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Boston, MA, United States

Massachusetts General Hospital is the original and largest teaching hospital of Harvard Medical School and a biomedical research facility located in the West End neighborhood of Boston, Massachusetts. It is the third oldest general hospital in the United States and the oldest and largest hospital in New England with 950 beds. Massachusetts General Hospital conducts the largest hospital-based research program in the world, with an annual research budget of more than $750 million. It is currently ranked as the #2 hospital in the United States by U.S. News & World Report. Wikipedia.

Lewiecki E.M.,University of New Mexico | Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center | Miller S.A.,Massachusetts General Hospital
American Journal of Public Health | Year: 2013

Suicide is a serious public health concern that is responsible for almost 1 million deaths each year worldwide. It is commonly an impulsive act by a vulnerable individual. The impulsivity of suicide provides opportunities to reduce the risk of suicide by restricting access to lethal means. In the United States, firearms, particularly handguns, are the most commonmeans of suicide. Despite strong empirical evidence that restrictionofaccesstofirearms reduces suicides, access to firearms in the United States is generally subject to few restrictions. Implementation and evaluation of measures such as waiting periods and permit requirements that restrict access to handguns should be a top priority for reducing deaths from impulsive suicide in the United States. Copyright © 2012 by the American Public Health Association®.

Brugge W.R.,Massachusetts General Hospital
Current Opinion in Gastroenterology | Year: 2013

PURPOSE OF REVIEW: The purpose of this review is to examine the recent developments in the use of endoscopic retrograde cholangio-pancreatography (ERCP) and endoscopic ultrasound (EUS) in the management of patients with pancreatic-biliary disease. RECENT FINDINGS: The use of ERCP to guide selective placement of pancreatic sphincterotomes, stone extraction balloons, and stents enables clinicians to treat pancreatic sphincteric and ductal disorders. Pancreatic stones are a remediable cause of recurrent pancreatitis and small calculi can be easily removed. The gold standard for the diagnosis of pancreas divisum remains ERCP and sphincterotomy is highly effective in the treatment of relapsing pancreatitis. Intraductal papillary mucinous neoplasms are the most common pancreatic malignancy and ERCP, as well as EUS can identify and sample the solid and cystic lesions. Mural nodules can be detected and sampled effectively by EUS-fine needle aspiration (FNA). The sensitivity of EUS-FNA for pancreatic adenocarcinoma is excellent (more than 85%). Although cyst fluid carcinoembryonic antigen is a very good marker for the presence of a mucinous cystic lesion, it is not an indicator of malignancy. SUMMARY: In summary, ERCP and EUS are important tools for the management of benign and malignant lesions of the pancreas. Copyright © 2013 Lippincott Williams & Wilkins.

Seton M.,Massachusetts General Hospital | Seton M.,Harvard University
Cleveland Clinic Journal of Medicine | Year: 2013

Paget disease of bone is a focal disorder of aging bonethat may be asymptomatic or may present with pain, bowing deformity, fracture, or a nonspecific rheumaticcomplaint. It is the second most common disease of bonein the elderly after osteoporosis, and the loss of structuralintegrity in affected bone conveys a risk of fracture. It may occur sporadically or in geographic or familialclusters. This article discusses the prevalence, pathology, workup, and treatment of Paget disease of bone.

