseline disease risk and could plausibly do so at several stages of life; smoking appears to negatively affect disease course. This review summarizes current evidence for these 3 putative multiple sclerosis risk factors and early attempts to develop risk models and examine gene-environment interactions for this complex disease. Mt Sinai J Med 78:221-230, © 2011 Mount Sinai School of Medicine.


Saito Y.A.,Mayo Medical School
Gastroenterology Clinics of North America | Year: 2011

Irritable bowel syndrome (IBS) is a common disorder that has been shown to aggregate in families and to affect multiple generations, but not in a manner consistent with a major Mendelian effect. Relatives of an individual with IBS are 2 to 3 times as likely to have IBS, with both genders being affected. To date, more than 100 genetic variants in more than 60 genes from various pathways have been studied in a number of candidate gene studies, with several positive associations reported. These findings suggest that there may be distinct, as well as shared, molecular underpinnings for IBS and its subtypes. © 2011 Elsevier Inc.


Staab J.P.,Mayo Medical School
NeuroRehabilitation | Year: 2011

Behavioral factors are an integral part of the overall morbidity of patients with vertigo, dizziness, and balance disorders. Anxiety, depression, and more importantly, loss of balance confidence and sense of debility and handicap beleaguer patients with acute and chronic vestibular symptoms. Vestibular rehabilitation originated as a physical therapy, but a careful look at its research development and clinical applications show it to be as much, or perhaps more, a behavioral intervention. More patients referred for vestibular rehabilitation require habituation to chronic vestibular symptoms and motion sensitivity than compensation for active peripheral or central vestibular deficits. Vestibular rehabilitation may exert a positive effect on behavioral morbidity, but the benefits are somewhat uneven and do not always correlate with physical improvements. Health anxiety (i.e., excessive worry about the cause and consequences of physical symptoms) is an emerging concept in clinical psychiatry and psychology. It may offer an important key to understanding the debility and handicap experienced by many patients with vestibular symptoms and enhance the ability of vestibular rehabilitation to ameliorate their suffering. © 2011-IOS Press and the authors. All rights reserved.


Significant increase in the literature regarding "residents as teachers" highlights the importance of providing opportunities and implementing guidelines for continuing medical education and professional growth. While most medical students are enthusiastic about their future role as resident-educators, both students and residents feel uncomfortable teaching their peers due to the lack of necessary skills. However, whilst limited and perhaps only available to select individuals, opportunities for developing good teaching practice do exist and may be identified in courses that offer basic sciences. The Department of Anatomy, College of Medicine, Mayo Clinic offers a teaching assistant (TA) elective experience to third- and fourth-year medical students through integrated apprenticeship and mentoring during the human structure didactic block. This article, aims to describe a curriculum for a TA elective within the framework of a basic science course through mentoring and apprenticeship. Opportunities for medical students to become TAs, process of TAs' recruitment, mentoring and facilitation of teaching and education research skills, a method for providing feedback and debriefing are described. Developing teaching practice based on apprenticeship and mentoring lends to more accountability to both TA's and course faculty by incorporating universal competencies to facilitate the TA experience.


Objective. - To draw attention to the syndrome of the trephined as a potential cause for orthostatic headaches without cerebrospinal fluid (CSF) leak. Background. - Orthostatic headaches typically result from CSF leaks but sometimes may occur in conditions without any evidence of CSF leakage. Methods. - A 37-year-old right-handed woman became comatose after a motor vehicle accident with cerebral contusions and massive left cerebral edema. A large frontoparietal craniectomy was carried out. In 5 months, she made good neurologic recovery. Freeze-preserved bone flap was placed back. In several weeks she was functionally near normal. Two years later, she began to complain of orthostatic headache and gradually additional manifestations appeared including progressive gait unsteadiness, imprecise speech, cognitive difficulties, and an increasing left hemiparesis along with progressive sinking of the skull defect and shift of the midline and ventricular distortion. She underwent removal of resorptive sinking bone flap and construction of an acrylic cranioplasty. Results. - At 6-month follow-up, there was complete resolution of the orthostatic headaches, remarkable neurologic improvement along with resolution of midline shift and ventricular distortion. Conclusion. - The syndrome of the trephined is yet another cause of orthostatic headaches without CSF leak. © 2010 American Headache Society.


Tefferi A.,Mayo Medical School | Barbui T.,Research Foundation
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.


De Strooper B.,Center for Human Genetics | Vassar R.,Northwestern University | Golde T.,Mayo Medical School
Nature Reviews Neurology | Year: 2010

The amyloid hypothesis has yielded a series of well-validated candidate drug targets with potential for the treatment of Alzheimer disease (AD). Three proteases that are involved in the processing of amyloid precursor proteinα-secretase, Β-secretase and γ-secretaseare of particular interest as they are central to the generation and modulation of amyloid-Β peptide and can be targeted by small compounds in vitro and in vivo. Given that these proteases also fulfill other important biological roles, inhibiting their activity will clearly be inherently associated with mechanism-based toxicity. Carefully determining a suitable therapeutic window and optimizing the selectivity of the drug treatments towards amyloid precursor protein processing might be ways of overcoming this potential complication. Secretase inhibitors are likely to be the first small-molecule therapies aimed at AD modification that will be fully tested in the clinic. Success or failure of these first-generation AD therapies will have enormous consequences for further drug development efforts for AD and possibly other neurodegenerative conditions. © 2010 Macmillan Publishers Limited. All rights reserved.


Immunoglobulin (Ig) G4-related disease (IgG4-RD), a fibroinflammatory condition that can affect multiple organs, is suggested by lymphoplasmacytic inflammation, fibrosis, phlebitis, and increased IgG4+ plasma cell (PC) tissue density. In patients with suspected IgG4-RD and skin changes, skin biopsy may serve as a diagnostic screen or to supplement nondiagnostic visceral biopsy specimens. We aimed to determine whether increased cutaneous IgG4+ PCs or IgG4/IgG ratio is specific for IgG4-RD. We examined 50 mucocutaneous specimens representing seven PC-rich dermatoses and reactive PC-rich infiltrates with IgG and IgG4 immunohistochemical stains. IgG4+ density exceeded 10 cells per high-power field in 22 (44%) of 50 specimens, representing six of seven diagnoses and reactive infiltrates. In five specimens (10%), the IgG4/IgG ratio exceeded 0.40. Moderately elevated IgG4+ PC density or IgG4/IgG ratio is a nonspecific finding in the skin. In cutaneous biopsy specimens showing increased IgG4+ PCs, careful consideration should be given to clinical, serologic, and other histopathologic features before attributing clinical changes to IgG4-RD.


Noheria A.,Mayo Medical School
Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing | Year: 2011

Atrial septal defects (ASD), including patent foramen ovale, have been linked to an increased prevalence of migraine headaches in the general population. A similar association with migraine is speculated for iatrogenic ASD due to atrial septal puncture during catheter ablation for atrial fibrillation (AF). A total of 2,069 patients who underwent catheter ablation for AF at Mayo Clinic, Rochester, MN between January 2001 and December 2008 were scheduled for follow-up at least at 3 months and annually thereafter. Data were collected from the questionnaires patients answered at follow-up inquiring about presence and characteristics of any headaches following the procedure and further chart review. Definite migraine was diagnosed based on clinical features per the International Classification of Headache Disorder-II definition. Twenty-two patients (1.1%) had a new-onset definite migraine, 12 (0.6%) had a new-onset probable migraine, ten (0.5%) with a previous history of migraine had worsened headaches, and four (0.2%) had headache due to an alternate identifiable cause; a total of 48 patients (2.3%) reported post-procedural headaches. Nineteen of 22 patients (86%) with definite migraine had complete resolution of symptoms at 1- to 2-year follow-up. New-onset migraine is an uncommon and usually temporary side effect of catheter ablation for AF. The mechanism for post-procedure headache remains unclear.


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.


Peng Y.,Mayo Medical School
Current topics in developmental biology | Year: 2012

The polarization of epithelial cells along an axis orthogonal to their apical-basal axis is increasingly recognized for roles in a variety of developmental events and physiological functions. While now studied in many model organisms, mechanistic understanding is rooted in intensive investigations of planar cell polarity (PCP) in Drosophila. Consensus has emerged that two molecular modules, referred to here as the global and core modules, operate upstream of effector proteins to produce morphological PCP. Proteins of the core module develop subcellular asymmetry, accumulating in two groups on opposite sides of cells, consistent with proposed functions in producing cell polarity and in communicating that polarity between neighboring cells. Less clear are the molecular and cell biological mechanisms underlying core module function in the generation and communication of subcellular asymmetry and the relationship between the global and the core modules. In this review, we discuss these two unresolved questions, highlighting important studies and potentially enlightening avenues for further investigation. It is likely that results from Drosophila will continue to inform our views of the growing list of examples of PCP in vertebrate systems. Copyright © 2012 Elsevier Inc. All rights reserved.


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.


Price K.A.R.,Mayo Medical School | Cohen E.E.,University of Chicago
Current Treatment Options in Oncology | Year: 2012

Opinion statement: Head and neck squamous cell carcinoma is now the 8th most common cancer affecting men in the United States largely due to a rising epidemic of oropharynx cancer (tonsil and tongue base) associated with the human papillomavirus (HPV). The median overall survival for recurrent or metastatic head and neck cancer (R/M HNSCC) remains less than 1 year despite modern chemotherapy and targeted agents. Palliative chemotherapy and the epidermal growth factor receptor inhibitor, cetuximab, constitute the backbone of treatment for patients with R/M HNSCC. Platinum doublets studied in phase III trials include cisplatin/5-FU, cisplatin/paclitaxel, and cisplatin/pemetrexed. Platinum chemotherapy in combination with 5-fluorouracil and cetuximab has resulted in the longest median overall survival. Combination platinum regimens increase response rates and toxicity but not survival and should be reserved for patients who are symptomatic from their disease for whom the benefit of a partial response may be worth the cost of increased treatment-related side effects. For many patients who are asymptomatic with a low disease burden, single agent regimens are appropriate to balance treatment with side effects. Drugs commonly used as single agents in the treatment of R/M HNSCC include docetaxel, paclitaxel, cetuximab, capecitabine, pemetrexed, and methotrexate. Best supportive care alone is often appropriate for poor performance status patients. Palliative radiation therapy is beneficial for treating symptomatic metastatic sites. Aggressive symptom management is imperative for all patients and often should include referral to experts in palliative care and pain management. New therapies currently under investigation include mTOR inhibitors, anti-angiogenic agents, and IGF1R inhibitors. Given the poor prognosis for most patients with R/M HNSCC, enrollment in clinical trials investigating novel approaches to therapy should be encouraged. © 2012 Springer Science+Business Media, LLC.


Richards M.L.,Mayo Medical School
Thyroid : official journal of the American Thyroid Association | Year: 2010

BACKGROUND: Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies, and 5% of these patients will have familial disease. This compares to 25% of patients with medullary thyroid cancer (MTC) having a familial form; however, this accounts for only 1% of all patients with thyroid cancer. Most cases of familial thyroid cancer are nonmedullary (NMFTC), and have been shown to be present in familial cancer syndromes such as familial adenomatous polyposis, Cowden syndrome, Carney complex, Pendred syndrome, and Werner syndrome. This review discusses the contemporary management of the patients with familial-syndrome-associated thyroid cancer based on their individual risks for developing thyroid cancer. SUMMARY: Most of the progress in the genetics of familial thyroid cancer has been in patients with MTC. The mutations in patients with isolated NMFTC have not been as well defined as in MTC. They are likely autosomal dominant with reduced penetrance. The patients with these familial syndromes most likely have a susceptibility gene that increases the risk of thyroid cancer. Most of the patients with a familial syndrome and NMFTC will have papillary thyroid carcinoma, suggesting that a specific gene for papillary thyroid carcinoma may also be present. In many cases, patients have a known familial syndrome that has defined risk for thyroid cancer. CONCLUSIONS: Patients with familial syndromes that are associated with thyroid cancer can be individually categorized based on syndrome risks for developing thyroid cancer. The clinician must also be knowledgeable in recognizing the possibility of an underlying familial syndrome when a patient presents with thyroid cancer.


Horlocker T.T.,Mayo Medical School
Orthopedics | Year: 2010

Patients undergoing total hip and knee arthroplasty experience substantial and sustained postoperative pain. Inadequate analgesia may impede recovery and delay hospital discharge. Traditionally, postoperative analgesia following arthroplasty was provided by intravenous patient-controlled analgesia or epidural analgesia, but each technique has distinct advantages and disadvantages. Recently, peripheral nerve blockade of the lumbosacral plexus has emerged as an alternative analgesic approach. An increasing number of studies have reported multimodal analgesia featuring unilateral peripheral block provide pain relief and functional outcomes similar to that of continuous epidural and superior to systemic analgesia but with fewer side effects. This review discusses the indications, benefits, and side effects associated with conventional and innovative analgesic approaches to facilitate rehabilitation and improve outcome following total joint arthroplasty. Copyright 2010, SLACK Incorporated.


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.


Razonable R.R.,Mayo Medical School
Immunotherapy | Year: 2010

Immune fitness is critical in the pathogenesis and outcome of cytomegalovirus (CMV) infection. CMV disease is seen almost exclusively among individuals with an immature or defective immune system, such as patients with AIDS, transplant recipients and the developing fetus. These observations have generated interest in immune-based strategies for the management of CMV disease. Among the immune-based therapies that have been investigated in experimental and clinical settings are: passive immunotherapy with immunoglobulin; CMV vaccination; adoptive CMV-specific T-cell immunotherapy; and immune reconstitution strategies (HAART in AIDS patients, and a reduction in pharmacologic immunosuppression among transplant recipients). However, except for immune reconstitution strategies, there is no widely accepted immune-based strategy that is proven to be highly effective for CMV disease management. The benefits of immunoglobulins remain debated in an era when antiviral therapy is widely available. CMV vaccination and adoptive immunotherapy, on the other hand, remain experimental, but have had encouraging preliminary results. © 2010 Future Medicine Ltd.


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.


Winters J.L.,Mayo Medical School
Journal of Clinical Apheresis | Year: 2012

Dilated cardiomyopathy (DCM) causes significant morbidity and mortality and is the number one indication for cardiac transplantation in the United States. A large percentage of cases of DCM have no identifiable cause with evidence suggesting that these may represent an autoimmune disorder triggered by viral myocarditis. There is a growing body of literature suggesting that a number of immunoadsorption techniques, as well as plasma exchange, may have a role in the treatment of idiopathic DCM. The hypothesized autoimmune mechanism behind idiopathic DCM as well as the published evidence for the use of apheresis in this disorder are reviewed. The available evidence suggests that apheresis may be an effective treatment, but additional research is needed to identify markers that will predict response and the most effective apheresis technique. Copyright © 2012 Wiley Periodicals, Inc.


Lindor K.D.,Mayo Medical School
Digestive Diseases | Year: 2011

Primary sclerosing cholangitis (PSC) is a progressive liver disease without adequate treatment. Because the pathogenesis of PSC is not well understood, specific therapies designed to alter the pathogenesis are not available. Animal models suggest a link between bacterial overgrowth, lipopolysaccharides from the bacterial cell walls and stimulation of endogenous TNF formation which can be inhibited by pentoxifylline. Unfortunately, in humans treated with pentoxifylline, little effect was seen. Antibiotics such as metronidazole, vancomycin, tetracycline and azithromycin in small studies show biochemical improvement. Docosahexanoic acid has been used for treating patients in a small pilot study and led to some improvement in liver biochemistries. Immunologic abnormalities have been considered to be potentially important. Attempts to treat PSC with mycophenolate mofetil and tacrolimus have been largely unsuccessful. Budesonide has shown a limited benefit, but perhaps more so in patients with elevated IgG4 levels. PSC is characterized by marked fibrosis. Modulation of the renin-angiotensin system as well as use of rapamycin may reduce fibrosis, but data from this approach has been scant. Bile acids have been tested, but initial doses used in primary biliary cirrhosis led only to biochemical improvement. Higher doses of ursodeoxycholic acid (28-30 mg/kg/day) seemed to be associated with a worsening outcome. Intermediate doses have been tested in a study where biochemical improvement was seen and trends towards enhanced survival were found, but only about two thirds of the anticipated enrollment occurred. Currently, there are multiple potential therapeutic avenues to explore for patients with PSC, and it is hoped that one of these will lead to identification of a proven therapy for this disease. Copyright © 2011 S. Karger AG, Basel.


Stegall M.D.,von Liebig Transplant Center | Chedid M.F.,von Liebig Transplant Center | Cornell L.D.,Mayo Medical School
Nature Reviews Nephrology | Year: 2012

Over the past decade, several studies have suggested that the complement system has an active role in both acute and chronic allograft rejection. These studies have been facilitated by improved techniques to detect antibody-mediated organ rejection, including immunohistological staining for C4d deposition in the allograft and solid-phase assays that identify donor-specific alloantibodies (DSAs) in the serum of transplant recipients. Studies with eculizumab, a humanized monoclonal antibody directed against complement component C5, have shown that activation of the terminal complement pathway is necessary for the development of acute antibody-mediated rejection in recipients of living-donor kidney allografts who have high levels of DSAs. The extent to which complement activation drives chronic antibody-mediated injury leading to organ rejection is less clear. In chronic antibody-mediated injury, early complement activation might facilitate chemotaxis of inflammatory cells into the allograft in a process that later becomes somewhat independent of DSA levels and complement factors. In this Review, we discuss the different roles that the complement system might have in antibody-mediated allograft rejection, with specific emphasis on renal transplantation. © 2012 Macmillan Publishers Limited. All rights reserved.


Alberts S.R.,Mayo Medical School
Critical Reviews in Oncology/Hematology | Year: 2012

Patients with colorectal liver metastases represent a distinct subset of metastatic colorectal cancer. Optimal management requires a multidisciplinary approach, local and systemic. Curative hepatic surgery is standard for resectable cases, but unfortunately, the majority of patients are not initially resectable due to the size, location, and/or extent of disease, inadequate remnant liver volume, or comorbidities. Other local approaches may be complementary (such as portal vein embolization) or alternative (such as ablation, hepatic arterial infusion, selective internal radiation therapy, and stereotactic body radiotherapy) to surgery. Systemic therapy can downsize disease, allowing surgical resection and, potentially, long-term survival, but it must be balanced against the potential for hepatotoxicity. Current standard approaches including cytotoxics and biologics, such as bevacizumab and particularly anti-epidermal growth factor receptor therapy, improve response rates and may enhance downsizing and resection rates. Optimization of local therapies and systemic conversion strategies via controlled, randomized trials is still a pending question. © 2012 Elsevier Ireland Ltd.


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.


Josephs K.A.,Mayo Medical School
Journal of Neurology | Year: 2015

It has been approximately 50 years since neurologists were introduced to the entities, “progressive supranuclear palsy” and “corticobasal degeneration”. Since the two seminal publications, there have been significant advancements in our understanding of these two neurodegenerative diseases, particularly the fact that both are associated with tau. Recent advances over the past 3 years that are notable to the field are discussed in this review that covers clinical diagnosis, pathological features, neuroimaging and CSF biomarkers, genetic associations and clinical trials related to progressive supranuclear palsy and corticobasal degeneration. © 2015, Springer-Verlag Berlin Heidelberg.


Tschumperlin D.J.,Mayo Medical School
Annals of the American Thoracic Society | Year: 2015

The extracellular matrix (ECM) of the lung serves as both a scaffold for resident cells and a mechanical support for respiratory function. The ECM is deposited during development and undergoes continuous turnover and maintenance during organ growth and homeostasis. Cells of the mesenchyme, including the tissue resident fibroblast, take a leading role in depositing and organizing the matrix and do so in an anatomically distinct fashion, with differing composition, organization, and mechanical properties within the airways, vessels, and alveoli of the lung. Recent technological advancements have allowed the lung's ECM biochemical composition and mechanical properties to be studied with improved resolution, thereby identifying novel disease-related changes in ECM characteristics. In parallel, efforts to study cells seeded on normal and disease-derived matrices have illustrated the powerful role the ECM can play in altering key functions of lung resident cells. The mechanical properties of the matrix have been identified as an important modifier of cell-matrix adhesions, with matrices of pathologic stiffness promoting profibrotic signaling and cell function. Ongoing work is identifying both mechanically activated pathways inmesenchymal cells and disease-related ECM molecules that biochemically regulate cell function. Uncovering the control systems by which cells respond to and regulate the matrix, and the failures in these systems that underlie aberrant repair, remains a major challenge. Progress in this area will be an essential element in efforts to engineer functional lung tissue for regenerative approaches and will be key to identifying new therapeutic strategies for lung diseases characterized by disturbed matrix architecture. Copyright © 2015 by the American Thoracic Society.