Among mesenchymal tumors of the uterus, smooth muscle neoplasms are most common. The wide morphologic spectrum, especially within the category of leiomyomas, is responsible for diagnostic problems more frequently with leiomyosarcoma (including mitotically active, apoplectic, and leiomyoma with bizarre nuclei) but also with endometrial stromal tumors. In the former scenario, clinical information, gross appearance as well as strict utilization of morphologic criteria including cytologic atypia, mitotic activity, and tumor cell necrosis are clues in establishing the correct diagnosis. It is important to keep in mind that mitotic rate thresholds vary for the different subtypes of leiomyosarcoma. Of note, p16 should be used with caution in supporting a diagnosis of leiomyosarcoma as it is often positive in leiomyomas with bizarre nuclei and leiomyomas with apoplectic change (in the latter most frequently and more intense near areas of necrosis). MED12 mutations have also a very limited role in this differential diagnosis. Endometrial stromal tumors are by far, less common than smooth muscle tumors, but can be confused with leiomyosarcomas if they are associated with an undifferentiated uterine sarcoma and the low-grade component is overlooked or they have a myxoid/fibroblastic morphology. The differential diagnosis may be confounded if the latter is associated with a high-grade endometrial stromal sarcoma. It is important to highlight that CD10 is not a reliable marker in these differentials and should be used as a part of a panel of antibodies that also includes desmin and h-caldesmon. Two other recently categorized tumors in the uterus that merit special mention are PEComa and inflammatory myofibroblastic tumor as they enter in the differential diagnosis of smooth muscle tumors. PEComa may be part of the tuberous sclerosis syndrome and may show either a predominantly epithelioid or spindle morphology or combination thereof. Rarely, it may contain melanin pigment. There is variable positivity for HMB-45, MelanA, MiTF, and CathepsinK, and some tumors have been shown to express TFE-3 especially when associated with clear cell morphology. Patients with adverse outcome have tumors with ≥2 of the following features: ≥5 cm, infiltration, high-grade cytologic features, mitotic rate ≥1/50 high-power fields, necrosis, or lymphovascular invasion. Inflammatory myofibroblastic tumor is important to recognize as it often mimics myxoid smooth muscle tumors, either benign or malignant. The presence of an associated lymphoplasmacytic infiltrate should alert to that possibility and ALK studies (immunostain or FISH) are helpful in establishing this diagnosis. These tumors can behave in a malignant manner if large, associated with abundant myxoid change, brisk mitotic rate or show tumor cell necrosis.

Melamed M.L.,Yeshiva University | Thadhani R.I.,Massachusetts General Hospital
Clinical Journal of the American Society of Nephrology | Year: 2012

Vitamin D has garnered much research and debate about supplementation in recent years, not only as it pertains to patients with kidney disease but also to those in the general population. This review discusses observational and available clinical trial evidence about the effects of both calcitriol and vitamin D analogs (active) and ergo-calciferol and cholecalciferol (nutritional) vitamin D in patients with CKD and ESRD. © 2012 by the American Society of Nephrology.

Billings J.A.,Massachusetts General Hospital
Critical Care Medicine | Year: 2012

Patient comfort is not assured by common practices for terminal extubation. Treatment guidelines suggest minimizing dosage of opioids and sedatives. Multiple lines of evidence indicate that clinicians are limited in their ability to recognize distress in such patients and tend to undermedicate patients in distress. Yet suffering of any significant degree should be unacceptable. For painful procedures, such as surgery, the analogous practice of postponing anesthesia until the patient evidences discomfort would never be tolerated. Waiting for signs of suffering before initiating excellent analgesia and sedation inexorably subjects patients to distress. Therefore, when death is inevitable and imminent after extubation, suffering should be anticipated, concerns about respiratory depression dismissed, and vigorous preemptive deep sedation or anesthesia provided. Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Strand J.J.,Mayo Medical School | Kamdar M.M.,Massachusetts General Hospital | Carey E.C.,Mayo Medical School
Mayo Clinic Proceedings | Year: 2013

With a focus on improving quality of life for patients, palliative care is a rapidly growing medical subspecialty focusing on the care of patients with serious illness. Basic symptom management, discussions of prognostic understanding, and eliciting treatment goals are essential pieces in the practice of nearly all physicians. Nonetheless, many complex patients with a serious, life-threatening illness benefit from consultation with palliative care specialists, who are trained and experienced in complex symptom management and challenging communication interactions, including medical decision making and aligning goals of care. This article discusses the changing role of modern palliative care, addresses common misconceptions, and presents an argument for early integration of palliative care in the treatment of patients dealing with serious illness. © 2013 Mayo Foundation for Medical Education and Research.