Swiecicki P.L.,Mayo Medical School
Blood | Year: 2013

Cold agglutinin disease is a rare and poorly understood disorder affecting 15% of patients with autoimmune hemolytic anemia. We reviewed the clinical and pathologic features, prognosis, and management in the literature and describe our institutional experience to improve strategies for accurate diagnosis and treatment. Retrospective analysis identified 89 patients from our institution with cold agglutinin disease from 1970 through 2012. Median age at symptom onset was 65 years (range, 41 to 83 years), whereas the median age at diagnosis was 72 years (range, 43 to 91 years). Median survival of all patients was 10.6 years, and 68 patients (76%) were alive 5 years after the diagnosis. The most common symptom was acrocyanosis (n = 39 [44%]), and many had symptoms triggered by cold (n = 35 [39%]) or other factors (n = 20 [22%]). An underlying hematologic disorder was detected in 69 patients (78%). Thirty-six patients (40%) received transfusions during their disease course, and 82% received drug therapy. Rituximab was associated with the longest response duration (median, 24 months) and the lowest proportion of patients needing further treatment (55%). Our institution's experience and review of the literature confirms that early diagnostic evaluation and treatment improves outcomes in cold agglutinin disease.


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.


Fass R.,Section of Gastroenterology | 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.


Stewart M.W.,Mayo Medical School
Expert Review of Clinical Pharmacology | Year: 2013

Aflibercept, a soluble receptor molecule that binds VEGF, has been recently approved for the treatment of exudative age-related macular degeneration. This fusion protein with binding sequences from VEGF receptors 1 and 2 possesses high binding affinity for isomers of VEGF-A, VEGF-B and PlGF, and prevents VEGF from initiating proliferation and migration of vascular endothelial cells. Phase III trials showed that intravitreal aflibercept given monthly or every 2 months produces visual improvement and decrease in macular thickness comparable with monthly ranibizumab. The second year of the trials demonstrated that as-needed aflibercept maintained vision with few required injections. Aflibercept promises to decrease the treatment burden faced by patients with exudative age-related macular degeneration. © 2013 Expert Reviews Ltd.


Ansell S.M.,Mayo Medical School
Current Opinion in Hematology | Year: 2015

Purpose of review The purpose of this article is to discuss the tumor microenvironment in lymphoma, and to review potential immune targets that are now becoming relevant because of clinical responses seen with the use of immune checkpoint inhibitors. Recent findings Recent data have shown that cells within the immune microenvironment in lymphoma express programmed death ligand-1 (PD-L1) and many of the intratumoral T cells with an exhausted immune phenotype express programmed cell death-1 (PD-1). This provides a novel opportunity to inhibit the immune checkpoints and initial clinical trials, utilizing antibodies that block the interaction between PD-1 and PD-L1 have demonstrated significant clinical responses in various lymphomas, including Hodgkin lymphoma. Summary The use of immune checkpoint inhibitors, including nivolumab and pembrolizumab, in relapsed and refractory patients with lymphoma is proving highly successful. Patients with Hodgkin lymphoma, in particular, have a very high response rate to PD-1 blockade and responses in these patients appear durable. Copyright © 2015 Wolters Kluwer Health, Inc.


McCabe P.J.,Mayo Medical School
The Journal of cardiovascular nursing | Year: 2010

Atrial fibrillation (AF) is a life-complicating illness adversely affecting morbidity, health-related quality of life (HRQOL), and healthcare use. Studies using HRQOL instruments suggest that patients diagnosed with AF experience more psychological distress than do healthy controls. Psychological distress in forms of anxiety and depression in patients with heart failure or coronary artery disease is related to increased mortality, morbidity, and consumption of healthcare. However, there is a critical lack of knowledge regarding the type and extent of psychological distress and its consequences in patients diagnosed with AF. This article will review the current state of scientific knowledge regarding psychological distress in patients with AF and offer suggestions for future studies. Medline, CINAHL, PscyhInfo, and Psychology and Behavioral Sciences Collection databases up to June 2009 were reviewed for key terms atrial fibrillation, psychological distress, affective distress, mood, emotional distress, psychological stress, negative affect, anxiety, depression, anger, and hostility. Ten studies using tested instruments to measure psychological distress were retained. The prevalence of psychological distress was not consistently reported. Combined findings revealed that psychological distress in the form of depression and/or anxiety uniquely contributed to greater AF symptom severity, diminished HRQOL, and recurrence of AF. Studies describing interventions to address psychological distress were not found. Lack of conceptual clarity and diversity of study purposes, designs, participants, and instruments limit the ability to draw coherent conclusions from findings. Nevertheless, findings suggest that psychological distress is present in a substantial portion of patients diagnosed with AF and its presence is related to adverse outcomes. Further study to identify the prevalence, characteristics, and consequences of psychological distress in patients diagnosed with AF is required to extend our knowledge and provide a foundation for development of interventions to address psychological distress in this rapidly increasing population.


Mrazek D.A.,Mayo Medical School
Dialogues in clinical neuroscience | Year: 2010

The clinical adoption of psychiatric pharmacogenomic testing has taken place rapidly over the past 7 years. Initially, drug-metabolizing enzyme genes, such as the cytochrome P450 2D6 gene (CYP2D6), were identified. Genotyping the highly variable cytochrome P450 2D6 gene now provides clinicians with the opportunity to identify both poor metabolizers and ultrarapid metabolizers of 2D6 substrate medications. Subsequently, genes influencing the pharmacodynamic response of medications have been made available for clinical practice. Among the earliest "target genes" was the serotonin transporter gene (SLC6A4) which has variants that have been shown to influence the clinical response of patients of European ancestry when they are treated with selective serotonin reuptake inhibitors. Genotyping of some of the serotonin receptor genes is also available to guide clinical practice. The quantification of the clinical utility of pharmacogenomic testing is evolving, and ethical considerations for testing have been established. Given the increasingly clear cost-effectiveness of genotyping, it has recently been predicted that pharmacogenomic testing will routinely be ordered to guide the selection and dosing of psychotropic medications.


Christensen K.N.,Mayo Medical School
Radiographics : a review publication of the Radiological Society of North America, Inc | Year: 2010

Virtual dissection is a three-dimensional (3D) display technique for CT colonography that could potentially reduce interpretation times. With virtual dissection, the 3D model of the colon is "sliced" open along a centerline trace, rendering a 360° view of the endoluminal mucosa as a rectangular image. However, one must be familiar with several pitfalls and limitations to avoid errors in interpretation. One of the main limitations is the anatomic distortion that results. Polyp shape and colonic folds can be distorted and colonic or polyp mobility can lead to mischaracterization of polyps. Distorted folds, which frequently occur at flexures, can mimic polyps. Annular constricting masses can lead to skip areas, where the abnormality is not displayed. Various entities including diverticula and stool can mimic polyps at virtual dissection. Finally, technical errors such as an inadequate centerline trace can render a polyp occult. The purpose of this review is to demonstrate the spectrum of appearances of polyps at virtual dissection, with an emphasis on more difficult to detect polyps. In addition, 10 interactive virtual dissection quiz cases are presented along with corresponding two-dimensional and 3D endoluminal fly-through views.


Alzheimer disease (AD) is one of, if not the most, feared diseases associated with aging. The prevalence of AD increases exponentially with age after 60 years. Increasing life expectancy coupled with the absence of any approved disease-modifying therapies at present position AD as a dominant public health problem. Major advances have occurred in the development of disease biomarkers for AD in the past 2 decades. At present, the most well-developed AD biomarkers are the cerebrospinal fluid analytes amyloid-b 42 and tau and the brain imaging measures amyloid positron emission tomography (PET), fluorodeoxyglucose PET, and magnetic resonance imaging. CSF and imaging biomarkers are incorporated into revised diagnostic guidelines for AD, which have recently been updated for the first time since their original formulation in 1984. Results of recent studies suggest the possibility of an ordered evolution of AD biomarker abnormalities that can be used to stage the typical 20-30-year course of the disease. When compared with biomarkers in other areas of medicine, however, the absence of standardized quantitative metrics for AD imaging biomarkers constitutes a major deficiency. Failure to move toward a standardized system of quantitative metrics has substantially limited potential diagnostic usefulness of imaging in AD. This presents an important opportunity that, if widely embraced, could greatly expand the application of imaging to improve clinical diagnosis and the quality and efficiency of clinical trials. © RSNA, 2012.


Amrami K.K.,Mayo Medical School
Radiologic Clinics of North America | Year: 2012

The seronegative spondyloarthropathies are a diverse group of conditions most commonly affecting the axial spine, often presenting with back pain of an inflammatory nature. The primary unifying feature of these disorders is sacroiliitis. The distinction between subtypes of spondyloarthritis is based on genotype (HLA-B27 positivity as in ankylosing spondylitis), peripheral manifestations of disease (psoriatic and reactive arthritis), and factors such as age, gender, and comorbidity. Although radiography has long been used to diagnose the spondyloarthropathies, advanced imaging with magnetic resonance is better able to diagnose these disorders at their earliest stages and monitor disease-modifying therapies. © 2012 Elsevier Inc.


Wright W.F.,University of Maryland Baltimore County | Pritt B.S.,Mayo Medical School
Diagnostic Microbiology and Infectious Disease | Year: 2012

Dengue is a mosquito-transmitted infection that poses significant global health risks for travelers and individuals living in the tropics and subtropics. The reported global incidence has increased dramatically in the past century, with dengue now ranking as the most common cause of febrile illness in travelers. While sporadic cases have been reported within the southern United States since 1980, autochthonous outbreaks have now been described in Hawaii, St. Croix (US Virgin Islands), along the Texas-Mexico border, and, most recently, in Key West, Florida. Although many infections are mild or asymptomatic, 5-10% of patients may experience hemorrhagic disease, with shock and even death. Laboratory identification commonly involves serologic and nucleic acid amplification methods. Due to rising incidence worldwide, physicians should be familiar with the clinical manifestations, laboratory diagnosis, and management of this illness. © 2012 Elsevier Inc.


Maus T.,Mayo Medical School
Physical Medicine and Rehabilitation Clinics of North America | Year: 2010

Imaging is an integral part of the clinical examination of the patient with back pain; it is, however, often used excessively and without consideration of the underlying literature. The primary role of imaging is the identification of systemic disease as a cause of the back or limb pain; magnetic resonance imaging (MRI) excels at this. Systemic disease as a cause of back or limb pain is, however, rare. Most back and radiating limb pain is of benign nature, owing to degenerative phenomena. There is no role for imaging in the initial evaluation of the patient with back pain in the absence of signs or symptoms of systemic disease. When conservative care fails, imaging may be undertaken with due consideration of its risks: labeling the patient as suffering from a degenerative disease, cost, radiation exposure, and provoking unwarranted minimally invasive or surgical intervention. Imaging can well depict disc degeneration and disc herniation. Imaging can suggest the presence of discogenic pain, but the lack of a pathoanatomic gold standard obviates any definitive conclusions. The imaging natural history of disc herniation is resolution. There is very poor correlation between imaging findings of disc herniation and the clinical presentation or course. Psychosocial factors predict functional disability due to disc herniation better than imaging. Imaging with MRI, computed tomography (CT), or CT myelography can readily identify central canal, lateral recess, or foraminal compromise. Only when an imaging finding is concordant with the patient's pain pattern or neurologic deficit can causation be considered. The zygapophysial (facet) and sacroiliac joint are thought to be responsible for axial back pain, although with less frequency than the disc. Imaging findings of the structural changes of osteoarthritis do not correlate with pain production. Physiologic imaging, either with single-photon emission CT bone scan, heavily T2-weighted MRI sequences (short-tau inversion recovery), or gadolinium enhancement, can detect inflammation and are more predictive of an axial pain generator. © 2010 Elsevier Inc.


Murthy N.S.,Mayo Medical School
Radiologic Clinics of North America | Year: 2012

Back pain caused by stress fractures, fatigue, or insufficiency, affects varied patient populations based on the level of physical activity and bone mineral density. Stress fractures may involve the vertebral body, pars interarticularis, and the pedicle; often overlooked are stress fractures of the sacrum or bony pelvis, which can mimic pain of spinal origin and delay diagnosis. The choice of optimal imaging (radiographs, nuclear medicine, magnetic resonance imaging, and computed tomography) also depends on the patient population under study and the clinically suspected diagnosis. The diagnosis typically determines which imaging modality is best to follow healing or progression. © 2012 Elsevier Inc.


Diehn F.E.,Mayo Medical School
Radiologic Clinics of North America | Year: 2012

This article reviews the imaging and relevant clinical details of infection of the extradural spine. Spine infections are increasing in incidence and in frequency of diagnosis. They are clinically important despite their relative rarity, because they may be life-threatening, and because early diagnosis leads to improved outcomes. The focus is on pyogenic spondylodiscitis. The also typically pyogenic conditions of epidural and subdural abscess, facet joint infection, and pyomyositis are discussed. Nonpyogenic, granulomatous infections are also addressed. Magnetic resonance imaging is emphasized. The radiologist's role in performing minimally invasive sampling procedures is highlighted. © 2012 Elsevier Inc.


Sorenson E.J.,Mayo Medical School
Neurologic Clinics | Year: 2012

The motor neuron diseases are a set of disorders associated with the selective degeneration of motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common and confers the gravest prognosis. Although ALS occurs with known genetic causes in a small minority, other motor neuron disorders have well-defined genetic mutations. Electrodiagnostic testing is important to distinguish these various disorders. Electrodiagnostic testing is also crucial for distinguishing potential mimic syndromes, such as multifocal motor neuropathy and inclusion body myositis. Newer neurophysiology techniques have been developed in the past several years. What role these techniques will play in clinical practice is currently unknown. © 2012 Elsevier Inc.


Prommer E.,Mayo Medical School
Clinical Journal of Pain | Year: 2012

Background: There has been increased recognition of calcineurin, a phosphoprotein serine/threonine phosphatase enzyme, in the regulation of many physiologic systems. Calcineurin mediates activation of lymphocytes, which play a role in immune response. Widely distributed in the central nervous system, calcinuerin also plays an important role in sensory neural function, via its role in the regulation of newly discovered 2-pore potassium channels, which greatly influence neuronal resting membrane potentials. Calcinuerin inhibition is the mechanism of action of immunomodulatory drugs such as cyclosporine and tacrolimus, which are widely used in transplantation medicine to prevent rejection. While important for immunosuppression, the use of calcineurin inhibitors has been associated with the development of a new pain syndrome called the calcineurin pain syndrome, which appears to be an untoward complication of the interruption of the physiologic function of calcineurin. Methods: This is a narrative review focusing on the epidemiology, pathophysiology, characterization of a newly recognized pain syndrome associated with the use of calcineurin inhibitors. Results: The use of immunosuppressants however is associated with several well-known toxicities to which the calcineurin pain syndrome can be added. The development of this syndrome most likely involves altered nociceptive processing due to the effect of calcineurin inhibition on neuronal firing, as well as effects of calcineurin on vascular tone. The most striking aspect of the treatment of this syndrome is the response to calcium channel blockers, which suggest that the effects of calcineurin inhibition on vascular tone play an important role in the development of the calcineurin pain syndrome. Conclusion: The calcineurin syndrome is a newly recognized complication associated with the use of calcineurin inhibitors. There is no standard therapy at this time but anecdotal reports suggest the effectiveness of calcium channel blockers. © 2012 by Lippincott Williams & Wilkins.


Wald J.T.,Mayo Medical School
Radiologic Clinics of North America | Year: 2012

Although most often back pain is of benign origin, it can occasionally be a harbinger of a more serious spinal condition, including spine neoplasm. Knowledge of the typical clinical history of spinal tumors and an understanding of the innervation of the spine and surrounding supporting structures may allow us to better understand when to pursue advanced imaging in the evaluation of spinal pain syndromes. Many radiologists have divided the differential diagnosis of neoplasms of the spine into compartments. These compartments include the extradural compartment, intradural/extramedullary compartment, and the intramedullary compartment. © 2012 Elsevier Inc.


The role of the posterior elements in generating axial back and neck pain is well established; the imaging detection of posterior element pain generators remains problematic. Morphologic imaging findings have proved to be nonspecific and are frequently present in asymptomatic patients. Edema, inflammation, and hypervascularity are more specific for sites of pain generation, but are often overlooked by imagers if physiologic imaging techniques such as fat-suppressed T2 or contrast-enhanced T1-weighted magnetic resonance imaging, radionuclide bone scanning with single-photon emission computed tomography (CT), or 18F-fluorodeoxyglucose positron emission tomography combined with CT are not used. © 2012 Elsevier Inc.


Roger V.L.,Mayo Medical School
Circulation Research | Year: 2013

Heart failure (HF) has been singled out as an epidemic and is a staggering clinical and public health problem, associated with significant mortality, morbidity, and healthcare expenditures, particularly among those aged ≥65 years. The case mix of HF is changing over time with a growing proportion of cases presenting with preserved ejection fraction for which there is no specific treatment. Despite progress in reducing HF-related mortality, hospitalizations for HF remain frequent and rates of readmissions continue to rise. To prevent hospitalizations, a comprehensive characterization of predictors of readmission in patients with HF is imperative and must integrate the impact of multimorbidity related to coexisting conditions. New models of patient-centered care that draw on community-based resources to support HF patients with complex coexisting conditions are needed to decrease hospitalizations. © 2013 American Heart Association, Inc.


Maleszewski J.J.,Mayo Medical School
The Journal of thoracic and cardiovascular surgery | Year: 2015

Inflammatory diseases of the aorta comprise a spectrum of disease with diverse clinical and histopathologic presentations. Broadly, they may be dichotomized into infectious and noninfectious varieties. Although uncommon, infectious forms, caused by bacteria, fungi, or mycobacteria, may result from hematogenous seeding of the aorta or direct spread from a contiguous infectious source. The noninfectious forms include a number of entities, the most common of which is atherosclerosis, a disease that primarily affects the aortic intima but has important secondary effects on the media and adventitia that may result in aneurysm formation. Other important noninfectious inflammatory diseases include giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegener granulomatosis), sarcoidosis, and lymphoplasmacytic aortitis. Importantly, there is increasing recognition that there is a subset of cases of lymphoplasmacytic aortitis perhaps better classified under the spectrum of so-called IgG4-related sclerosing disease, with important clinical and therapeutic ramifications. This review focuses on the variable and defining characteristics of the inflammatory aortopathies, specifically those affecting the ascending aorta, and discusses areas of important clinical and pathological distinction between them. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.


Kopecky S.,Mayo Medical School
American Journal of Cardiovascular Drugs | Year: 2012

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a potent risk factor for stroke and transient ischemic attack. Most patients with AF receive antithrombotic stroke prophylaxis, often in the form of a vitamin K antagonist, typically warfarin. Drug treatment with warfarin is associated with significant management issues, such as an unpredictable dose response necessitating dose adjustments, frequent laboratory monitoring, and multiple interactions with other medications, as well as foods. A new generation of novel anticoagulants has emerged that includes dabigatran etexilate, a direct thrombin inhibitor, and rivaroxaban and apixaban, both highly selective factor Xa inhibitors. These newer agents possess a highly predictable pharmacokinetic-pharmacodynamic relationship, allowing for fixed dosing and no necessity for routine laboratory monitoring; additionally these agents have minimal drug interactions. Dabigatran etexilate and apixaban are both twice-daily medications, whereas rivaroxaban is administered once daily for stroke prophylaxis. The impact of dosing frequency on medication adherence with these agents has not been prospectively evaluated; however, the frequency of dosing intervals has been shown to affect medication adherence, which in turn may influence patient outcomes. © 2012 Springer International Publishing AG. All rights reserved.


Gibbons R.J.,Mayo Medical School
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2011

There are a variety of approaches to assess the efficacy of reperfusion therapy, and myocardial protection, in acute myocardial infarction. This review summarizes the available evidence validating the use of technetium-99m sestamibi single-photon emission computed tomography (SPECT) for this purpose. Multiple lines of evidence have validated its clinical utility. SPECT sestamibi infarct size has been used as an endpoint in multiple randomized clinical trials. A smaller number of clinical trials have used both early and later imaging with SPECT sestamibi to assess myocardium at risk and myocardial salvage. SPECT sestamibi has a number of limitations which must be recognized. Nevertheless, SPECT sestamibi infarct size is a well-validated measurement with a long track record of performance as an endpoint in multicenter, randomized clinical trials. © The Author(s) 2011.