Zietman A.,Massachusetts General Hospital
Reports of Practical Oncology and Radiotherapy | Year: 2013

This paper evaluates the reasons behind the rise in the use of proton beam for prostate cancer, the economics drivers behind it, and the evidence that exists to support it. It concludes that clinical outcome data underlying the notion that this is a superior treatment remains sparse and discusses what is needed to fill in the gaps. © 2013 Greater Poland Cancer Centre.

Fang Q.,Massachusetts General Hospital | Kaeli D.R.,Northeastern University
Biomedical Optics Express | Year: 2012

In this report, we discuss the use of contemporary ray-tracing techniques to accelerate 3D mesh-based Monte Carlo photon transport simulations. Single Instruction Multiple Data (SIMD) based computation and branch-less design are exploited to accelerate ray-tetrahedron intersection tests and yield a 2-fold speed-up for ray-tracing calculations on a multicore CPU. As part of this work, we have also studied SIMD-accelerated random number generators and math functions. The combination of these techniques achieved an overall improvement of 22% in simulation speed as compared to using a non-SIMD implementation. We applied this new method to analyze a complex numerical phantom and both the phantom data and the improved code are available as open-source software at http://mcx.sourceforge.net/mmc/. © 2012 Optical Society of America.

Baselga J.,Massachusetts General Hospital
The oncologist | Year: 2011

The phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research for a number of years, but is new to most clinicians responsible for the daily challenges of breast cancer management. In fact, the PI3K pathway is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway are frequent in breast cancer, causing resistance to human epidermal growth factor receptor 2-targeted agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well as PI3K inhibitors, Akt inhibitors, rapamycin analogs, and mammalian target of rapamycin (mTOR) catalytic inhibitors. Multiple PI3K inhibitors are currently under development, including pure PI3K inhibitors, compounds that block both PI3K and mTOR (dual inhibitors), pure catalytic mTOR inhibitors, and inhibitors that block Akt. It is likely that these agents will have to be given in combination with other signal inhibitors because anti-mTOR agents and PI3K inhibitors may result in the activation of compensatory feedback loops that would in turn result in decreased efficacy. This article reviews current data related to the PI3K pathway, its role in breast cancer, the frequency with which PI3K is aberrant in breast cancer, and the potential clinical implications of using agents that target the PI3K pathway.

Dzik W.S.,Massachusetts General Hospital
Transfusion | Year: 2012

Anticoagulant drugs are taken by millions of patients throughout the world. Warfarin has been the most widely prescribed anticoagulant for decades. In recent years, new oral anticoagulants have been approved for use, are being positioned as alternatives to warfarin, and represent an enormous market opportunity for pharmaceutical companies. Requests for urgent reversal of anticoagulants are not uncommon especially in the setting of critical bleeding. This review summarizes information on reversal of warfarin by vitamin K, plasma, prothrombin complex concentrates, and recombinant VIIa. In addition, we emphasize the lack of current evidence supporting reversibility of the new oral direct thrombin inhibitors and Factor Xa inhibitors. This review is presented to assist transfusion medicine specialists, hematologists, and other clinicians who prescribe blood components for reversal of drug-induced anticoagulation. © 2012 American Association of Blood Banks.

Hong T.S.,Massachusetts General Hospital | Tome W.A.,University of Wisconsin - Madison | Harari P.M.,University of Wisconsin - Madison
Radiotherapy and Oncology | Year: 2012