Pathak J.,Mayo Medical School
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium | Year: 2012

The ability to conduct genome-wide association studies (GWAS) has enabled new exploration of how genetic variations contribute to health and disease etiology. However, historically GWAS have been limited by inadequate sample size due to associated costs for genotyping and phenotyping of study subjects. This has prompted several academic medical centers to form "biobanks" where biospecimens linked to personal health information, typically in electronic health records (EHRs), are collected and stored on large number of subjects. This provides tremendous opportunities to discover novel genotype-phenotype associations and foster hypothesis generation. In this work, we study how emerging Semantic Web technologies can be applied in conjunction with clinical and genotype data stored at the Mayo Clinic Biobank to mine the phenotype data for genetic associations. In particular, we demonstrate the role of using Resource Description Framework (RDF) for representing EHR diagnoses and procedure data, and enable federated querying via standardized Web protocols to identify subjects genotyped with Type 2 Diabetes for discovering gene-disease associations. Our study highlights the potential of Web-scale data federation techniques to execute complex queries.


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.


Sargent D.J.,Sunnybrook Research Institute | Grothey A.,Mayo Medical School
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.


Purpose: To conduct post-hoc analysis of National CT Colonography Trial data and compare the sensitivity and specificity of computed tomographic (CT) colonography in participants younger than 65 years with those in participants aged 65 years and older. Materials and Methods: Of 2600 asymptomatic participants recruited at 15 centers for the trial, 497 were 65 years of age or older. Approval of this HIPAA-compliant study was obtained from the institutional review board of each site, and informed consent was obtained from each subject. Radiologists certified in CT colonography reported lesions 5 mm in diameter or larger. Screening detection of large (≥10-mm) histologically confirmed colorectal neoplasia was the primary end point; screening detection of smaller (6-9-mm) colorectal neoplasia was a secondary end point. The differences in sensitivity and specificity of CT colonography in the two age cohorts (age < 65 years and age ≥ 65 years) were estimated with bootstrap confidence intervals (CIs). Results: Complete data were available for 477 participants 65 years of age or older (among 2531 evaluable participants). Prevalence of adenomas 1 cm or larger for the older participants versus the younger participants was 6.9% (33 of 477) versus 3.7% (76 of 2054) (P < .004). For large neoplasms, mean estimates for CT colonography sensitivity and specificity among the older cohort were 0.82 (95% CI: 0.644, 0.944) and 0.83 (95% CI: 0.779, 0.883), respectively. For large neoplasms in the younger group, CT colonography sensitivity and specificity were 0.92 (95% CI: 0.837, 0.967) and 0.86 (95% CI: 0.816, 0.899), respectively. Per-polyp sensitivity for large neoplasms for the older and younger populations was 0.75 (95% CI: 0.578, 0.869) and 0.84 (95% CI: 0.717, 0.924), respectively. For the older and younger groups, per-participant sensitivity was 0.72 (95% CI: 0.565, 0.854) and 0.81 (95% CI: 0.745, 0.882) for detecting adenomas 6 mm in diameter or larger. Conclusion: For most measures of diagnostic performance and in most subsets, the difference between senior-aged participants and those younger than 65 years was not statistically significant. © RSNA, 2012.


Textor S.C.,Mayo Medical School
Current Opinion in Nephrology and Hypertension | Year: 2013

PURPOSE OF REVIEW: Management of renovascular hypertension remains controversial and problematic, in part, due to failure of prospective trials to demonstrate added benefit to revascularization. RECENT FINDINGS: Effective drug therapy often can achieve satisfactory blood pressure control, although concerns persist of the potential for progressive, delayed loss of kidney function beyond a stenotic lesion. Recent studies highlight benefits of renal artery stenting in subsets of patients including those with recurrent pulmonary edema and those intolerant to blockade of the renin-angiotensin system. Occasional patients with recent deterioration in renal function recover sufficient glomerular filtration rate after stenting to avoid requirements for renal replacement therapy. Emerging paradigms from both clinical and experimental studies suggest that hypoxic injury within the kidney activates inflammatory injury pathways and microvascular rarification that may not recover after technically successful revascularization alone. Initial data suggest that additional measures to repair the kidney, including the use of cell-based therapy, may offer the potential to recover kidney function in advanced renovascular disease. SUMMARY: Specific patient groups benefit from renal revascularization. Nephrologists will increasingly be asked to manage complex renovascular patients, different from those in randomized trials, that require intensely individualized management.


Borlaug B.A.,Mayo Medical School
Nature Reviews Cardiology | Year: 2013

No therapy has been proven to reduce morbidity and mortality in patients with heart failure and preserved ejection fraction (HFpEF). Owing to the deleterious cardiovascular effects of aldosterone, mineralocorticoid antagonists hold promise to treat this disorder. The Aldo-DHF trial provides valuable insights into the effects of these agents in HFpEF. © 2013 Macmillan Publishers Limited.


McLaughlin S.A.,Mayo Medical School
Surgical Clinics of North America | Year: 2013

The twentieth century has witnessed dramatic changes in the surgical management of breast cancer. Herein we focus on the evolution of breast conservation surgery and current surgical trends of lumpectomy, mastectomy and contralateral prophylactic mastectomy. Margin analysis, specimen localization and processing, and the benefits of magnetic resonance imaging remain controversial. Neoadjuvant chemotherapy can offer prognostic information and aid in surgical planning while radiation therapy continues to reduce the risk of local recurrence after breast conserving surgery. Despite these advances, mastectomy remains a popular choice for many women and the use of nipple sparing procedures is increasing. Overall the low rates of local recurrence are attributed to the combination of surgery and targeted adjuvant and radiation therapies. © 2013 Elsevier Inc.


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.


Knopman D.S.,Mayo Medical School
American Journal of Epidemiology | Year: 2010

This commentary considers the implications of the association between albuminuria and cognitive decline described by Jassal et al. in this issue of the Journal (Am J Epidemiol. 2010;171(3):290-291). The authors report that men with albuminuria had a greater likelihood than men without albuminuria of experiencing declines in cognitive function over a 6.6-year period. Albuminuria is the result of endothelial damage in the kidney, which, in turn, is the result of microvascular disease. If one of the key mechanisms of brain microvascular disease is leakage of serum proteins into the brain extracellular space, in a fashion parallel to albuminuria that occurs in nephrosclerosis, several facets of cerebrovascular disease and cognitive decline are explained. First, brain microvascular disease would not be recognized by traditional clinical features of cerebrovascular disease because brain microvascular disease occurs gradually and insidiously. Second, the extravasation of serum proteins as a result of brain microvascular disease would account for the perivascular distribution of white matter hyperintensities on magnetic resonance imaging. Albuminuria might be a useful screening test for generalized microvascular disease and, if detected, might reasonably prompt brain imaging and more intensive therapeutic efforts to forestall further endothelial dysfunction in the kidney, brain, and elsewhere.


Wijdicks E.F.M.,Mayo Medical School
Epilepsia | Year: 2013

After seizures have been controlled, long-term care of status epilepticus may be needed and collectively involves every major organ. First, as a result of rapid escalation of antiepileptic drugs, there are initial concerns with hypotension, acid-base abnormalities, and cardiac arrhythmias. Second, refractory status epilepticus and the continuous need for intravenous administration of anesthetic drugs will lead to a multitude of systemic complications that require long-term complex care. Most anticipated problems are infectious complications with a high risk of pneumonia and sepsis, but thromboembolism due to immobilization and catheter placement are also common. If a good outcome is possible or anticipated in a patient with refractory status epilepticus, physicians should plan for a surveillance and treatment protocol to adequately support these patients. © 2013 International League Against Epilepsy.


Wijdicks E.F.M.,Mayo Medical School
Neurology | Year: 2016

In "Dark Victory," released in theaters in 1939, the diagnosis and management of a progressive brain tumor was a central part of the screenplay, and this film marked the beginnings of the depiction of neurologic disease in cinema. Bette Davis' cinematic portrayal of a young woman dying from a brain tumor is close to the reality of denial, bargaining, a hope for a cure, and final acceptance. "Dark Victory" includes part of a neurologic examination (funduscopy, testing of strength, testing of stereognosis, and tendon reflexes). The film also alludes to decisions on what to tell the patient (better say nothing) and shows an implausible clinical course (an abrupt peaceful ending). The film is unusual in depicting the presentation of a brain tumor, but the cinematic portrayal of the vicissitudes of living with a brain tumor is often close to reality. © 2016 American Academy of Neurology.


Butterfield J.H.,Mayo Medical School
Prostaglandins and Other Lipid Mediators | Year: 2010

Cysteinyl leukotrienes such as LTE4 are produced by mast cells, neutrophils, eosinophils, and macrophages. LTE4 levels have not been reported in systemic mastocytosis, a disorder with a large increase in mast cell numbers. Urinary LTE4 from patients referred for symptoms potentially due to mast cell degranulation or systemic mastocytosis was measured by a commercial cysteinyl leukotriene enzyme immunoassay kit. The diagnosis of systemic mastocytosis was established using current World Health Organization criteria. Compared with a control group of patients with various potential mast cell-related symptoms (e.g., "spells"), patients with systemic mastocytosis had a significant (P = .01) increase in urinary LTE4 excretion, whether expressed as LTE4 ng/g creatinine or as LTE4 ng/24 h. There was a moderate correlation of LTE4 ng/24 h with excretion of N-methyl histamine and serum tryptase but not with urinary 11β-prostaglandin F2α (11β-PGF2α) excretion. LTE4 excretion is increased in patients with systemic mastocytosis and potentially contributes to clinical symptoms. © 2010 Elsevier Inc. All rights reserved.


Textor S.C.,Mayo Medical School
Clinical Journal of the American Society of Nephrology | Year: 2014

This case represents an individual with accelerating hypertension and declining kidney function associated with atherosclerotic renal artery stenosis. Key features include loss of GFR (reaching stage V CKD) during intensified antihypertensive drug therapy including agents that block the renin-angiotensin system and failure to appreciate the extent to which moderate renal artery stenosis was affecting his better kidney. Interpretation of duplex ultrasound studies was complicated by a discrepancy between near-normal peak systolic velocities and markedly abnormal segmental arterial waveforms. It was essential to recognize that both kidneys were abnormal and focus on recovery of perfusion to the better of these kidneys. Successful revascularization of one kidney allowed major improvement in GFR and BP control. © 2014 by the American Society of Nephrology.


Thompson W.G.,Mayo Medical School
Work (Reading, Mass.) | Year: 2011

Time spent sitting increases all-cause mortality. Sedentary occupations are a major contributor to the obesity epidemic. A treadmill desk offers the potential to increase activity while working; however, it is important to make sure that productivity does not decline. The purpose of this study is to evaluate productivity while using a treadmill desk. Eleven experienced medical transcriptionists participated in the study. Transcriptionists were given 4 hours training in the use of a treadmill desk. They were asked to transcribe tapes for 8 hours both while sitting and while using the treadmill desk. Speed and accuracy of transcription were compared as were the average expended calories per hour. The accuracy of transcription did not differ between sitting and walking transcriptions. The speed of transcription was 16% slower while walking than while sitting (p < 0.001). The transcriptionists expended 100 calories per hour more when they transcribed while walking than when they transcribed while sitting (p < 0.001). The treadmill desk offers a way to reduce sedentariness in the workplace and has potential to reduce employee obesity and health care costs. However, more than 4 hours of training will be necessary to prevent a significant drop in employee productivity.


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.


Suri H.S.,Mayo Medical School
Orphanet journal of rare diseases | Year: 2012

Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic hallmark of PLCH is the accumulation of Langerhans and other inflammatory cells in small airways, resulting in the formation of nodular inflammatory lesions. While the overwhelming majority of patients are smokers, mechanisms by which smoking induces this disease are not known, but likely involve a combination of events resulting in enhanced recruitment and activation of Langerhans cells in small airways. Bronchiolar inflammation may be accompanied by variable lung interstitial and vascular involvement. While cellular inflammation is prominent in early disease, more advanced stages are characterized by cystic lung destruction, cicatricial scarring of airways, and pulmonary vascular remodeling. Pulmonary function is frequently abnormal at presentation. Imaging of the chest with high resolution chest CT scanning may show characteristic nodular and cystic abnormalities. Lung biopsy is necessary for a definitive diagnosis, although may not be required in instances were imaging findings are highly characteristic. There is no general consensus regarding the role of immunosuppressive therapy in smokers with PLCH. All smokers must be counseled on the importance of smoking cessation, which may result in regression of disease and obviate the need for systemic immunosuppressive therapy. The prognosis for most patients is relatively good, particularly if longitudinal lung function testing shows stability. Complications like pneumothoraces and secondary pulmonary hypertension may shorten life expectancy. Patients with progressive disease may require lung transplantation.


Tatum W.O.,Mayo Medical School
Neurology | Year: 2013

The EEG is a unique measure of electrical brain function and is widely used in patients with seizures. Many normal variants and variations of normal EEG have a predilection for the temporal lobe and mimic epileptiform discharges. The high prevalence of temporal lobe epilepsy and the propensity for normal variants to occupy the temporal lobe may result in an undesired bias, leading to misidentification of normal waveforms. Learning the common pitfalls, such as the variations of normal EEG, benign variants, and common artifacts, are essential lessons in EEG. Continuing education and acquiring experience in EEG interpretation are the basic tools to ensure patient safety. Above all, judging the results of the EEG interpretation in light of the patient's clinical symptoms is a prerequisite to ensure proper management. © 2012 American Academy of Neurology.


Lim K.G.,Mayo Medical School
Lung | Year: 2010

Chronic cough is a common symptom-based diagnostic challenge for primary care physicians and respiratory specialists. Measurement of exhaled nitric oxide is a convenient, reproducible, and inexpensive point-of-service test. It can simplify the evaluation process of chronic cough by providing information regarding the state of airway inflammation. If exhaled nitric oxide is elevated, this is predictive of a favorable response to inhaled corticosteroids. This has the effect of reducing empirical trials for cough-variant asthma or eosinophilic bronchitis. The inclusion of exhaled nitric oxide in the diagnostic approach to chronic cough should be considered. © 2009 Springer Science+Business Media, LLC.


Williams A.W.,Mayo Medical School
Clinical Journal of the American Society of Nephrology | Year: 2012

Estimates suggest that one third of United States health care spending results from overuse or misuse of tests, procedures, and therapies. The American Board of Internal Medicine Foundation, in partnership with Consumer Reports, initiated the "Choosing Wisely" campaign to identify areas in patient care and resource use most open to improvement. Nine subspecialty organizations joined the campaign; each organization identified five tests, procedures, or therapies that are overused, are misused, or could potentially lead to harm or unnecessary health care spending. Each of the American Society of Nephrology's (ASN's) 10 advisory groups submitted recommendations for inclusion. The ASN Quality and Patient Safety Task Force selected five recommendations based on relevance and importance to individuals with kidney disease. Recommendations selected were: (1)Do not perform routine cancer screening for dialysis patients with limited life expectancies without signs or symptoms; (2) do not administer erythropoiesis-stimulating agents to CKD patients with hemoglobin levels ≥10 g/dl without symptoms of anemia; (3) avoid nonsteroidal anti-inflammatory drugs in individuals with hypertension, heart failure, or CKD of all causes, including diabetes; (4) do not place peripherally inserted central catheters in stage 3-5 CKD patients without consulting nephrology; (5) do not initiate chronic dialysis without ensuring a shared decision-making process between patients, their families, and their physicians. These five recommendations and supporting evidence give providers information to facilitate prudent care decisions and empower patients to actively participate in critical, honest conversations about their care, potentially reducing unnecessary health care spending and preventing harm. © 2012 by the American Society of Nephrology.


Caviness J.N.,Mayo Medical School
Parkinsonism and Related Disorders | Year: 2012

There is a growing interest in presymptomatic diagnosis of Parkinson's disease (PD), but the best and most practical method to screen and confirm asymptomatic individuals for PD needs further study. The Banner-Sun Health Brain and Body Donation program in Sun City, Arizona has studied primarily PD and Alzheimer's disease. Enrollees receive annual prospective standardized evaluation that includes clinical, biomarker testing, and at autopsy, neuropathological examination is performed followed by a consensus conference that determines final diagnosis. Since numerous Controls receive these assessments, these subjects become an excellent cohort to study presymptomatic PD. We found that Controls with partial diagnostic criteria for PD (1 of either rest tremor or bradykinesia) had a 6.6 relative risk for eventually developing full diagnostic criteria for PD. Neuropathologic examination has uncovered cases of "incidental Lewy body disease"(ILBD). We have shown that ILBD cases during life demonstrated no significant differences in clinical assessment versus similarly assessed controls. However, electrophysiological assessment showed subclinical low frequency rest discharges in some ILBD cases. Electroencephalography spectral frequency of ILBD cases was lower than for controls but not as low as for PD cases. The longitudinal assessments of this brain bank offer significant opportunities for the study of presymptomatic PD. © 2011 Elsevier Ltd.


Holubar S.D.,Mayo Medical School
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: Pouchitis may occur following ileal pouch-anal anastomosis for chronic ulcerative colitis in approximately 30% of patients. OBJECTIVES: The primary objective was to determine the efficacy of medical therapies for pouchitis (including antibiotic, probiotic, and other agents) as substantiated by data from randomized controlled trials (RCTs). SEARCH STRATEGY: A search for RCTs from 1966 to October 2009 was performed using the MEDLINE, Cochrane Library, EMBASE, Web of Science, and Scopus databases. SELECTION CRITERIA: Randomized controlled treatment or prevention trials of adult patients who underwent ileal pouch-anal anastomosis for ulcerative colitis who subsequently developed pouchitis or were at risk for pouchitis were considered for inclusion. DATA COLLECTION AND ANALYSIS: Extracted data were converted to 2X2 tables and then synthesized in to a summary statistic using the Peto odds ratio (OR) and [95% confidence intervals], or weighted mean difference (WMD), using RevMan-5 for Mac OS 10.6. MAIN RESULTS: Eleven RCTs fulfilled the inclusion criteria and were included in the review. The efficacy of 10 different pharmacologic agents was assessed. For the treatment of acute pouchitis (4 RCTS, 5 agents), ciprofloxacin was more effective at inducing remission than metronidazole. Neither rifaximin nor lactobacillus GG were more effective than placebo, while budesonide enemas and metronidazole were similarly effective, for inducing remission of acute pouchitis. For the treatment and maintenance of remission of chronic pouchitis (4 RCTs, 4 agents), glutamine suppositories were not more effective than butyrate suppositories, and bismuth carbomer foam enemas were not more effective than placebo, while VSL#3 was more effective than placebo in maintaining remission of chronic pouchitis in patients with chronic pouchitis who achieved remission with antibiotics. For the prevention of pouchitis (3 RCTs, 2 agents), in one study VSL#3 was more effective than placebo while in another study VSL#3 was not more effective than no treatment. Allopurinol was not more effective than placebo, while inulin was more effective than placebo but the results were not clinically significant. AUTHORS' CONCLUSIONS: For acute pouchitis, ciprofloxacin was more effective than metronidazole, while budesonide enemas and metronidazole were similarly effective. For chronic pouchitis, VSL#3 was more effective than placebo. For the prevention of pouchitis, VSL#3 was more effective than placebo. Larger RCTs are needed to determine the optimal agent(s) for the treatment and prevention of pouchitis.


Rademakers R.,Mayo Medical School | Neumann M.,University of Zurich
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.


Diaz-Melean C.M.,Mayo Medical School
Current atherosclerosis reports | Year: 2013

Obesity is an epidemic that threatens the health of millions of people worldwide and is a major risk factor for cardiovascular diseases, hypertension, diabetes, and dyslipidemia. There are multiple and complex mechanisms to explain how obesity can cause cardiovascular disease. In recent years, studies have shown some limitations in the way we currently define obesity and assess adiposity. This review focuses on the mechanisms involved in the cardiometabolic consequences of obesity and on the relationship between obesity and cardiovascular comorbidities, and provides a brief review of the latest studies focused on normal weight obesity and the obesity paradox.


Ding W.,Mayo Medical School
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

A 55-year-old man presented with fever, night sweats, and weight loss of about 20 lbs. in the prior 6 months. Physical examination revealed multiple cervical, axillary, and inguinal lymphadenopathy. The spleen was enlarged. A complete blood count revealed leukocytosis with absolute lymphocytosis: 30,000/μL. Peripheral blood-flow cytometric analysis showed a clonal lymphocyte population with immunophenotypes positive for CD5, CD20(dim), and monotypic kappa light chain. Fluorescence in situ hybridization (FISH) analysis revealed del(11q22.3), but negative for t(11:14). What should be used to treat his chronic lymphocytic leukemia (CLL) disease?