Purpose: To assess patterns of H&N IMRT practice with particular emphasis on elective target delineation. Materials and methods: Twenty institutions with established H&N IMRT expertise were solicited to design clinical target volumes for the identical H&N cancer case. To limit contouring variability, a primary tonsil GTV and ipsilateral level II node were pre-contoured. Participants were asked to accept this GTV, and contour their recommended CTV and PTV. Dose prescriptions, contouring time, and recommendations regarding chemotherapy were solicited. Results: All 20 institutions responded. Remarkable heterogeneity in H&N IMRT design and practice was identified. Seventeen of 20 centers recommended treatment of bilateral necks whereas 3/20 recommended treatment of the ipsilateral neck only. The average CTV volume was 250 cm 3 (range 37-676 cm 3). Although there was high concordance in coverage of ipsilateral neck levels II and III, substantial variation was identified for levels I, V, and the contralateral neck. Average CTV expansion was 4.1 mm (range 0-15 mm). Eight of 20 centers recommended chemotherapy (cisplatin), whereas 12/20 recommended radiation alone. Responders prescribed on average 69 and 68 Gy to the tumor and metastatic node GTV, respectively. Average H&N target volume contouring time was 102.5 min (range 60-210 min). Conclusion: This study identifies substantial heterogeneity in H&N IMRT target definition, prescription, neck treatment, and use of chemotherapy among practitioners with established H&N IMRT expertise. These data suggest that continued efforts to standardize and simplify the H&N IMRT process are desirable for the safe and effective global advancement of H&N IMRT practice. © 2012 Elsevier Ireland Ltd. All rights reserved.

Hamilos D.L.,Massachusetts General Hospital
American Journal of Rhinology and Allergy | Year: 2015

The goal of this review is to elucidate the pathogenic factors, histopathologic features, and special considerations that relate to pediatric versus adult chronic rhinosinusitis (CRS) and to emphasize differences and similarities between the adult and pediatric conditions. Emphasis is placed on understanding of the differences in pathogenic mechanisms, host-microbial interactions, potential defects in innate antimicrobial immunity, and the role of biofilm formation in pediatric versus adult CRS and how these translate to different approaches toward both medical and surgical management. Pediatric CRS can be viewed as evolving from acute bacterial rhinosinusitis into an uncomplicated "early" stage of CRS, later evolving into a persistent stage and, in some cases, evolving into a late "maladaptive-eosinophilic" stage disease. Given this potential evolution toward more irreversible disease, a plea can be made for improved recognition of and more aggressive early intervention for pediatric CRS, it is hoped, to prevent these long-term consequences. For the primary care physician, this may necessitate enlisting the support of a sinus specialist before the symptoms of CRS have persisted for months or years. It may also necessitate, in some cases, the use of sinus computed tomography imaging to demonstrate that sinus abnormalities have resolved. Other arguments can be made for prompt and comprehensive management of pediatric CRS, including the need to reduce the burden of illness, reduce health care costs, avoid unnecessary antibiotic use and its attendant effects toward promoting antibiotic resistant infections and, potentially, to reduce the development of important comorbidities, e.g., asthma. © 2015, OceanSide Publications, Inc., USA.

Deshpande V.,Massachusetts General Hospital
Seminars in Diagnostic Pathology | Year: 2012

IgG4-related disease (IgG4-RD) is a chronic and relapsing disease. The diagnosis of IgG4-RD is based on a combination of features that include clinical, imaging, serologic, histology, and immunohistochemistry. Nonetheless, histopathology has emerged as the gold standard for the diagnosis of IgG4-RD. Guidelines for the pathologic diagnosis of this condition have been published by an international group of experts: a triumvirate of histologic features allows for a confident diagnosis of IgG4-RD to be made in most cases: (1) a dense lymphoplasmacytic infiltrate, (2) storiform-type fibrosis, and (3) obliterative phlebitis. Elevated numbers of IgG4-positive plasma cells are essential for the diagnosis, but this feature is not sufficient in, and of, itself. IgG4-positive plasma cells are also seen in a variety of inflammatory and neoplastic diseases. An elevated IgG4 to IgG ratio, more than 40%, improves the specificity of this stain. A wide range of inflammatory and neoplastic diseases including antineutrophil cytoplasmic antibody (ANCA)-related vasculitis, chronic infections, mesenchymal neoplasms, carcinoma, and lymphoma should be excluded before arriving at a diagnosis of IgG4-RD. This review aims to provide the histopathologist with a set of practical guidelines for the diagnosis of IgG4-RD, and also addresses the many controversies associated with the diagnostic aspects of this disease. © 2012 Elsevier Inc.