Background Defining competence in colonoscopy is elusive because there is no objective means by which to assess skills. Objective We describe the development and validation of the Mayo Colonoscopy Skills Assessment Tool (MCSAT) designed for the assessment of cognitive and motor skills during colonoscopy training. Design Prospective development and analysis of the validity evidence of a unique colonoscopy skills assessment tool. Setting Outpatient endoscopy center, Mayo Clinic in Rochester, Minn, from July 2007 through May 2010. Subjects All gastroenterology fellows in training at this institution during the study period. Intervention The MCSAT was developed and used to assess fellow performance over a 3-year period. Main Outcome Measurements A descriptive report of the form's development, correlation of each MCSAT assessment parameter with overall competency scores, and a comparison of MCSAT scores at various stages of training. Results There is strong individual item correlation to overall skills assessment for many of the parameters as well as significant improvement in all parameter scoring at increasing stages of experience. Limitations Compliance with MCSAT completion was 62% of all colonoscopies performed. Conclusions The MCSAT provides a valid means to objectively assess individual cognitive and motor skills in a continuous manner throughout colonoscopy training. The resultant data can eventually be used to establish average learning curves in colonoscopic skills and define competency thresholds based on performance scores rather than basing assessment simply on numbers of procedures performed. © 2010 American Society for Gastrointestinal Endoscopy.


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.


Sandborn W.J.,Mayo Medical School
Digestive Diseases | Year: 2010

Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn's disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6-Mercaptopurine is then either converted to the putative active metabolites, the 6-thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6-thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn's disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn's disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids. © 2010 S. Karger AG, Basel.


Bruining D.H.,Mayo Medical School
Digestive Diseases | Year: 2010

CT enterography has rapidly emerged as the preferred small bowel imaging modality at several tertiary care medical centers. It utilizes negative or neutral oral contrast agents to enhance small bowel mural assessments. A high sensitivity and specificity for active inflammation and its ability to detect extra-intestinal disease set CT enterography apart from more traditional imaging methods. It has also been shown to be of great value for the detection of occult penetrating disease, changing physician level of confidence, and altering management plans in a large proportion of patients. Concerns regarding radiation exposure will likely become less of an issue with new dose reduction techniques. CT enterography has begun to revolutionize Crohn's disease evaluations for luminal and extraluminal disease, and its role will likely continue to expand in diagnostic and management algorithms. © 2010 S. Karger AG, Basel.


Leung N.,Mayo Medical School
Clinical journal of the American Society of Nephrology : CJASN | Year: 2012

Multiple myeloma is responsible for a wide variety of renal pathologies. Urinary protein and monoclonal spike cannot be used to diagnose cast nephropathy (CN). Because albuminuria is a hallmark of glomerular disease, this study evaluated the percentage of urinary albumin excretion (%UAE) as a tool to differentiate CN from Ig light chain amyloidosis (AL), light chain deposition disease (LCDD), and acute tubular necrosis (ATN). Patients were selected from the Renal Biopsy Database and the Dysproteinemia Database. Participants were excluded if laboratory data were missing within 1 week of the renal biopsy. The %UAE was obtained from urine protein electrophoresis. From 1992 to 2011, 260 patients were biopsied (177 with AL, 28 with LCDD, 43 with CN, and 12 with ATN). The %UAE for CN patients was significantly lower (7%) than for ATN (25%), LCDD (55%), and AL (70%) patients (P<0.001). Significant differences were also found in serum creatinine, serum albumin, free light chain ratio, total urine protein, and urine monoclonal spike; only the %UAE remained independently associated with CN in a logistic regression model (P<0.001). The area under the curve for the receiver operator characteristic curve for %UAE was 0.99. At <25%, the %UAE had a sensitivity of 0.98, specificity of 0.94, positive predictive value of 0.75, and negative predictive value of 0.99. This study showed that %UAE was significantly less in CN than the other three renal lesions and %UAE may thus be helpful in diagnosis of CN.


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 Academy of Allergy, Asthma & Immunology.


Gershlick A.H.,University of Leicester | Banning A.P.,Oxford Radcliffe Hospitals | Myat A.,Kings 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.


Cheshire W.P.,Mayo Medical School
Autonomic Neuroscience: Basic and Clinical | Year: 2013

Sudden unexplained death in epilepsy (SUDEP) is an important unresolved problem affecting many patients with recurrent seizures. Amongst the mechanisms postulated are ictal or postictal cardiac arrhythmias, central hypoventilation or apnea, and neurogenic pulmonary edema. Across these categories, a common element appears to be some form of autonomic dysregulation. Accordingly, the search for biomarkers of SUDEP risk has focused increasingly on autonomic findings. Emerging models implicate attenuated cardiac vagal modulation coupled with surging cardiac sympathetic activity, neuronal dropout in the nucleus tractus solitarii, and in some cases genetic factors affecting ion channel behavior. Explicating the crucial links between brain and heart in epilepsy benefits from collaboration amongst neurologists, cardiologists, physiologists, and other specialists with an interest in the autonomic nervous system. © 2013 Elsevier B.V.


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.


Perez E.A.,Mayo Medical School
The oncologist | Year: 2011

A personalized approach to breast cancer management is increasingly possible with state of the art diagnostics and treatments. However, many challenges still exist in choosing the right therapeutic strategy and the right dosing for a specific patient population. Biomarkers such as estrogen receptor, progesterone receptor, and HER-2 status are used to tailor therapy, but success rates with targeted therapy suggest that appropriate patient populations still require greater definition. The introduction of the genomic era has likewise advanced the ability to offer a tailored approach to breast cancer management, but much work is still needed in this area as well. Microarray-based gene expression profiles have demonstrated initial promise, but we need a better understanding of more complex tumor signaling pathways. Strategies include annotated tumor specimens, next-generation gene sequencing, proteomics, and metabolomics. An individualized approach to breast cancer management has the potential to offer clear clinical benefits and the ability to bring more tailored, cost-effective strategies to the market. The current issues facing the delivery of individualized breast cancer care will be the focus of this discussion.


Tefferi A.,Mayo Medical School
Blood | Year: 2011

It is currently assumed that myelofibrosis (MF) originates from acquired mutations that target the hematopoietic stem cell and induce dysregulation of kinase signaling, clonal myeloproliferation, and abnormal cytokine expression. These pathogenetic processes are interdependent and also individually contributory to disease phenotype-bone marrow stromal changes, extramedullary hematopoiesis, ineffective erythropoiesis, and constitutional symptoms. Molecular pathogenesis of MF is poorly understood despite a growing list of resident somatic mutations that are either functionally linked to Janus kinase (JAK)-signal transducer and activator of transcription hyperactivation (eg JAK2, MPL, and LNK mutations) or possibly involved in epigenetic dysregulation of transcription (TET2, ASXL1, or EZH2 mutations). Current prognostication in primary MF is based on the Dynamic International Prognostic Scoring System-plus model, which uses 8 independent predictors of inferior survival to classify patients into low, intermediate 1, intermediate 2, and high-risk disease groups; corresponding median survivals are estimated at 15.4, 6.5, 2.9, and 1.3 years. Such information is used to plan a risk-adapted treatment strategy for the individual patient, which might include observation alone, conventional or investigational (eg, JAK inhibitors, pomalidomide) drug therapy, allogenic stem cell transplantation with reduced- or conventional-intensity conditioning, splenectomy, or radiotherapy. I discuss these treatment approaches in the context of who should get what and when. © 2011 by The American Society of Hematology.


Leischow S.J.,Mayo Medical School
American Journal of Health Behavior | Year: 2014

Objectives: To evaluate nicotine delivery from the NJOY® King Bold Electronic Nicotine Delivery System (ENDS) and its short-term potential for smoking reduction or cessation. Methods: One week of ad libitum use was followed by measurements of plasma nicotine, heart rate, and craving and withdrawal after 12 hours of nicotine abstinence in 25 adult smokers not interested in quitting. Results: After 5 minutes of use, blood nicotine levels increased by a mean of 3.5 ng/mL (p < .001), heart rate increased, and craving was reduced by 55%. Cigarettes per day were reduced by 39% during the test week, and perceptions of use for reduction or cessation were positive. Conclusions: The NJOY® King Bold ENDS delivers nicotine and led to short-term smoking reduction. Copyright (c) PNG Publications. All rights reserved.


Reeder C.B.,Mayo Clinic Arizona | Ansell S.M.,Mayo Medical School
Blood | Year: 2011

Several novel targeted therapies have recently emerged as active in the treatment of non-Hodgkin lymphoma, including small molecules that inhibit critical signaling pathways, promote apoptotic mechanisms, or modulate the tumor microenvironment. Other new agents target novel cell surface receptors or promote DNA damage. Although most of these drugs have single-agent activity, none have sufficient activity to be used alone. This article reviews the utility and potential role of these new agents in the treatment of non-Hodgkin lymphoma with a specific focus on data that highlight how these agents may be incorporated into current standard treatment approaches. © 2011 by The American Society of Hematology.


Lindor K.D.,Mayo Medical School
Current Opinion in Gastroenterology | Year: 2011

Purpose of review: This review will provide an overview of the role of nuclear receptors in bile acid homeostasis with a focus on the farnesoid X receptor (FXR) and its potential therapeutic use in cholestatic liver diseases. Recent findings: Nuclear receptors have emerged as important mediators of a variety of metabolic and transport functions involving the liver. The role of FXR, in particular, has come to light because of its important role in bile acid homeostasis. The use of potent FXR ligands has recently been shown to offer potentially important therapeutic benefits in patients with primary biliary cirrhosis, an important cholestatic liver disease of adults. This recent finding has now opened the door for future therapeutic trials for use of FXR agonists such as obeticholic acid for the treatment of chronic cholestatic liver diseases. Summary: Further understanding of the role of farnesoid X receptor agonists and the potential role of ligands in animal models of other forms of cholestasis will be important to set the stage for future applications to human disease. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Watt K.D.,Mayo Medical School
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Improvements in overall survival early after liver transplantation result in a growing number of patients with the potential for long-term survival. Data available on long-term survival, to date, reflect the situation of patients who received their liver transplant during a very different health-care era. Translating these data into the current medical era of liver transplantation is an important task, as a better understanding of aspects associated with morbidity and mortality is fundamental in improving the long-term outcome of liver transplant recipients. Malignancy screening, optimal treatment of recurrent disease and adequate management of metabolic disease are crucial contributions to advance patient care. In this Review, data specific to the liver transplant recipient will be evaluated and, in the absence of sufficient evidence at this time, recommendations and guidelines for the general population on management of long-term concerns will be assessed for their applicability after liver transplantation. In addition, other preventive strategies relating to pregnancy, contraception and vaccination are reviewed in detail. © 2015 Macmillan Publishers Limited.


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).


Niewold T.B.,Mayo Medical School
Current Opinion in Rheumatology | Year: 2015

Purpose of review The field of systemic lupus erythematosus (SLE) genetics has been advancing rapidly in recent years. This review will summarize recent advances in SLE genetics. Recent findings Genome-wide-association and follow-up studies have greatly expanded the list of associated polymorphisms, and much current work strives to integrate these polymorphisms into immune system biology and the pathogenic mediators involved in the disease. This review covers some current areas of interest, including genetic studies in non-European SLE patient populations, studies of pathogenic immune system subphenotypes such as type I interferon and autoantibodies, and a rapidly growing body of work investigating the functional consequences of the genetic polymorphisms associated with SLE. Summary These studies provide a fascinating window into human SLE disease biology. As the work proceeds from genetic association signal to altered human biology, we move closer to tailoring interventions based upon an individuals genetic substrate. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


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.


Nickels K.C.,Mayo Medical School
Nature Reviews Neurology | Year: 2016

Cognitive and behavioural comorbidities are often seen in children with epilepsy, and are more common and severe in refractory epilepsy. These comorbidities are associated with worse quality of life, increased behavioural and language problems and worse social skills, all of which adversely affect long-term psychosocial functioning. To enable early intervention and therapy, children and teens with epilepsy should be periodically screened for cognitive comorbidities. The location of the epileptic focus can, to a certain degree, predict the type(s) of comorbidity; however, the spectrum of disability is often broad, presumably because focal perturbations can cause network dysfunction. Comorbidities often result from underlying structural or functional pathology that has led to seizures. In selected cases, therapy targeting the underlying cause, such as the ketogenic diet for GLUT1 deficiency syndromes, may be remarkably effective in ameliorating both seizures and cognitive concerns. In many cases, however, cognitive impairment persists despite seizure control. In epileptic encephalopathies, frequent seizures and/or interictal epileptiform abnormalities exacerbate neurocognitive dysfunction, owing to synaptic reorganization or impaired neurogenesis, or to other effects on developing neural circuits, and prompt initiation of effective antiepileptic therapy is essential to limit cognitive comorbidities. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


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.


Sharp R.R.,Biomedical Ethics Program | 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.


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.


Moreno-Aspitia A.,Mayo Medical School
Critical Reviews in Oncology/Hematology | Year: 2012

Neoadjuvant (preoperative) chemotherapy is becoming a commonly used option for women with early-stage breast cancer, allowing a greater proportion of patients to undergo breast conservation surgery. Neoadjuvant chemotherapy also allows the early assessment of response or resistance to chemotherapy and facilitates chemotherapy delivery prior to any surgical alterations to the vasculature. Ongoing research is examining the potential benefits of neoadjuvant therapy with cytotoxic agents as well as other treatments, including endocrine therapies and biologic agents. Additionally, biomarkers are being intensively investigated as methods for identifying patients who will most likely benefit from neoadjuvant chemotherapy. As of yet, neoadjuvant chemotherapy has not demonstrated a definitive benefit over adjuvant (postoperative) chemotherapy with regard to prolonging survival. It remains to be seen whether novel cytotoxic agents used in the neoadjuvant setting will improve pathologic clinical response rates and ultimately improve long-term outcome in women with early-stage breast cancer. © 2011 Elsevier Ireland Ltd.


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.


Pardanani A.,Mayo Medical School
American Journal of Hematology | Year: 2012

Disease Overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk Stratification: The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. Investigational Drugs: Dasatinib's in vitro anti-KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients. © 2012 Wiley Periodicals, Inc.


Dispenzieri A.,Mayo Medical School
American Journal of Hematology | Year: 2014

Disease overview: POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. Diagnosis: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria. Risk stratification: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the PCD is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. Risk-adapted therapy: For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3-6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes. © 2014 Wiley Periodicals, Inc.


Sampathkumar P.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2014

A severe viral illness caused by a newly discovered coronavirus was first reported in the Middle East in 2012. The virus has since been named the Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV cases have been reported in several countries around the world in travelers from the Middle East. The illness has a high mortality rate. Limited human-to-human transmission has occurred including transmission to health care workers. The source of the virus remains unclear, but camels are a possible source. Two unrelated imported cases of MERS-CoV have been reported in the United States. Neither a vaccine nor effective therapy against the virus is available. International cooperation and information sharing will be key to understanding and ending the MERS-CoV outbreak. © 2014 Mayo Foundation for Medical Education and Research.


Rabinstein A.A.,Mayo Medical School
Current Treatment Options in Neurology | Year: 2010

Cerebral edema is very common in patients with acute liver failure and encephalopathy. In severe cases, it produces brain tissue shift and potentially fatal herniation. Brain swelling in acute liver failure is produced by a combination of cytotoxic (cellular) and vasogenic edema. Accumulation of ammonia and glutamine leads to disturbances in the regulation of cerebral osmolytes, increased free radical production and calcium-mediated mitochondrial injury, and alterations in glucose metabolism (inducing high levels of brain lactate), resulting in astrocyte swelling. Activation of inflammatory cytokines can cause increased blood-brain barrier permeability leading to vasogenic edema, although the relative contribution of vasogenic edema is probably minor compared with cellular swelling. Cerebral blood flow is disturbed and generally increased in patients with acute liver failure; persistent vasodilatation and loss of autoregulation may generate hyperemia, and the consequent augmentation in cerebral blood volume may exacerbate brain edema. Adequate management of intracranial hypertension demands continuous monitoring of intracranial pressure and cerebral perfusion pressure. Coagulation status should be assessed and bleeding diathesis should be treated prior to insertion of the intracranial pressure monitor. Standard treatment measures such as hyperventilation and osmotic agents (e.g., mannitol, hypertonic saline) remain useful first-line interventions. Although hypertonic saline may be preferred in patients with coexistent hyponatremia, the rate of correction of hyponatremia must be gradual to avoid the risk of osmotic demyelination. Barbiturate coma and intravenous indomethacin are available options in refractory cases. The most promising novel therapeutic alternative is the induction of moderate hypothermia (aiming for a core temperature of 32-34°C). However, the safety and efficacy of therapeutic hypothermia for brain swelling caused by liver failure still needs to be proven in randomized, controlled clinical trials. Management of intracranial pressure in patients with acute liver failure should be guided by well-defined treatment protocols. © Springer Science+Business Media, LLC 2010.


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.


Stanhope T.J.,Mayo Medical School
Clinical journal of the American Society of Nephrology : CJASN | Year: 2012

SLE is a multi-organ autoimmune disease that affects women of childbearing age. Renal involvement in the form of either active lupus nephritis (LN) at the time of conception, or a LN new onset or flare during pregnancy increases the risks of preterm delivery, pre-eclampsia, maternal mortality, fetal/neonatal demise, and intrauterine growth restriction. Consequently, current recommendations advise that the affected woman achieve a stable remission of her renal disease for at least 6 months before conception. Hormonal and immune system changes in pregnancy may affect disease activity and progression, and published evidence suggests that there is an increased risk for a LN flare during pregnancy. The major goal of immunosuppressive therapy in pregnancy is control of disease activity with medications that are relatively safe for a growing fetus. Therefore, the use of mycophenolate mofetil, due to increasing evidence supporting its teratogenicity, is contraindicated during pregnancy. Worsening proteinuria, which commonly occurs in proteinuric renal diseases toward the end of pregnancy, should be differentiated from a LN flare and/or pre-eclampsia, a pregnancy-specific condition clinically characterized by hypertension and proteinuria. These considerations present challenges that underscore the importance of a multidisciplinary team approach when caring for these patients, including a nephrologist, rheumatologist, and obstetrician who have experience with these pregnancy-related complications. This review discusses the pathogenesis, maternal and fetal risks, and management pertinent to SLE patients with new onset or a history of LN predating pregnancy.


Charlton M.,Mayo Medical School
Current Opinion in Organ Transplantation | Year: 2013

Purpose of review: Nonalcoholic steatohepatitis (NASH), obesity, and the metabolic syndrome are highly prevalent. NASH, a rare indication for liver transplantation in the early 1990s, is now the third most common indication. This review considers key aspects of the liver transplantation for NASH. Recent findings: NASH is one consequence of obesity, almost always occurring in the context of metabolic syndrome and oxidative stress. Recurrence of NASH can be severe. The components of metabolic syndrome are often exacerbated following liver transplantation by factors such as immunosuppression, and are important predictors of patient morbidity and mortality. Many aspects of the metabolic syndrome are modifiable. The roles bariatric surgery, nutritional and pharmacotherapy of NASH, and the impact of established and new immunosuppressive agents have recently evolved. Summary: A nuanced approach is needed in management of obesity, metabolic syndrome, and immunosuppression in liver transplant recipients. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Cornell L.D.,Mayo Medical School
Current Opinion in Organ Transplantation | Year: 2013

Purpose of review: Patterns of renal allograft injury associated with alloantibody have been increasingly recognized over the past 2 decades. The use of more sensitive serum testing has brought to light the range of alloantibody-associated changes on biopsy at different time points posttransplant. There is likely to be an increasing number of patients with preformed alloantibody undergoing kidney transplantation, and so alloantibody-associated injury will become more prevalent. Recent findings: Acute antibody-mediated rejection (AMR) is a major complication in kidney transplant patients with preformed donor-specific antibody (DSA), particularly in the early posttransplant period. Acute AMR is characterized by acute tissue injury and is likely to be antibody mediated and complement mediated. A recent study showed a decreased risk of acute AMR with terminal complement pathway inhibition. Other studies have shown endothelialitis, a vascular lesion traditionally associated with acute cellular rejection, in AMR. Features of chronic AMR are common and include transplant glomerulopathy, peritubular capillary basement membrane multilamination, and accelerated arteriosclerosis. Although previously a diagnosis of humoral rejection usually required complement factor C4d deposition in the graft, we now recognize chronic features because of DSA even in the absence of C4d deposition. Summary: Acute and chronic AMR are major contributors to renal allograft dysfunction and loss. Recognition of tissue injury patterns associated with alloantibody can lead to treatment strategies in patients with DSA and can aid in interpreting biopsies in patients who are receiving new therapies. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Kalogera E.,Mayo Medical School
Obstetrics and gynecology | Year: 2013

To investigate the effects of enhanced recovery (a multimodal perioperative care enhancement protocol) in patients undergoing gynecologic surgery. Consecutive patients managed under an enhanced recovery pathway and undergoing cytoreduction, surgical staging, or pelvic organ prolapse surgery between June 20, 2011, and December 20, 2011, were compared with consecutive historical controls (March to December 2010) matched by procedure. Wilcoxon rank-sum, χ, and Fisher's exact tests were used for comparisons. Direct medical costs incurred in the first 30 days were obtained from the Olmsted County Healthcare Expenditure and Utilization Database and standardized to 2011 Medicare dollars. A total of 241 enhanced recovery women in the case group (81 cytoreduction, 84 staging, and 76 vaginal surgery) were compared with women in the control groups. In the cytoreductive group, patient-controlled anesthesia use decreased from 98.7% to 33.3% and overall opioid use decreased by 80% in the first 48 hours with no change in pain scores. Enhanced recovery resulted in a 4-day reduction in hospital stay with stable readmission rates (25.9% of women in the case group compared with 17.9% of women in the control group) and 30-day cost savings of more than $7,600 per patient (18.8% reduction). No differences were observed in rate (63% compared with 71.8%) or severity of postoperative complications (grade 3 or more: 21% compared with 20.5%). Similar, albeit less dramatic, improvements were observed in the other two cohorts. Ninety-five percent of patients rated satisfaction with perioperative care as excellent or very good. Implementation of enhanced recovery was associated with acceptable pain management with reduced opioids, reduced length of stay with stable readmission and morbidity rates, good patient satisfaction, and substantial cost reductions. II.


Cornell L.D.,Mayo Medical School
Seminars in Diagnostic Pathology | Year: 2012

IgG4-related kidney disease is a term that refers to any form of renal involvement by IgG4-related disease (IgG4-RD), a recently recognized systemic immune-mediated disease. The most common renal manifestation is IgG4-related tubulointerstitial nephritis (IgG4-TIN), which presents as acute or chronic renal insufficiency, renal mass lesions, or both. On biopsy, IgG4-TIN shows a plasma cell-rich interstitial inflammatory infiltrate with increased IgG4+ plasma cells, along with expansile interstitial fibrosis; tubular basement membrane immune complex deposits are common. IgG4-TIN usually shows a brisk response to immunosuppressive therapy. Glomeruli may be affected by IgG4-RD, usually in the form of membranous glomerulonephritis. Other patterns of glomerular disease include IgA nephropathy, membranoproliferative glomerulonephritis, and endocapillary or mesangioproliferative immune complex glomerulonephritis. IgG4-related plasma cell arteritis has also been observed in the kidney. This review describes the histopathologic and immunophenotypic patterns of renal involvement by IgG4-RD, with associated clinical, radiographic, and serologic features. © 2012 Elsevier Inc.


Graham R.P.,Mayo Medical School
The American journal of surgical pathology | Year: 2012

Radioactive seed localization (RSL) is an increasingly utilized and effective approach to surgical excision of radiographically identified lesions in the breast. This approach has been reported to be at least as convenient to the patient, radiologist, and surgeon as the standard wire localized approach but with the considerable added benefit of a lower positive margin rate in some studies. To date, there is little information in the published medical literature concerning the optimal handling of these specimens in the pathology laboratory. The US Nuclear Regulatory Commission and its Agreement States oversee the use of radioactive materials in clinical practice and provide guidelines for the performance of RSL procedures, including the safe handling of radioactive seeds. The RSL procedure involves multiple departments, and a robust process should be in place to ensure appropriate accountability, seed tracking, and minimal radiation exposure to staff. This article describes how to properly and safely handle RSL breast specimens, including regulation requirements, specimen labeling and receipt, specimen dissection, protective wear, and seed retrieval, transport, and disposal.


Benzo R.P.,Mayo Medical School
Chronic Respiratory Disease | Year: 2013

There is no conclusive evidence about the way to a promote behavior change in self-management programs for patients with chronic obstructive pulmonary disease (COPD). The latter is a significant knowledge gap as there is a need to promote a sustained effect in interventions like Pulmonary Rehabilitation or Supporting Programs. Embracing patient's values seems to be a key ingredient to ignite genuine motivation for behavior change. This manuscript describes two pilot qualitative studies carried out in patients with severe COPD aimed to engage the patient inner experience and promote self-management: a trial testing motivational interviewing (MI) as one style of helping patients with severe COPD make changes in their behavior and second a trial testing a mindfulness-based intervention. The MI study consisted of a 3-month program of weekly coaching phone calls after one face-to-face visit. The following themes were outstanding: patients value the supportive communication with coach and believe the MI-based coaching created increased level of awareness and accountability. They perceived an increase in physical activity and reported "feeling better" or other benefits not directly related to exercise. The Mindfulness for Health Program was a mandatory 8-week program that consisted on 2-hour classes aimed to cultivate nonjudgmental attention in the moment (through different meditative practices and sharing) plus monthly face-to-face encounters aimed to sustain practice and sharing of life experiences for 1 year. The following themes (at 1 year) were outstanding: appreciating life by seeing hardships as opportunities, valuing the self through compassion and awareness, cultivating connectedness with others, acquiring joy, and adopting healthy behaviors. In the search for the "holy grail" for self-management programs that can promote a behavior change, mindfulness and MI seem promising for cultivating a way to live a life in which people are fully present and consciously agree with. © 2013 The Author(s).


Folpe A.L.,Mayo Medical School
Modern Pathology | Year: 2014

Epithelioid morphology, mimicking carcinoma, is a key or defining feature of several soft tissue tumors and may be seen in a wide variety of other tumors. This review will focus on those tumors defined at least in part by their epithelioid morphology, in particular epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, and sclerosing epithelioid fibrosarcoma. The role of loss of the SMARCB1 tumor-suppressor gene in the pathogenesis of these epithelioid soft tissue tumors will be discussed, as will their differential diagnosis with non-mesenchymal tumors, in particular carcinoma and melanoma. © 2014 USCAP, Inc.


Tatum W.O.,Mayo Medical School
Neurology | Year: 2013

Potentials that do not conform to an expected electrical field generated by the brain characterize an extracerebral source or artifact. Artifact is present in virtually every EEG. It is an essential component for routine visual analysis, yet it may beguile the interpreter into falsely identifying waveforms that simulate epileptiform discharges (ED). The principal importance of artifact is represented by the frequency of its occurrence in contrast to the limited frequency of normal variants that may imitate pathologic ED. Continuous EEG monitoring has uncovered newly identified artifacts unique to prolonged recording. The combined use of video and EEG has revolutionized our ability to distinguish cerebral and extracerebral influences through behavioral correlation that is time-locked to the electrophysiologic features that are present on EEG. Guidelines exist to ensure minimal standards of recording. Precise definitions are present for ED. Still, the ability to distinguish artifact from pathologic ED requires a human element that is to provide the essential identification of an abnormal EEG. The ramification of a misinterpreted record carries an acute risk of treatment and long-term consequences for diagnosis-related harm. © 2012 American Academy of Neurology.


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.


Murthy N.S.,Mayo Medical School
Journal of Hand Surgery | Year: 2013

Fractures of the scaphoid are the most common surgically treated carpal fracture, and early diagnosis is critical to minimize complications including osteonecrosis. If the initial radiographs after the injury are inconclusive, early magnetic resonance imaging (MRI) provides an immediate diagnosis to allow for proper management. This has been shown to be cost effective both in direct measureable costs and likely in difficult-to-measure indirect costs related to lost productivity. In the cases in which no scaphoid fracture is present, MRI provides alternate diagnoses such as identification of other fractures (eg, other carpals and distal radius), osseous contusions, and soft tissue injuries (preferably ≥ 1.5T). When MRI is contraindicated, computed tomography (CT) is a reasonable alternative after the initial and repeat negative radiographs. MRI is the best imaging modality for assessing osteonecrosis of the proximal pole in a scaphoid nonunion. Unfortunately, the most useful imaging sequences remain controversial. My institution relies on the noncontrast T1-weighted images for the primary diagnosis of osteonecrosis with dynamic contrast enhancement used in a supplemental fashion. © 2013 ASSH. Published by Elsevier, Inc. All rights reserved.


Rodriguez-Porcel M.,Mayo Medical School
Current Cardiology Reports | Year: 2010

Regenerative medicine using stem cells has appeared as a potential therapeutic alternative for coronary artery disease, and stem cell clinical studies are currently on their way. However, initial results of these studies have provided mixed information, in part because of the inability to correlate organ functional information with the presence/absence of transplanted stem cells. Recent advances in molecular biology and imaging have allowed the successful noninvasive monitoring of transplanted stem cells in the living subject. In this article, different imaging strategies (direct labeling, indirect labeling with reporter genes) to study the viability and biology of stem cells are discussed. In addition, the limitations of each approach and imaging modality (eg, single photon emission computed tomography, positron emission tomography, and MRI) and their requirements for clinical use are addressed. Use of these strategies will be critical as the different regenerative therapies are being tested for clinical use. © 2010 Springer Science+Business Media, LLC.


Berger R.A.,Mayo Medical School
Hand Clinics | Year: 2013

Resection of the ulnar head in cases of debilitating pain owing to arthrosis of the distal radioulnar joint can provide satisfying relief. However, there is mounting evidence that pain with heavier use, instability, and torque-generating weakness in more active individuals may result in less satisfying outcomes. Implant arthroplasty can provide a means to stabilize the radius to the ulna after ulnar head resection, but it requires significant attention to requisite soft tissue stabilization and alignment of the distal radius to the implant to be successful. © 2013 Elsevier Inc.


Sarr M.G.,Mayo Medical School
Polskie Archiwum Medycyny Wewnetrznej | Year: 2013

Recently, the original Atlanta classification of 1992 was revised and updated by the Working Group using a web-based consultative process involving multiple international pancreatic societies. The new understanding of the disease, its natural history, and objective description and classification of pancreatic and peripancreatic fluid collections make this new 2012 classification a potentially valuable means of international communication and interest. This revised classification identifies 2 phases of acute pancreatitis - early (first 1 or 2 weeks) and late (thereafter). Acute pancreatitis can be either edematous interstitial pancreatitis or necrotizing pancreatitis, the latter involving necrosis of the pancreatic parenchyma and peripancreatic tissues (most common), pancreatic parenchyma alone (least common), or just the peripancreatic tissues (∼20%). Severity of the disease is categorized into 3 levels: mild, moderately severe, and severe. Mild acute pancreatitis lacks both organ failure (as classified by the modified Marshal scoring system) and local or systemic complications. Moderately severe acute pancreatitis has transient organ failure (organ failure of <2 days), local complications, and/or exacerbation of coexistent disease. Severe acute pancreatitis is defined by the presence of persistent organ failure (organ failure that persists for ≥2 days). Local complications are defined by objective criteria based primarily on contrast-enhanced computed tomography; these local complications are classified as acute peripancreatic fluid collections, pseudocyst (which are very rare in acute pancreatitis), acute (pancreatic/peripancreatic) necrotic collection, and walled-off necrosis. This classification will help the clinician to predict the outcome of patients with acute pancreatitis and will allow comparison of patients and disease treatment/management across countries and practices. Copyright by Medycyna Praktyczna, Kraków 2013.


Key Points 1. Obesity is common in patients with end-stage liver disease of any cause. 2. Obesity is associated with comorbidities that can affect liver transplant candidacy, such as metabolic syndrome (diabetes, hyperlipidemia, and hypertension), cardiovascular disease, pulmonary disorders (related to obstructive sleep apnea), renal dysfunction, and malignancies. 3. Nonalcoholic steatohepatitis is the only indication for transplantation that is increasing in frequency, and it may soon become the leading indication. 4. There is no set body mass index above which liver transplantation is contraindicated. Transplant candidacy and outcomes depend on the cumulative comorbidities of the individual patient. 5. Weight loss is an important component of metabolic syndrome management and is recommended before liver transplantation. 6. Bariatric surgery may be considered in carefully selected patients with well-compensated cirrhosis but is not recommended in patients with decompensated cirrhosis. © 2012 AASLD.


Gertz M.A.,Mayo Medical School
American Journal of Hematology | Year: 2014

Disease Overview: Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Diagnosis: Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. Prognosis: N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. Therapy: All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT-proBNP <5,000 ng/mL, troponin T <0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone or cyclophosphamide-bortezomib-dexamethasone. Other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide have documented activity. Future Challenges: Late diagnosis remains a major obstacle to initiating effective therapy. Recognizing the presenting syndromes is necessary for improving survival. © 2014 Wiley Periodicals, Inc.


Ansell S.M.,Mayo Medical School
American Journal of Hematology | Year: 2014

Disease overview: Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,200 new patients annually and representing approximately 11.5% of all lymphomas in the United States. Diagnosis: HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. Risk stratification: An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy. Risk-adapted therapy: Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered. Am. J. Hematol. 89:772-779, 2014. © 2014 Wiley Periodicals, Inc.


Endothelial dysfunction is a key feature of preeclampsia and may contribute to increased cardiovascular disease risk years after pregnancy. Flow-mediated dilation (FMD) is a non-invasive endothelial function test that predicts cardiovascular event risk. New protocols allow researchers to measure three components of the FMD response: FMD, low flow-mediated constriction, and shear stimulus. This review encourages researchers to think beyond "low FMD" by examining how these three components may provide additional insights into the mechanisms and location of vascular dysfunction. The review then examines what FMD studies reveal about vascular dysfunction in preeclampsia while highlighting opportunities to gain greater mechanistic insight from new protocols. Studies using traditional protocols show that FMD is low in mid-pregnancy prior to preeclampsia, at diagnosis, and for 3 years post-partum. However, FMD returns to normal by 10 years post-partum. Studies using new protocols are needed to gain more mechanistic insight. © 2014 Springer Science+Business Media New York.


Tefferi A.,Mayo Medical School
American journal of hematology | Year: 2013

Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus and a small risk of disease progression into acute myeloid leukemia or myelofibrosis. Almost all patients with PV harbor a JAK2 mutation. When PV is suspected, the presence of a JAK2 mutation highly suggests the diagnosis and its absence, combined with normal or increased serum erythropoietin level, excludes the diagnosis. Differential diagnosis of ET should include reactive thrombocytosis, chronic myeloid leukemia, prefibrotic myelofibrosis and RARS-T (refractory anemia with ring sideroblasts associated with marked thrombocytosis). A JAK2 mutation is found in 50-70% of patients with ET, myelofibrosis or RARS-T and is capable of distinguishing reactive from clonal thrombocytosis. Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications: 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 considers JAK2V617F and cardiovascular (CV) risk factors as additional risk factors for thrombosis. Presence of extreme thrombocytosis (platelet count >1,000 × 10(9) /L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include advanced age, leukocytosis, and history of thrombosis. Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is <1%/1% in ET and <3%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications. In low risk patients, this is effectively and safely accomplished by the use of low-dose aspirin in both PV and ET and phlebotomy (hematocrit target of <45%) in PV. In high risk patients, treatment with hydroxyurea is additionally recommended, although not mandated in older patients without JAK2V617F or CV risk factors. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures. Screening for clinically significant AvWS is recommended before administrating aspirin in the presence of extreme thrombocytosis. Copyright © 2013 Wiley Periodicals, Inc.


Rajkumar S.V.,Mayo Medical School
American Journal of Hematology | Year: 2016

There have been major advances in the diagnosis, staging, risk-stratification, and management of multiple myeloma (MM). In addition to established CRAB (hypercalcemia, renal failure, anemia, and lytic bone lesions) features, new diagnostic criteria include three new biomarkers to diagnose the disease: bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain ratio ≥100, and >1 focal lesion on magnetic resonance imaging. MM can be classified into several subtypes based on baseline cytogenetics, and prognosis varies according to underlying cytogenetic abnormalities. A Revised International Staging System has been developed which combines markers of tumor burden (albumin, beta-2 microglobulin) with markers of aggressive disease biology (high-risk cytogenetics and elevated serum lactate dehydrogenase). Although the approach to therapy remains largely the same, the treatment options at every stage of the disease have changed. Carfilzomib, pomalidomide, panobinostat, daratumumab, elotuzumab, and ixazomib have been approved for the treatment of the disease. These drugs combined with older agents such as cyclophosphamide, dexamethasone, thalidomide, bortezomib, and lenalidomide dramatically increase the repertoire of regimens available for the treatment of MM. This review provides a concise overview of recent advances in MM, including updates to diagnostic criteria, staging, risk-stratification, and management. Am. J. Hematol. 91:90-100, 2016. © 2015 Wiley Periodicals, Inc.


Tefferi A.,Mayo Medical School
American Journal of Hematology | Year: 2016

Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR-ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK-STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, "driver" mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50-58, 2016. © 2015 Wiley Periodicals, Inc.


Nichols F.C.,Mayo Medical School
Current Treatment Options in Oncology | Year: 2014

Opinion statement Patients with untreated metastatic disease have a less than 5 % to 10 % 5-year survival, and for the patient who has metastatic disease isolated to the lungs, pulmonary metastasectomy remains the best hope for cure. Pulmonary metastasectomy has been performed for decades. However, despite hundreds of studies spanning several decades, randomized control data in support of pulmonary metastasectomy is still lacking, and the evidence upon which we base this commonly accepted surgical practice is for the most part weak. While well-accepted surgical selection criteria exist, controversies related to pulmonary metastasectomy abound. Unanswered and clearly debatable are questions related to: optimal preoperative imaging, if mediastinal staging should be performed and if so when, is video-assisted thoracic surgery (VATS) equivalent to open thoracotomy, is finger palpation of the lung mandatory, is repeat pulmonary metastasectomy justified, and what is the interrelationship of pulmonary metastasectomy to other treatments. Current practice to the surgical approach to pulmonary metastasectomy remains quite variable. © 2014 Springer Science+Business Media New York.


Levine J.A.,Mayo Medical School
Diabetologia | Year: 2015

Sitting too much kills. Epidemiological, physiological and molecular data suggest that sedentary lifestyle can explain, in part, how modernity is associated with obesity, more than 30 chronic diseases and conditions and high healthcare costs. Excessive sitting―sitting disease―is not innate to the human condition. People were designed to be bipedal and, before the industrial revolution, people moved substantially more throughout the day than they do presently. It is encouraging that solutions exist to reverse sitting disease. Work environments, schools, communities and cities can be re-imagined and re-invented as walking spaces, and people thereby offered more active, happier, healthier and more productive lives. © 2015, Springer-Verlag Berlin Heidelberg.


Stewart E.A.,Mayo Medical School
New England Journal of Medicine | Year: 2015

A 47-year-old black woman has heavy menstrual bleeding and iron-deficiency anemia. She reports nocturia and urinary frequency. A colonoscopy is negative. Ultrasonography shows a modestly enlarged uterus with three uterine fibroids. She is not planning to become pregnant. How should this case be evaluated and managed? Copyright © 2015 Massachusetts Medical Society.


Ahlskog J.E.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2011

Treatment of seniors with Parkinson disease is within the domain of primary care physicians and internists. A good working knowledge of carbidopa/levodopa principles should allow excellent care of most patients, at least during the early years of the disease. Even later, when levodopa responses become more complicated (eg, dyskinesias, motor fluctuations, insomnia, anxiety), levodopa adjustments may be all that is necessary. A dozen tips for optimizing treatment of Parkinson disease are discussed herein. © 2011 Mayo Foundation for Medical Education and Research.


Prommer E.,Mayo Medical School
American Journal of Hospice and Palliative Medicine | Year: 2015

Bone metastases cause devastating clinical complications leading patients to have pain, poor quality of life, loss of mobility, and autonomy. Complications from osseous metastases cause a big economic burden reflected by repeated admissions for uncontrolled symptoms. Management of symptoms associated with bone metastasis includes systemic analgesics, glucocorticoids, radiation (external beam radiation and radiopharmaceuticals), ablative techniques (radiofrequency ablation and cryoablation), chemotherapeutic agents, hormonal therapies, interventional techniques (eg, kyphoplasty), and surgical approaches. Bisphosphonates have become a standard therapy for bony metastasis. They bind to bone eventually inhibiting osteoclast action. Bisphosphonates decrease fractures when given routinely. Adverse effects of bisphosphonates include osteonecrosis of the jaw and renal insufficiency. Late last year, the Food and Drug Administration approved denosumab to prevent skeletal-related events (SREs) associated with metastatic solid tumors. This drug is a monoclonal antibody that inhibits the receptor activator of nuclear factor κB (RANK)–RANK ligand interaction. Clinical trials have shown superiority over bisphosphonates for the prevention of SREs. This article reviews the mechanism of action, pharmacology, adverse effects, and clinical trial evidence for this new drug. © 2014, © The Author(s) 2014.


Oderich G.S.,Mayo Medical School
Journal of Endovascular Therapy | Year: 2015

In summary, Dr Greenberg's contributions are legion. He accumulated the world's largest experience in almost every complex endovascular technique. He delivered many insightful presentations and authored a large number of important publications. He invented and registered over 50 patents, including helical branches, imaging processing techniques, and a percutaneous supra-annular aortic valve. His most important contribution, however, was his pivotal role in the development and dissemination of endovascular skills, which in an exponential fashion will be perpetuated by his trainees. © The Author(s) 2015.


Grant C.S.,Mayo Medical School
Clinical Therapeutics | Year: 2014

Objective The goal of this article was to describe the optimal individualized surgical management of patients with papillary thyroid cancer (PTC). Methods This summary reviews the relevant literature that takes into account description of the context of disease incidence, current practice guidelines, controversies in the management of thyroid resection and management of central neck lymph nodes, alternative methods of treatment, and evidence from the author's institution to support the final recommendations. Results Combining the rationale for treatment decisions from the Mayo Clinic's surgical management of PTC, plus recently published large institutional series and a meta-analysis of patient outcomes, the recommendations for PTC >1 cm include the following: (1) preoperative ultrasound to identify and map the location of lateral jugular lymph node metastasis; (2) bilateral total or near-total thyroidectomy; (3) routine central neck (compartment VI) lymph node dissection; and (4) inclusion of lateral neck lymph node dissection when indicated. Alterations are advised depending on either the level of expertise or anatomic findings at the time of performing the thyroidectomy and lymph node dissection. Conclusions Because all of the data presented from the Mayo Clinic and the literature fall short of Level 1 evidence, these recommendations should not be considered dogmatic nor should they exclude reasonable alternatives that are also presented. © 2014 Elsevier HS Journals, Inc. All rights reserved.


Stan M.N.,Mayo Medical School
Thyroid : official journal of the American Thyroid Association | Year: 2010

BACKGROUND: Graves' ophthalmopathy (GO) significantly impairs the quality of life of affected individuals and the most severe cases can be sight threatening. Given the limited therapeutic options, a strong emphasis should be placed on disease prevention to diminish the significant morbidity associated with this disease. SUMMARY: GO is most prevalent in women and most severe in men. Although some genetic differences between GO patients and Graves' disease patients without ophthalmopathy have been identified, none of the polymorphisms identified to date impart a high enough risk of GO to justify genetic testing to guide therapy or preventive strategies. Poorly defined mechanical factors that appear also to play a role in GO susceptibility will likely be better elucidated with advances in imaging techniques. Tobacco smoking has been consistently linked to development or deterioration of GO. Smokers who receive radioactive iodine have the highest incidence of unfavorable GO outcome, which is proportional to the number of cigarettes smoked per day. Several studies have reported an association between radioactive iodine treatment for Graves' disease and worsening or development of GO. Observational studies suggest that the same appears to be true for thyroid dysfunction, including both hyper- and hypothyroidism. While thyrotropin receptor antibody levels appear to be useful in predicting the course of disease and response to therapy, it is not known whether they are predictive of GO development. The puzzling scenarios of euthyroid or clinically unilateral GO, the large number of nonsmoking GO patients, and the occasional development of GO years after thyroid dysfunction has been treated all underline the multifactorial etiology of this disorder in which no single factor determines the clinical outcome. CONCLUSIONS: GO appears to have a complex genetic basis with multiple susceptibility alleles that act in combination with nongenetic factors to contribute to disease expression.


Wijdicks E.F.M.,Mayo Medical School
Brain | Year: 2012

In 1976, the Royal College of Physicians published neurological criteria of death. The memorandum stated that-after preconditions and exclusion criteria were met-the absence of brainstem function, including apnoea testing, would suffice. In the USA, many experts felt that brain death could be only determined by demonstrating death of the entire brain. In the history of further refinement of UK and USA brain death criteria, one particular period stands out that would bring about an apparent transatlantic divide. On 13 October 1980, the British Broadcasting Corporation aired a programme entitled 'Transplants: Are the Donors Really Dead?' Several United States experts not only disagreed with the United Kingdom criteria, but claimed that patients diagnosed with brain death using United Kingdom criteria could recover. The fallout of this television programme was substantial, as indicated by a media frenzy and a 6-month period of heated correspondence within The Lancet and The British Medical Journal. Members of the Parliament questioned the potential long-term effect on the public's trust in organ transplantation. Given the concerns raised, the British Broadcasting Corporation commissioned a second programme, which was broadcast on 19 February 1981 entitled 'A Question of Life or Death: The Brain Death Debate.' Two panels debated the issues on the accuracy of the electroencephalogram and its place, the absolute need for assessing preconditions before an examination, the problems with recognition of toxins and the feasibility of doing a new prospective study in the United Kingdom, which would follow patients' examination assessed with United Kingdom criteria until cardiac standstill. The positions of the United States and United Kingdom remained diametrically opposed to each other. This article revisits this landmark moment and places it in a wider historical context. In the USA, the focus was not on the brainstem, and the definition of brain death became rapidly infused with terms such as whole brain death (all intracranial structures above the foramen magnum), cerebral death (all supratentorial structures) or higher brain death (cortical structures) virtually synonymous with persistent vegetative state. This review also identifies the fortitude of neurosurgeon Bryan Jennett and neurologist Christopher Pallis by introducing new corroborative data on the diagnosis of brain death and clarifying the United Kingdom position. Both understood that brainstem death was the infratentorial consequence of a supratentorial catastrophe. With the 1995 American Academy of Neurology practice parameters, the differences between the UK and USA brain death determination would become much less apparent. © 2012 The Author.


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.


Young Jr. W.F.,Mayo Medical School
Hormones and Cancer | Year: 2011

The objectives of this study were to review how conventional imaging for adrenocortical carcinoma has evolved over the past 100 years and to highlight the current role for computed tomography (CT) and magnetic resonance imaging (MRI). Using historical cases from the Mayo Clinic archives, the approaches to conventional imaging for adrenocortical carcinoma are described, and pertinent literature is reviewed. Limited conventional imaging options in the first 75 years of the twentieth century were supplemented with keen clinical observation and clinical intuition. With the development of CT and MRI, technologic advances in the computed image-based assessment of adrenocortical carcinoma have been truly remarkable. CT and MRI can help determine whether an adrenal mass is an adrenocortical carcinoma and can also assess for local tumor invasion and metastatic disease. CT and MRI provide the clinician and surgeon with key information to guide medical and surgical management. Three decades from now, what we currently view as conventional imaging (e. g., CT and MRI) will be the imaging equivalents to the plain abdominal roentogram and intravenous pyelogram of the mid-twentieth century. © 2011 Springer Science+Business Media, LLC.


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.


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.


Rajkumar S.V.,Mayo Medical School
American Journal of Hematology | Year: 2012

Disease overview: Multiple myeloma accounts for ~10% of all hematologic malignancies. Diagnosis: The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of end-organ damage felt to be related to the underlying plasma-cell disorder. Risk stratification: Patients with 17p deletion, t(14;16), t(14;20), or high-risk gene expression profiling signature have high-risk myeloma. Patients with t(4;14) translocation, karyotypic deletion 13, or hypodiploidy are considered to have intermediate-risk disease. All others are considered to have standard-risk myeloma. Risk-adapted therapy: Standard-risk patients are treated with nonalkylator-based therapy such as lenalidomide plus low-dose dexamethasone (Rd) followed by autologous stem-cell transplantation (ASCT). An alternative strategy is to continue initial therapy after stem-cell collection, reserving ASCT for first relapse. Intermediate-risk and high-risk patients are treated with a bortezomib-based induction followed by ASCT and then bortezomib-based maintenance. Patients not eligible for ASCT can be treated with Rd for standard risk disease, or with a bortezomib-based regimen if intermediate-risk or high-risk features are present. To reduce toxicity, when using bortezomib, the once-weekly subcutaneous dose is preferred; similarly, when using dexamethasone, the low-dose approach (40 mg once a week) is preferred, unless there is a need for rapid disease control. Management of refractory disease: Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. The most promising new agents in development are pomalidomide and carfilizomib. © 2011 Wiley Perodicals, Inc.


Staab J.P.,Mayo Medical School
CONTINUUM Lifelong Learning in Neurology | Year: 2012

Purpose of Review: In 1986, the German neurologists Thomas Brandt and Marianne Dieterich described a syndrome of phobic postural vertigo (PPV) based on clinical observations of patients with nonvertiginous dizziness that could not be explained by then-known neuro-otologic disorders. Subsequent research by an American team led by Jeffrey Staab and Michael Ruckenstein confirmed the core physical symptoms of PPV, clarified its relationship to behavioral factors, and streamlined its definition, calling the syndrome chronic subjective dizziness (CSD). This article reviews the 26-year history of PPV and CSD and places it within the context of current neurologic practice.Recent Findings: Recent investigations in Europe, the United States, Israel, and Japan have validated the primary symptoms of CSD; identified its provoking factors and precipitants; elucidated its long-term clinical course, differential diagnosis, and common comorbidities; developed successful treatment strategies with serotonergic antidepressants, vestibular habituation, and possibly cognitive-behavioral therapy; and raised new hypotheses about pathophysiologic processes that initiate and maintain the disorder. In tertiary neuro-otology centers where it is recognized, CSD is the second most common diagnosis among patients presenting with vestibular symptoms.Summary: A quarter century of research has established CSD as a common clinical entity in neurologic and otorhinolaryngologic practice. Its identification and treatment offer relief to many patients previously thought to have enigmatic and unmanageable cases of persistent dizziness. Internationally sanctioned diagnostic criteria for CSD are under development for the first edition of the International Classification of Vestibular Disorders, scheduled for publication in early 2013. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


Ahlskog J.E.,Mayo Medical School
Neurology | Year: 2010

Rasagiline has been studied as a Parkinson disease (PD) neuroprotective agent in 2 major clinical trials, utilizing the delayed-start design in an attempt to separate symptomatic drug benefits from a disease-modifying effect. The ostensibly positive outcomes of these studies, however, are obscured by potential confounding factors that seem intrinsic to this trial design, including 1) very small changes in clinical outcome measures that could easily be overshadowed by other influences; 2) probable incomplete blinding to study end; 3) subjective components of the Unified ParkinsonÊ's Disease Rating Scale (UPDRS) scoring system; and 4) practice influences from repeated scoring. Interpretation of the recent Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trials is especially problematic given 1) divergent results with the 2 symptomatically beneficial doses and 2) variability in UPDRS scores with active rasagiline, which was twice the magnitude of the major finding of the study. These studies further illustrate the difficulty in documenting a disease-modifying effect when considering a PD drug with symptomatic benefit. Copyright © 2010 by AAN Enterprises, Inc. All rights reserved.


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.


Fractures of the acromion or scapular spine are recognized complications of reverse arthroplasty. This study reviewed the outcome of reverse arthroplasties with such fractures and compared the results to arthroplasties without the fractures. A consecutive series of 125 reverse arthroplasties were reviewed for the development of a postoperative acromial or scapular spine fracture. Nine cases were identified, all treated nonoperatively. Five fractures occurred from falls, and the remainder were fatigue fractures. These results were compared to 67 patients with similar diagnoses in the series without such fractures. No significant differences existed between the 2 groups in terms of age, sex, side of surgery, or diagnosis. Preoperatively, both groups had substantial pain, limitation of motion, and poor American Shoulder and Elbow Surgeons (ASES) and Simple Shoulder Test (SST) outcome scores. No significant differences existed between the 2 groups. At minimum 1-year follow-up, results in the shoulders with fractures were improved. Mean visual analog score (VAS) was 4.0, flexion was 89.3°, ASES score was 47.9, and SST score was 5.6. Nevertheless, these results were inferior to those in shoulders without a fracture, whose mean VAS was 0.7, flexion was 152.1°, ASES score was 87.7, and SST score was 10.2. Nonoperative management was chosen in these cases due to a concern that stable fixation would not be obtained with surgery. Although the final outcome was diminished, these patients improved their preoperative state. A decision for surgical treatment will need to weigh the challenges of internal fixation with the incremental improvement that may occur with improved fracture healing.


CD123 is the α-subunit of the interleukin-3 receptor; it represents a potential therapeutic target in systemic mastocytosis (SM) given its absent expression on normal/reactive mast cells (MCs) and aberrant expression on neoplastic MCs. We studied 58 SM patients to define CD123 expression patterns by immunohistochemistry and its clinical significance. Two hematopathologists independently scored bone marrow slides using predefined histologic parameters. In all, 23 patients had indolent SM (ISM), 10 aggressive SM (ASM), 23 SM with associated hematological neoplasm (SM-AHN) and 2 had mast cell leukemia (MCL). MC_CD123 expression was demonstrable in 37 (64%) cases; expression rates were 100%, 61%, 57% and 0% in ASM, ISM, SM-AHN and MCL, respectively (P=0.02). Focal proliferation of plasmacytoid dendritic cells (PDCs) around MC aggregates, suggesting a tumor-promoting role for PDCs, was noted in 44 (76%) cases, and was significantly higher in CD123-positive versus -negative cases (87% versus 50%, P=0.005). CD123 expression and its staining intensity had prognostic value in SM-chronic myelomonocytic leukemia and nonindolent SM patients, respectively. These observations suggest that targeting CD123 in SM may have direct (via MCs) and indirect (via PDCs) antitumor effects and clinical trials to that effect require laboratory correlative studies to address the observed target expression heterogeneity.Leukemia advance online publication, 12 January 2016; doi:10.1038/leu.2015.348. © 2015 Macmillan Publishers Limited


Joyner M.J.,Mayo Medical School
Progress in Biophysics and Molecular Biology | Year: 2015

In this essay I argue that Neo-Darwinism ultimately led to an oversimplified genotype equals phenotype view of human disease. This view has been called into question by the unexpected results of the Human Genome Project which has painted a far more complex picture of the genetic features of human disease than was anticipated. Cell centric Systems Biology is now attempting to reconcile this complexity. However, it too is limited because most common chronic diseases have systemic components not predicted by their intracellular responses alone. In this context, congestive heart failure is a classic example of this general problem and I discuss it as a systemic disease vs. one solely related to dysfunctional cardiomyocytes. I close by arguing that a physiological perspective is essential to reconcile reductionism with what is required to understand and treat disease. © 2014 Elsevier Ltd.


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.


Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.Oncogene advance online publication, 18 May 2015; doi:10.1038/onc.2015.163. © 2015 Macmillan Publishers Limited


Dowdy S.C.,Mayo Medical School
Gynecologic Oncology | Year: 2014

This review will examine existing results on the postoperative treatment of women with high-risk and advanced stage endometrial cancer. Preliminary data suggests that response to treatment is highly dependent on both grade and stage. It is hoped that this discussion will highlight deficiencies in our collective knowledge base to be addressed in future clinical trials for the benefit of women with endometrial cancer. © 2014 Elsevier Inc.


Rady M.Y.,Mayo Medical School | Verheijde J.L.,Arizona State University
Journal of Intensive Care Medicine | Year: 2014

Left ventricular assist devices (LVADs) and total artificial hearts (TAHs) are surgically implanted as permanent treatment of unrecoverable heart failure. Both LVADs and TAHs are durable mechanical circulatory support (MCS) devices that can prolong patient survival but also alter end-of-life trajectory. The permissibility of discontinuing assisted circulation is controversial because device deactivation is a life-ending intervention. Durable MCS is intended to successfully replace native physiological functions in heart disease. We posit that the presence of new lethal pathophysiology (ie, a self-perpetuating cascade of abnormal physiological processes causing death) is a central element in evaluating the permissibility of deactivating an LVAD or a TAH. Consensual discontinuation of durable MCS is equivalent with allowing natural death when there is an onset of new lethal pathophysiology that is unrelated to the physiological functions replaced by an LVAD or a TAH. Examples of such lethal conditions include irreversible coma, circulatory shock, overwhelming infections, multiple organ failure, refractory hypoxia, or catastrophic device failure. In all other situations, deactivating the LVAD/TAH is itself the lethal pathophysiology and the proximate cause of death. We postulate that the onset of new lethal pathophysiology is the determinant factor in judging the permissibility of the life-ending discontinuation of a durable MCS. © The Author(s) 2012.


The goal of therapy for patients with advanced-stage Hodgkin lymphoma is to ensure that as many patients as possible are healthy and free of disease decades after completing treatment. To achieve this, the treating physician needs to select the most effective therapeutic regimen, but also needs to choose a treatment strategy that limits long-term toxicity. One approach to achieve this is to use a less intense combination, such as ABVD chemotherapy, as initial treatment and intensify therapy only in those patients who do not become PET negative or who subsequently relapse. © 2014 Elsevier Inc.


Bell D.A.,Mayo Medical School
International Journal of Gynecological Pathology | Year: 2014

The creation of the category of borderline/atypical proliferative tumors in the World Health Organization Classification of Ovarian Tumors in 1973 prompted extensive investigation of the clinicopathologic and genetic features of low-grade serous ovarian tumors (borderline tumors/atypical proliferative tumors, noninvasive micropapillary tumors, and invasive low-grade serous carcinomas). The clinicopathologic studies of these tumors resulted in clarification of the prognostic significance of several histologic features of the ovarian tumors and their associated peritoneal lesions. The genetic studies resulted in a reassessment of the relationship between low-grade and high-grade serous carcinoma and their differing pathways of origin. This review focuses on several of the morphologic findings, their diagnostic criteria, differential diagnosis and biologic significance, and discusses the dualistic classification of serous carcinomas into high-grade and low-grade tumors. © 2014 International Society of Gynecological Pathologists.


Schornack M.M.,Mayo Medical School
Clinical and Experimental Optometry | Year: 2011

Background: Limbal stem cell deficiency (LSCD) results from damage to or destruction of corneal stem cells. Methods: A retrospective review of clinical records of a patient with LSCD describes the use of scleral lenses in disease management. Results: A patient presented with a one-year history of clinically diagnosed LSCD, which was worsening despite aggressive topical and systemic medical therapy. The condition resolved rapidly with initiation of scleral lens wear. The integrity of the ocular surface was maintained for 18 months even after the cessation of lens wear. Conclusion: Scleral lenses might allow some patients with LSCD to delay or avoid more aggressive surgical intervention. © 2011 Mayo Foundation for Medical Education and Research. Clinical and Experimental Optometry © 2011 Optometrists Association Australia.


Grothey A.,Mayo Medical School
Clinical Cancer Research | Year: 2011

Detection of guanylyl cyclase C mRNA in lymph nodes of resected stage II colorectal cancer is highly correlated with the risk of tumor recurrence. If validated, these results could have significant implications for the selection of patients for adjuvant therapy in this disease. ©2011 AACR.


Pang Y.-P.,Mayo Medical School
Biochemical and Biophysical Research Communications | Year: 2015

High resolution protein crystal structures resolved with X-ray diffraction data at cryogenic temperature are commonly used as experimental data to refine forcefields and evaluate protein folding simulations. However, it has been unclear hitherto whether the C-H bond lengths in cryogenic protein structures are significantly different from those defined in forcefields to affect protein folding simulations. This article reports the finding that the C-H bonds in high resolution cryogenic protein structures are 10-14% shorter than those defined in current AMBER forcefields, according to 3709C-H bonds in the cryogenic protein structures with resolutions of 0.62-0.79Å. Also, 20 all-atom, isothermal-isobaric, 0.5-μs molecular dynamics simulations showed that chignolin folded from a fully-extended backbone formation to the native β-hairpin conformation in the simulations using AMBER forcefield FF12SB at 300K with an aggregated native state population including standard error of 10±4%. However, the aggregated native state population with standard error reduced to 3±2% in the same simulations except that C-H bonds were shortened by 10-14%. Furthermore, the aggregated native state populations with standard errors increased to 35±3% and 26±3% when using FF12MC, which is based on AMBER forcefield FF99, with and without the shortened C-H bonds, respectively. These results show that the 10-14% bond length differences can significantly affect protein folding simulations and suggest that re-parameterization of C-H bonds according to the cryogenic structures could improve the ability of a forcefield to fold proteins in molecular dynamics simulations. © 2015 The Author.


Pectoralis major transfer (partial or complete) is the most common transfer to the scapula for winging as a result of serratus anterior paralysis or injury. The most commonly described technique is to transfer the pectoralis major prolonged with tendon allograft or autograft to the scapula. We present a technique that entails direct transfer of the sternal head of the pectoralis major with its bony insertion to the lower scapula. © 2014 by the American Society for Surgery of the Hand. All rights reserved.).


PURPOSE: A research photon-counting computed tomography (CT) system that consists of an energy-integrating detector (EID) and a photon-counting detector (PCD) was installed in our laboratory. The scanning fields of view of the EID and PCD at the isocenter are 500 and 275 mm, respectively. When objects are larger than the PCD scanning field of view, a data-completion scan (DCS) using the EID subsystem is needed to avoid truncation artifacts in PCD images. The goals of this work were to (1) find the impact of a DCS on noise of PCD images and (2) determine the lowest possible dose for a DCS such that truncation artifacts are negligible in PCD images. METHODS: First, 2 semianthropomorphic abdomen phantoms were scanned on the PCD subsystem. For each PCD scan, we acquired 1 DCS with the maximum effective mAs and 5 with lower effective mAs values. The PCD image reconstructed using the maximum effective mAs was considered as the reference image, and those using the lower effective mAs as the test images. The PCD image reconstructed without a DCS was considered the baseline image. Each PCD image was assessed in terms of noise and CT number uniformity; the results were compared among the baseline, test, and reference images. Finally, the impact of a DCS on PCD image quality was qualitatively assessed for other body regions using an anthropomorphic torso phantom. RESULTS: The DCS had a negligible impact on the noise magnitude in the PCD images. The PCD images with the minimum available dose (CTDIvol < 2 mGy) showed greatly enhanced CT number uniformity compared with the baseline images without noticeable truncation artifacts. Further increasing the effective mAs of a DCS did not yield noticeable improvement in CT number uniformity. CONCLUSIONS: A DCS using the minimum available dose had negligible effect on image noise and was sufficient to maintain satisfactory CT number uniformity for the PCD scans. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Restoration of femoral posterior condylar offset (PCO) may contribute to maximum flexion after total knee arthroplasty. Accurate radiographic measurement of postoperative PCO is possible, as the prosthesis margins can be easily identified; however, preoperative measurement of PCO may be inaccurate, as the remaining cartilage thickness of the posterior condyles is not included. This error may contribute to the controversy surrounding the importance of PCO. In this institutional review board-approved study, the cartilage thickness of posterior condylar specimens resected during total knee arthroplasty was measured. Mean cartilage thicknesses of the posterior condyles were 1.7 mm (range, 0-4 mm) medially and 2.0 mm (range, 0-5 mm) laterally. As the cartilage thickness is variable, future studies of PCO must adjust the preoperative radiographic measurements by the cartilage thickness measured intraoperatively. © 2012 Elsevier Inc.


Gertz M.,Mayo Medical School
Leukemia and Lymphoma | Year: 2013

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma. A serum monoclonal IgM protein is required to establish this diagnosis. The clinical features patients develop include normochromic normocytic anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy and signs of hyperviscosity. The International Staging System for Waldenstr m macroglobulinemia divides patients prognostically based on age, hemoglobin, platelet count, IgM level, and β2 microglobulin. Some patients with Waldenstr m macroglobulinemia have a smoldering form and can be observed without intervention. Active agents in the treatment of Waldenstr m macroglobulinemia include rituximab, chlorambucil, cyclophosphamide, fludarabine, bortezomib, lenalidomide, bendamustine, everolimus, and alemtuzumab. The current preferred Mayo Clinic non-study treatment is rituximab, cyclophosphamide, and dexamethasone. The median survival associated with this disease is now over 10 years. © 2013 Informa UK, Ltd.


Perez E.A.,Mayo Medical School
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.


Prakash Y.S.,Mayo Medical School
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2013

It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca2+]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. © 2013 the American Physiological Society.


Milone M.,Mayo Medical School | Wong L.-J.,Baylor College of Medicine
Molecular Genetics and Metabolism | Year: 2013

Mitochondria are ubiquitous organelles and play crucial roles in vital functions, most importantly, the oxidative phosphorylation and energy metabolism. Therefore, mitochondrial dysfunction can affect multiple tissues, with muscle and nerve preferentially affected. Mitochondrial myopathy is a common clinical phenotype, which is characterized by early fatigue and/or fixed muscle weakness; rhabdomyolysis can seldom occur. Muscle biopsy often identifies signs of diseased mitochondria by morphological studies, while biochemical analysis may identify respiratory chain deficiencies. The clinical, morphological and biochemical data guide molecular analysis. Being the mitochondrial function under the control of both mitochondrial DNA and nuclear DNA, the search for mitochondrial DNA mutations and mitochondrial DNA quantitation, may not be sufficient for the molecular diagnosis of mitochondrial myopathies. Approximately 1500 nuclear genes can affect mitochondrial structure and function and the targeting of such genes may be necessary to reach the diagnosis. The identification of causative molecular defects in nuclear or mitochondrial genome leads to the definite diagnosis of mitochondrial myopathy. © 2013 Elsevier Inc.


Bellolio M.F.,Mayo Medical School
The Cochrane database of systematic reviews | Year: 2014

People with hyperglycaemia concomitant with an acute stroke have greater mortality, stroke severity, and functional impairment when compared with those with normoglycaemia at stroke presentation. This is an update of a Cochrane Review first published in 2011. To determine whether intensively monitoring insulin therapy aimed at maintaining serum glucose within a specific normal range (4 to 7.5 mmol/L) in the first 24 hours of acute ischaemic stroke influences outcome. We searched the Cochrane Stroke Group Trials Register (September 2013), CENTRAL (The Cochrane Library 2013, Issue 8), MEDLINE (1950 to September 2013), EMBASE (1980 to September 2013), CINAHL (1982 to September 2013), Science Citation Index (1900 to September 2013), and Web of Science (ISI Web of Knowledge) (1993 to September 2013). We also searched ongoing trials registers and SCOPUS. Randomised controlled trials (RCTs) comparing intensively monitored insulin therapy versus usual care in adults with acute ischaemic stroke. We obtained a total of 1565 titles through the literature search. Two review authors independently selected the included articles and extracted the study characteristics, study quality, and data to estimate the odds ratio (OR) and 95% confidence interval (CI), mean difference (MD) and standardised mean difference (SMD) of outcome measures. We resolved disagreements by discussion. We included 11 RCTs involving 1583 participants (791 participants in the intervention group and 792 in the control group). We found that there was no difference between the treatment and control groups in the outcomes of death or dependency (OR 0.99, 95% CI 0.79 to 1.23) or final neurological deficit (SMD -0.09, 95% CI -0.19 to 0.01). The rate of symptomatic hypoglycaemia was higher in the intervention group (OR 14.6, 95% CI 6.6 to 32.2). In the subgroup analyses of diabetes mellitus (DM) versus non-DM, we found no difference for the outcomes of death and disability or neurological deficit. The number needed to treat was not significant for the outcomes of death and final neurological deficit. The number needed to harm was nine for symptomatic hypoglycaemia. After updating the results of our previous review, we found that the administration of intravenous insulin with the objective of maintaining serum glucose within a specific range in the first hours of acute ischaemic stroke does not provide benefit in terms of functional outcome, death, or improvement in final neurological deficit and significantly increased the number of hypoglycaemic episodes. Specifically, those people whose glucose levels were maintained within a tighter range with intravenous insulin experienced a greater risk of symptomatic and asymptomatic hypoglycaemia than those people in the control group.


Garrity J.A.,Mayo Medical School
Cleveland Clinic Journal of Medicine | Year: 2012

Ophthalmic manifestations of vasculitis can be orbital, ocular (affecting the globe), or intraocular. Orbital inflammation manifests as sudden onset of pain, erythema, and proptosis, and can be sight-threatening. In the globe, red eye is typical in both episcleritis and scleritis. Episcleritis is usually otherwise asymptomatic with blanching upon instillation of topical phenylephrine, whereas scleritis is painful and does not blanch. Infectious and rheumatic diseases are present in nearly 50% of patients with scleritis. The symptoms of keratitis are similar to those of scleritis; superficial keratitis is benign but peripheral ulcerative keratitis can be sight-threatening. Anterior uveitis is the most frequent ocular manifestation of Behçet disease. Approximately 30% of patients with granulomatosis with polyangiitis (Wegener's granulomatosis) have ocular involvement, with orbital disease being most common. With ophthalmic manifestations of vasculitis, tissue biopsy of any site that is amenable to biopsy is recommended. Biopsy must be interpreted within the context of treatment.


Renovascular hypertension (RVHT) increases cardiovascular morbidity and mortality. Renal revascularization with percutaneous transluminal renal angioplasty and stenting (PTRS) may reverse RVHT but may not fully regress cardiac remodeling and damage, possibly due to persistent myocardial insults. Bendavia is a mitochondrial targeted peptide that reduces ischemic cardiomyopathy by improving mitochondrial function. However, its potential for attenuating residual myocardial damage after reversal of RVHT has not been explored. We hypothesized that treatment with Bendavia as an adjunct to PTRS would improve cardiac function and oxygenation, and decrease myocardial injury in swine RVHT. After 6 weeks of RVHT (unilateral renal artery stenosis) or control, pigs underwent PTRS (or sham), with adjunct continuous infusion of Bendavia (0.05 mg/kg intravenously, 30 min before to 3.5 h after PTRS) or vehicle (n = 7 each). Four weeks later, systolic and diastolic function were assessed by multidetector computed tomography, myocardial oxygenation by blood oxygen level-dependent MRI, and myocardial morphology, apoptosis, mitochondrial biogenesis, and fibrosis evaluated ex vivo. PTRS restored blood pressure in both groups, yet E/A ratio remained decreased. Myocardial oxygenation and mitochondrial biogenesis improved, and myocardial inflammation, oxidative stress, and fibrosis normalized in association with improvement in diastolic function in RVHT + PTRS + Bendavia animals. Adjunct Bendavia during PTRS in swine RVHT improved diastolic function and oxygenation and reversed myocardial tissue damage. This approach may allow a novel strategy for preservation of cardiac function and structure in RVHT.


Sedlack R.E.,Mayo Medical School
Gastrointestinal Endoscopy | Year: 2011

Background: How to define competency in colonoscopy, how to assess it, and how much training is required are questions that experts in endoscopy have grappled with since the advent of the procedure. Objective: To describe methods to assess core endoscopy skills in trainees and learning curves for these parameters and to define competency thresholds for these skills. Design: A prospective descriptive assessment of trainee colonoscopy performance. Setting: Mayo Clinic, Rochester, Minnesota. Subjects: Gastroenterology fellows undergoing endoscopy training. Intervention: From July 2007 through June 2010, fellows' core cognitive and motor colonoscopy skills were assessed by using the Mayo Colonoscopy Skills Assessment Tool (MCSAT). Main Outcome Measurements: Average MCSAT item scores and learning curves are described. Minimal competence thresholds for each MSCAT item are established by using the contrasting groups method. Results: Forty-one GI fellows performed 6635 colonoscopies; 4103 procedures (62%) were assessed by using the MCSAT. Average scores of 3.5 set the competency bar for each of the core skills and were reached by 275 procedures on average. Independent cecal intubation rates of 85% and cecal intubation times of 16 minutes or less were also achieved at 275 procedures on average. Limitations: Limited to a single center. Conclusions: Learning curves for core colonoscopy skills are described. MCSAT scores of 3.5, cecal intubation rates of 85%, and intubation times of less than 16 minutes are recommended as minimal competency criteria. It takes on average 275 procedures to achieve competence in colonoscopy. This is more than previous gastroenterology training recommendations and far more than current training requirements in other specialties. © 2011 American Society for Gastrointestinal Endoscopy.


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.


Mandrekar J.N.,Mayo Medical School
Journal of Thoracic Oncology | Year: 2011

Kappa statistics is used for the assessment of agreement between two or more raters when the measurement scale is categorical. In this short summary, we discuss and interpret the key features of the kappa statistics, the impact of prevalence on the kappa statistics, and its utility in clinical research. We also introduce the weighted kappa when the outcome is ordinal and the intraclass correlation to assess agreement in an event the data are measured on a continuous scale. Copyright © 2010 by the international Association fot the Study of lung Cancer.


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.


Vincent Rajkumar S.,Mayo Medical School
American Journal of Hematology | Year: 2014

Disease overview: Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis: The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. If end-organ damage is not present, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma. Risk stratification: In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk. Risk-adapted intial therapy: Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high-risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients who are not candidates for transplant, initial therapy is given for approximately 12 to 18 months. Maintenance therapy: After initial therapy, lenalidomide maintenance is considered for standard risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in patients with intermediate or high risk myeloma. Management of refractory disease: Patients with indolent relapse can be treated first with 2-drug or 3-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. © 2014 Wiley Periodicals, Inc.


Gertz M.A.,Mayo Medical School
American Journal of Hematology | Year: 2011

Disease overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. Diagnosis: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. Risk stratification: Age, hemoglobin level, platelet count, β 2-microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Risk adapted therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analogue, or both. The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Management of refractory disease: Bortezomib, thalidomide, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. © 2011 Wiley-Liss, Inc.


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.


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.


Dispenzieri A.,Mayo Medical School
American Journal of Hematology | Year: 2011

Disease overview: POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. Diagnosis: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Risk stratification: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. Risk-adapted therapy: For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes. © 2011 Wiley-Liss, Inc..


Caselli R.J.,Mayo Medical School | Reiman E.M.,University of Arizona
Journal of Alzheimer's Disease | Year: 2013

Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer's disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the ε4 allele of apolipoprotein E (APOE). Neuropathological studies of young deceased ε4 carriers have shown modest but abnormal amounts of neocortical amyloid and medial temporal neurofibrillary tangles that is also reflected in cerebrospinal fluid (CSF) biomarkers, amyloid-β, and phospho-tau in particular. MRI studies have shown progressive hippocampal and gray matter atrophy with the advent of mild cognitive impairment (MCI), and fluorodeoxyglucose PET scans show reduced cerebral metabolism in posterior cingulate and related AD regions evident even in 30 year olds. Cerebral amyloidosis disclosed by more recent amyloid ligand PET studies in asymptomatic 60 year olds increases in parallel with ε4 gene dose. Longitudinal neuropsychological studies have revealed accelerated memory decline in ε4 carriers beginning around age 55-60 years whose severity again parallels ε4 gene dose. The clinico-pathological correlation of declining memory and AD-like neuropathological change defines preclinical AD and has set the stage for the accelerated evaluation of presymptomatic AD treatments. In this article, we briefly consider some of the earliest detectable changes associated with the predisposition to AD, and some of the prevention trial strategies that have been proposed to help find treatments to reduce the risk, postpone the onset of, or completely prevent AD symptoms as soon as possible. © 2013 - IOS Press and the authors. All rights reserved.


Schwedt T.J.,Mayo Medical School
Headache | Year: 2013

"Thunderclap headaches" are severe intensity headaches that reach maximum intensity in less than 1 minute. There are numerous etiologies of thunderclap headache, some associated with substantial morbidity and mortality and others with benign outcomes. Evaluation of the patient with thunderclap headache must occur urgently in order to assess for dangerous etiologies such as subarachnoid hemorrhage. When a cause for thunderclap headache is not identified after initial testing that includes brain computed tomography and cerebrospinal fluid evaluation, additional testing is typically indicated to determine the etiology. "Primary thunderclap headache" is diagnosed when a complete evaluation fails to identify a specific cause for thunderclap headache. © 2013 American Headache Society.


Smyrk T.C.,Mayo Medical School
Current Opinion in Rheumatology | Year: 2011

Purpose of review: The spectrum of IgG4-related systemic disease (IgG4-RSD) continues to widen. At most of the sites involved by this condition, the clinical presentation can mimic neoplasm. Pathologic assessment of small biopsies can be critical to proper management. This review summarizes the histologic features of IgG4-RSD and the role of immunohistochemistry of IgG4 in the diagnosis. Recent findings: The review period saw further expansion of the list of sites putatively involved by IgG4-RSD, with new, or more detailed, entries related to lung, lymph nodes, stomach, and thyroid. A tentative consensus was reached on the issue of subtypes of autoimmune pancreatitis. The role of immunohistochemistry for IgG4 as an adjunct to the diagnosis of IgG4-RSD was further clarified. Summary: Sclerosing lymphoplasmacytic inflammation at almost any site can represent a manifestation of IgG4-RSD. There are several histologic features that can suggest the diagnosis. Immunohistochemistry for IgG4 is a useful diagnostic test to further support the diagnosis. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Ringler M.D.,Mayo Medical School
Journal of Hand Surgery | Year: 2013

The optimal imaging protocols for magnetic resonance imaging (MRI) of the wrist ligaments are discussed, including the use of magnetic resonance arthrography, and 3 Tesla (T) versus 1.5 T magnetic field strength. The normal MRI appearance of the triangular fibrocartilage complex, capsular, and interosseous wrist ligaments is briefly covered to point out potential diagnostic pitfalls. Numerous examples of common ligamentous pathology discernible on MRI are provided, along with the latest estimates of diagnostic sensitivity and specificity provided by the literature. © 2013 ASSH. Published by Elsevier, Inc. All rights reserved.


Gertz M.A.,Mayo Medical School
American Journal of Hematology | Year: 2013

Disease Overview: Immunoglobulin (Ig) light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of Ig light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Diagnosis: Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is of immunoglobulin origin is mandatory. Prognosis: N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. Therapy: All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT-proBNP <5,000 ng/mL, troponin T<0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide or bortezomib)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide. Future Challenges: Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improving survival. © 2013 Wiley Periodicals, Inc.


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.


Kannoth S.,Mayo Medical School
Annals of Indian Academy of Neurology | Year: 2012

Paraneoplastic neurological syndromes (PNS) are rare disorders associated with cancer, not caused by direct invasion, metastasis or consequences of treatment. They are usually autoimmune in nature. Often, PNS precedes the manifestations of cancer. Onconeural antibodies are important in the diagnosis and management of these disorders. These antibodies are specific for the malignancy rather than for a particular neurological syndrome. Often, there are different antibodies associated with the same syndrome. Multiple antibodies are also known to coexist in a given patient with malignancy. While investigating a patient for suspected PNS, the entire gamut of onconeural antibodies should be investigated so as not to miss the diagnosis. In 30-40% of the cases, PNS can occur without antibodies. Investigations for identifying the underlying cancer can be directed by the antibody panel. If conventional screening for cancer is negative, a positron emission scanning/computed tomography scan can be useful. Patients need follow-up surveillance for cancer if not detected in the first instance. Cancer detection and treatment, immunotherapy and supportive care are important components of treatment of PNS. Immunotherapy is very effective in PNS associated with cell membrane-associated antibodies like voltage-gated potassium channel complex, NMDA receptor antibodies and voltage-gated calcium channel antibodies. Immunotherapy includes steroids, IVIgG, plasmaphereis, cytotoxic medications and rituximab. Supportive therapy includes symptomatic treatment with antiepileptic and analgesic medications, physiotherapy, speech therapy and occupational therapy. PNS can mimic any neurologic syndrome. A high index of clinical suspicion is important for early diagnosis and prompt management and better outcome.


Gertz M.A.,Mayo Medical School
American Journal of Hematology | Year: 2011

Immunoglobulin (Ig) light chain amyloidosis is a clonal but nonproliferative plasma cell disorder in which fragments of an Ig light chain are deposited in tissues. The clinical features depend on the organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, and peripheral/autonomic neuropathy. Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. N-terminal pro-brain natriuretic peptide and serum troponin T values are used to classify patients into three groups of approximately equal size; median survivals are 26.4, 10.5, and 3.5 months, respectively. All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and to prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is a preferred technique, but only 20% of patients are eligible. Requirements for safe SCT include mild or no cardiac involvement, troponin T value <0.06 ng/mL, age younger than 70 years, <3 organs involved, and serum creatinine value ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide. Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improvement in survival. © 2010 Wiley-Liss, Inc.


Ong A.C.M.,University of Sheffield | Harris P.C.,Mayo Medical School
Kidney International | Year: 2015

It is 20 years since the identification of PKD1, the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), followed closely by the cloning of PKD2. These major breakthroughs have led in turn to a period of intense investigation into the function of the two proteins encoded, polycystin-1 and polycystin-2, and how defects in either protein lead to cyst formation and nonrenal phenotypes. In this review, we summarize the major findings in this area and present a current model of how the polycystin proteins function in health and disease.


Mclean P.,Mayo Medical School
Therapeutic Advances in Neurological Disorders | Year: 2014

Parkinson's disease is a slowly progressive neurodegenerative disorder typically characterized by the loss of dopaminergic neurons within the substantia nigra pars compacta, and the intraneuronal deposition of insoluble protein aggregates chiefly comprised of α-synuclein. Patients experience debilitating symptoms including bradykinesia, rigidity and postural instability. No curative treatment currently exists and therapeutic strategies are restricted to symptomatic treatment only. Over the past decade a class of molecular chaperones called the heat shock proteins has emerged as a potentially promising therapeutic target. Heat shock proteins aid in the folding and refolding of proteins, and target denatured proteins to degradation systems. By targeting heat shock proteins through various means including overexpression and pharmacological enhancement, researchers have shown that α-synuclein aggregation and its associated cytotoxicity can be therapeutically modulated in an array of cell and animal models. This review highlights the relevant progress in this field and discusses the relevance of heat shock proteins as therapeutic modulators of α-synuclein toxicity to the rapidly evolving understanding of Parkinson's disease pathogenesis. © The Author(s), 2013.


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.


Mokri B.,Mayo Medical School
Headache | Year: 2013

Spontaneous intracranial hypotension typically results from spontaneous cerebrospinal fluid (CSF) leak, often at spine level and only rarely from skull base. Once considered rare, it is now diagnosed far more commonly than before and is recognized as an important cause of headaches. CSF leak leads to loss of CSF volume. Considering that the skull is a rigid noncollapsible container, loss of CSF volume is typically compensated by subdural fluid collections and by increase in intracranial venous blood which, in turn, causes pachymeningeal thickening, enlarged pituitary, and engorgement of cerebral venous sinuses on magnetic resonance imaging (MRI). Another consequence of CSF hypovolemia is sinking of the brain, with descent of the cerebellar tonsils and brainstem as well as crowding of the posterior fossa noted on head MRI. The clinical consequences of these changes include headaches that are often but not always orthostatic, nausea, occasional emesis, neck and interscapular pain, cochleovestibular manifestations, cranial nerve palsies, and several other manifestations attributed to pressure upon or stretching of the cranial nerves or brain or brainstem structures. CSF lymphocytic pleocytosis or increase in CSF protein concentration is not uncommon. CSF opening pressure is often low but can be within normal limits. Stigmata of disorders of connective tissue matrix are seen in some of the patients. An epidural blood patch, once or more, targeted or distant, at one site or bilevel, has emerged as the treatment of choice for those who have failed the conservative measures. Epidural injection of fibrin glue of both blood and fibrin glue can be considered in selected cases. Surgery to stop the leak is considered when the exact site of the leak has been determined by neurodiagnostic studies and when less invasive measures have failed. Subdural hematomas sometimes complicate the CSF leaks; a rebound intracranial hypertension after successful treatment of a leak is not rare. Cerebral venous sinus thrombosis as a complication is fortunately less common, and superficial siderosis and bibrachial amyotrophy are rare. Short-term recurrences are not uncommon, and long-term recurrences are not rare. © 2013 American Headache Society.


Juhn Y.J.,Mayo Medical School
Journal of Allergy and Clinical Immunology | Year: 2014

Most of the research effort regarding asthma has been devoted to its causes, therapy, and prognosis. There is also evidence that the presence of asthma can influence patients' susceptibility to infections, yet research in this aspect of asthma has been limited. There is additional debate in this field, with current literature tending to view the increased risk of infection among atopic patients as caused by opportunistic infections secondary to airway inflammation, especially in patients with severe atopic diseases. However, other evidence suggests that such risk and its underlying immune dysfunction might be a phenotypic or clinical feature of atopic conditions. This review argues (1) that improved understanding of the effects of asthma or other atopic conditions on the risk of microbial infections will bring important and new perspectives to clinical practice, research, and public health concerning atopic conditions and (2) that research efforts into the causes and effects of asthma must be juxtaposed because they are likely to guide each other. © 2014 American Academy of Allergy, Asthma and Immunology.


Patterson M.C.,Mayo Medical School
Handbook of Clinical Neurology | Year: 2013

The gangliosidoses comprise a family of lysosomal storage diseases characterized by the accumulation of complex glycosphingolipids in the nervous system and other tissues, secondary to the deficient activity of lysosomal hydrolases or their associated activator proteins. GM1 and GM2 gangliosidosis are associated with deficiency of β-galactosidase and β-hexosaminidase respectively. All gangliosidoses are characterized by progressive neurodegeneration, the severity of which is proportional to the residual enzyme activity. The GM1 gangliosidoses are characterized by dysostosis, organomegaly and coarsening in their most severe forms, whereas children with classic infantile GM2 gangliosidosis (Tay-Sachs disease) are usually spared systemic involvement, except in the case of the Sandhoff variant, in which organomegaly may occur. Cherry-red macular spots occur in the early onset forms of the gangliosidoses, but are less frequently seen in the less severe, later onset phenotypes. Macrocephaly, an exaggerated startle response, cognitive decline, seizures, ataxia, and progressive muscular atrophy may occur in different forms of gangliosidosis. The diagnosis is made by assay of enzyme activity, and can be confirmed by mutation analysis. Carrier screening for Tay-Sachs disease has been remarkably successful in reducing the incidence of this disease in the at-risk Ashkenazi population. There are no proven disease-modifying therapies for the gangliosidoses. © 2013 Elsevier B.V.


Patel T.,Mayo Medical School
Nature Reviews Gastroenterology and Hepatology | Year: 2011

Cholangiocarcinomas are a diverse group of tumors that are presumed to originate from the biliary tract epithelium either within the liver or the biliary tract. These cancers are often difficult to diagnose, their pathogenesis is poorly understood, and their dismal prognosis has resulted in a nihilistic approach to their management. The two major clinical phenotypes are intrahepatic, mass-forming tumors and large ductal tumors. Among the ductal cancers, lesions at the liver hilum are most prevalent. The risk factors, clinical presentation, natural history and management of these two types of cholangiocarcinoma are distinct. Efforts to improve outcomes for patients with these diseases are affected by several challenges to effective management. For example, designations based on anatomical characteristics have been inconsistently applied, which has confounded analysis of epidemiological trends and assessment of risk factors. The evaluation of therapeutic options, particularly systemic therapies, has been limited by a lack of appreciation of the different phenotypes. Controversies exist regarding the appropriate workup and choice of management approach. However, new and emerging tools for improved diagnosis, expanded indications for surgical approaches, an emerging role for locoregional and intrabiliary therapies and improved systemic therapies provide optimism and hope for improved outcomes in the future. © 2011 Macmillan Publishers Limited. All rights reserved.


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.


Li D.,Mayo Medical School
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium | Year: 2012

With increasing adoption of electronic health records (EHRs), the need for formal representations for EHR-driven phenotyping algorithms has been recognized for some time. The recently proposed Quality Data Model from the National Quality Forum (NQF) provides an information model and a grammar that is intended to represent data collected during routine clinical care in EHRs as well as the basic logic required to represent the algorithmic criteria for phenotype definitions. The QDM is further aligned with Meaningful Use standards to ensure that the clinical data and algorithmic criteria are represented in a consistent, unambiguous and reproducible manner. However, phenotype definitions represented in QDM, while structured, cannot be executed readily on existing EHRs. Rather, human interpretation, and subsequent implementation is a required step for this process. To address this need, the current study investigates open-source JBoss® Drools rules engine for automatic translation of QDM criteria into rules for execution over EHR data. In particular, using Apache Foundation's Unstructured Information Management Architecture (UIMA) platform, we developed a translator tool for converting QDM defined phenotyping algorithm criteria into executable Drools rules scripts, and demonstrated their execution on real patient data from Mayo Clinic to identify cases for Coronary Artery Disease and Diabetes. To the best of our knowledge, this is the first study illustrating a framework and an approach for executing phenotyping criteria modeled in QDM using the Drools business rules management system.


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.


Tatum W.O.,Mayo Medical School
Journal of Clinical Neurophysiology | Year: 2012

Temporal lobe epilepsy (TLE) is the most common form of adult localization-related epilepsy. Hippocampal onset accounts for at least 80% of all temporal lobe seizures. The electroencephalogram (EEG) of mesial TLE contains interictal features often associated with anterior temporal epileptiform discharges with a maximal voltage over the basal temporal electrodes. Localized ictal patterns on scalp EEGs characteristically reveal unilateral 5-to 9-Hz rhythmic ictal theta or alpha epileptiform activity maximal in the anterior temporal scalp electrodes. Invasive-scalp EEG comparisons have yielded direct information about mesial temporal sources and their corresponding electrical fields. Refinement of macroscopic spatial and the temporal resolution suggest that a more precise seizure localization may exist beyond 1-to 35-Hz frequencies observed in routine scalp recording. Defining the focal areas of ictogenesis within the medial temporal lobe demonstrates a rich connection to a broad network that goes beyond the medial structures and even the temporal lobe itself. Advanced electrophysiologic application in TLE may further our understanding of ictogenesis to perfect surgical treatment and to elucidate the neurophysiologic corollaries of epileptogensis itself. Copyright © 2012 by the American Clinical Neurophysiology Society.


Tefferi A.,Mayo Medical School
American Journal of Hematology | Year: 2011

Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Diagnosis: Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. Risk stratification: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10 9/L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10 9/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of ∼ 15.4, 6.5, 2.9, and 1.3 years, respectively. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes ≥40 × 10 9/L or other unfavorable karyotype. Risk-adapted therapy: Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation or experimental drug therapy is considered for intermediate-2/ high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 risk disease. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain. © 2011 Wiley-Liss, Inc.


Oberg A.L.,Mayo Medical School
BMC bioinformatics | Year: 2012

Mass Spectrometry utilizing labeling allows multiple specimens to be subjected to mass spectrometry simultaneously. As a result, between-experiment variability is reduced. Here we describe use of fundamental concepts of statistical experimental design in the labeling framework in order to minimize variability and avoid biases. We demonstrate how to export data in the format that is most efficient for statistical analysis. We demonstrate how to assess the need for normalization, perform normalization, and check whether it worked. We describe how to build a model explaining the observed values and test for differential protein abundance along with descriptive statistics and measures of reliability of the findings. Concepts are illustrated through the use of three case studies utilizing the iTRAQ 4-plex labeling protocol.


Nguyen J.H.,Mayo Medical School
Neurochemistry International | Year: 2012

Brain edema remains a challenging obstacle in the management of acute liver failure (ALF). Cytotoxic mechanisms associated with brain edema have been well recognized, but evidence for vasogenic mechanisms in the pathogenesis of brain edema in ALF has been lacking. Recent reports have not only shown a role of matrix metalloproteinase-9 in the pathogenesis of brain edema in experimental ALF but have also found significant alterations in the tight junction elements including occludin and claudin-5, suggesting a vasogenic injury in the blood-brain barrier (BBB) integrity. This article reviews and explores the role of the paracellular tight junction proteins in the increased selective BBB permeability that leads to brain edema in ALF. © 2011 Elsevier Ltd. All rights reserved.


Power A.H.,Mayo Medical School
Journal of vascular surgery | Year: 2012

This study assessed neurovascular complications in the surgical management of carotid body tumors (CBTs), with emphasis on those treated with and without preoperative embolization. We reviewed the clinical data of all consecutive patients with CBTs treated by surgical resection at our institution from 1985 to 2010. Outcomes were compared between Shamblin class II and III CBTs treated with preoperative embolization (EMB group) and with no preoperative embolization (NEMB group). A total of 131 patients (80 women, 51 men), who were aged 48 years (range, 16-84 years), had resection of 144 CBTs and 12 concurrent cervical paragangliomas. This included 18 patients who had bilateral resections and 29 with familial CBTs. Succinate dehydrogenase (SDHx) mutations were confirmed in 17 patients. Mean tumor volume was 20.5 cm(3) (range, 0.8-101.3 cm(3)), and there were two biochemically active CBTs (1%). There were 71 Shamblin II and 33 Shamblin III. The EMB group underwent 33 CBT resections, and the NEMB group underwent 71. There were more patients in the EMB group with bilateral (48% vs 22%; P = .01) and familial (34% vs 14%; P = .01) CBT; otherwise, patient demographics, Shamblin class, and tumor diameter and volumes were similar. No strokes or other major complications occurred after preoperative embolization with polyvinyl alcohol particles 1 day before surgery. The EMB group required less extensive procedures (simple excision in 97% vs 82%, P = .03; internal carotid artery clamping in 15% vs 37%, P = .04) and had less blood loss (mean estimated blood loss, 263 vs 599 mL; P = .002) than the NEMB group. However, there were no significant differences in operative time (250 vs 265 minutes; P = .49), temporary cranial nerve injury (52% vs 38%; P = .21), clinically apparent cranial nerve deficits after 1 year (12% vs 7%; P = .46), deaths (0% vs 0%; P > .99), stroke (0% vs 1%; P > .99), or postoperative length of stay (4.1 vs 4.2 days; P = .91). Large CBTs can be resected safely with or without preoperative embolization. Preoperative embolization may simplify the conduct of the operation and reduce blood loss but does not decrease rates of cranial nerve injury, although most are temporary. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.


Ingle J.N.,Mayo Medical School
Steroids | Year: 2011

The third-generation aromatase inhibitors are an important class of drugs for use in adjuvant therapy for postmenopausal women with resected estrogen receptor positive breast cancer. Multiple large prospective randomized trials have established their value in this setting and provided guidance for their use in clinical management. This review will outline the trials that have provided evidence on the value of the aromatase inhibitors in the adjuvant setting as well as the ongoing trials that will expand our knowledge of how to use them most effectively. © 2011 Elsevier Inc. All rights reserved.


Roger V.L.,Mayo Medical School
International Journal of Environmental Research and Public Health | Year: 2010

Heart failure has been singled out as an emerging epidemic, which could be the result of increased incidence and/or increased survival leading to increased prevalence. Knowledge of the responsibility of each factor in the genesis of the epidemic is crucial for prevention. Population-based studies have shown that, over time, the incidence of heart failure remained overall stable, while survival improved. Therefore, the heart failure epidemic is chiefly one of hospitalizations. Data on temporal trends in the incidence and prevalence of heart failure according to ejection fraction and how it may have changed over time are needed while interventions should focus on reducing the burden of hospitalizations in hear failure. © 2010 by the authors.


Hocker S.,Mayo Medical School
Epilepsy and Behavior | Year: 2015

Systemic complications occur at every stage of status epilepticus, involve every organ system, and may worsen outcome. Initially, there is a massive catecholamine release and hyperadrenergic state that may result in neurocardiogenic, pulmonary, and, sometimes, musculoskeletal or renal injury. Further medical complications accompany the various treatments used to abort the seizures including the use of nonanesthetic antiseizure drugs and high-dose anesthetic infusions. Later, sequelae of prolonged immobility and critical illness occur and add to the cumulative morbidity of these patients. Clinicians should follow a protocol to guide screening for early markers of systemic injury, complications of specific pharmacologic and adjunctive treatments, and periodic surveillance for complications related to prolonged immobility. © 2015 Elsevier Inc.


Staab J.P.,Mayo Medical School
Journal of Vestibular Research: Equilibrium and Orientation | Year: 2011

Recent years have witnessed an upsurge of interest in migraine as a cause of vestibular symptoms. Starting with 1970s case reports linking migraine to childhood vertigo, neurotologists worldwide have increasingly diagnosed migraine. Various syndromes of vestibular migraine (VM) have been described, diagnostic criteria proposed, epidemiologic data collected, and neurophysiologic models developed. Yet, the concept that migraine causes vestibular symptoms rests on a surprisingly thin research database. Current concepts of VM are based on expert opinion, not empirical data. No general consensus exists about the definition of VM. No studies have analyzed its essential features. Just one well-controlled medication trial has been published. No biomarkers are known. To stimulate more rigorous research, this paper poses three questions about clinical investigations into migraine and vestibular symptoms: What variables should be measured? What patients should be studied? How might clinical trials yield both clinically useful results and greater insights into pathophysiologic processes? Using these questions, the limits of current knowledge are explored. Applicable research methods from epidemiology to genetics are examined. Pilot data demonstrating pharmacologic and genetic dissection techniques are presented. Ambitious, but practical, near-term clinical research goals are enumerated, including rigorous validation of diagnostic criteria and development of empirically derived management guidelines.


Background: We desire to review our experience with bladder augmentation in spina bifida patients followed in a transitional and adult urologic practice. This paper will specifically focus on three major complications: Bladder calculi, the most frequent complication found following bladder augmentation, perforation of the augmentation, its most lethal complication and finally we will address loss of renal function as a direct result of our surgical reconstructive procedures. Methods: We reviewed a prospective data base maintained on patients with spina bifida followed in our transitional and adult urology clinic from 1986 to date. Specific attention was given to patients who had developed bladder calculi, sustained a spontaneous perforation of the augmented bladder or had developed new onset of renal scarring or renal insufficiency (≥ stage 3 renal failure) during prolonged follow-up. Results: The development of renal stones (P < 0.05) and symptomatic urinary tract infections (P < 0.0001) were found to be significantly reduced by the use of high volume (≥240 mL) daily bladder wash outs. Individuals who still developed bladder calculi recalcitrant to high volume wash outs were not benefited by the correction of underlying metabolic abnormalities or mucolytic agents. Spontaneous bladder perforations in the adult patient population with spina bifida were found to be directly correlated to substance abuse and noncompliance with intermittent catheterization, P < 0.005. Deterioration of the upper tracts as defined by the new onset of renal scars occurred in 40% (32/80) of the patients managed by a ileocystoplasty and simultaneous bladder neck outlet procedure during a median follow-up interval 14 years (range, 8-45 years). Development of ≥ stage 3 chronic renal failure occurred within 38% (12/32) of the patients with scarring i.e., 15% (12/80) of the total patient population. Prior to the development of the renal scarring, 69% (22/32) of the patients had been noncompliant with intermittent catheterization. The onset of upper tract deterioration (i.e., new scar formation, hydronephrosis, calculus development, decrease in renal function) was silent, that is, clinically asymptomatic in one third (10/32 pts). Conclusions: This paper documents the need for high volume bladder irrigations to both prevent the most common complication following bladder augmentation, which is the development of bladder calculi and to reduce the incidence of symptomatic urinary tract infections. It provides a unique perspective regarding the impact of substance abuse and patient non-compliance with medical directives as being both the most common cause for both spontaneous bladder rupture following augmentation cystoplasty and for deterioration of the upper tracts. These findings should cause the surgeon to reflect on his/her assessment of a patient prior to performing a bladder augmentation procedure and stress the need for close follow-up. © Translational Andrology and Urology. All rights reserved.


Mardini S.,Mayo Medical School
Plastic and reconstructive surgery | Year: 2010

BACKGROUND: Esophageal defects are reconstructed using a variety of methods and tissue types. The choice depends on the location of the defect, the condition of the patient, and the flaps that are available for reconstruction. Often, patients with esophageal defects also lack a mechanism for voice production following a total laryngectomy procedure. METHODS: A review of the literature was performed for esophagus reconstruction and voice rehabilitation following laryngectomy. Methods of voice restoration using intestinal transfers are presented based on the authors' experience. RESULTS: Several methods of esophagus and voice restoration can achieve excellent functional outcomes. CONCLUSION: Esophagus reconstruction and voice rehabilitation following esophageal resection and total laryngectomy are possible using a variety of flaps with good functional outcomes.


Petersen R.C.,Mayo Medical School
Journal of Nutrition, Health and Aging | Year: 2010

A goal of many clinical trials for Alzheimer's disease is to develop disease-modifying therapies for the pre-dementia period of the Alzheimer's disease process. However, there are no clinical criteria for characterizing subjects in this range. The construct of amnestic mild cognitive impairment has been extensively investigated and may provide useful clinical criteria for this clinical stage. It is proposed that the clinical criteria for mild cognitive impairment be enriched with imaging and other biomarkers to improve the specificity of the outcome, and these criteria might suffice for pre-dementia clinical trials.


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.