Besnard A.,Harvard University | Sahay A.,Harvard University | Sahay A.,Harvard Stem Cell Institute | Sahay A.,Massachusetts General Hospital
Neuropsychopharmacology | Year: 2016

The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)-CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal-cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD. © 2016 American College of Neuropsychopharmacology. All rights reserved.

Sadri-Vakili G.,Massachusetts General Hospital
Brain Research | Year: 2015

Acute and repeated exposure to cocaine induces long-lasting alterations in neural networks that underlie compulsive drug seeking and taking. Cocaine exposure triggers complex adaptations in the brain that are mediated by dynamic patterns of gene expression that are translated into enduring changes. Recently, epigenetic modifications have been unveiled as critical mechanisms underlying addiction that contribute to drug-induced plasticity by regulating gene expression. These alterations are also now linked to the heritability of cocaine-induced phenotypes. This review focuses on how changes in the epigenome, such as altered DNA methylation, histone modifications, and microRNAs, regulate transcription of specific genes that contribute to cocaine addiction. This article is part of a Special Issue entitled SI:Addiction circuits. © 2014 Elsevier B.V. All rights reserved.

Russell S.J.,Massachusetts General Hospital | Beck R.W.,Jaeb Center for Health Research
Diabetes Care | Year: 2016

The development of artificial pancreas systems has evolved to the point that pivotal studies designed to assess efficacy and safety are in progress or soon to be initiated. These pivotal studies are intended to provide the necessary data to gain clearance from the U.S. Food and Drug Administration, coverage by payers, and adoption by patients and clinicians. Although there will not be one design that is appropriate for every system, there are certain aspects of protocol design that will be considerations in all pivotal studies designed to assess efficacy and safety. One key aspect of study design is the intervention to be used by the control group. A case can be made that the control group should use the currently available best technology, which is sensor-augmented pump therapy. However, an equally, if not more, compelling case can be made that the control intervention should be usual care. In this Perspective, we elaborate on this issue and provide a pragmatic approach to the design of clinical trials of artificial pancreas systems. © 2016 by the American Diabetes Association.

Kasaie P.,University of Cincinnati | Andrews J.R.,Massachusetts General Hospital | Kelton W.D.,University of Cincinnati
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: Household contact tracing has recently been endorsed for global tuberculosis (TB) control, but its potential population-level impact remains uncertain. Objectives: To project the maximum impact of household contact tracing for TB in a moderate-burden setting. Methods: We developed a stochastic, agent-based simulation model of a simplified TB epidemic, calibrated to a setting of moderate TB incidence. We used data from the literature to generate "community-driven" and "household-driven" scenarios in which 22 and 50% of TB transmission occurred within the household, respectively. In each scenario, we simulated an intervention in which the household members are screened and treated for TB at the time of an index patient's active TB diagnosis. Measurements and Main Results: By the time of TB diagnosis, 75 to 95% of initial household infections had already occurred, but only 1.5 to 3.0% of contacts had sufficient time to progress to active TB. With 100% sensitive tracing of all contacts for 5 consecutive years, TB incidence declined by 10 to 15%, with a mean year-over-year decline of 2% per year. Effects were sustained for many years after stopping the intervention. Providing preventive therapy with contact tracing nearly doubled this impact (17-27% decline in incidence). Impact was proportional to sensitivity and coverage; thus, if 50% of contacts were screened with a 50% sensitive test, TB incidence declined by only 0.5% per year. Conclusions: Household contact tracing is unlikely to transform TB epidemiology in isolation but has the potential, especially with provision of preventive therapy, to augment a comprehensive package of interventions that could substantially reduce the population-level burden of TB. Copyright © 2014 by the American Thoracic Society.

Vassoler F.M.,University of Pennsylvania | White S.L.,University of Pennsylvania | Schmidt H.D.,University of Pennsylvania | Sadri-Vakili G.,Massachusetts General Hospital | Christopher Pierce R.,University of Pennsylvania
Nature Neuroscience | Year: 2013

We delineated a heritable phenotype resulting from the self-administration of cocaine in rats. We observed delayed acquisition and reduced maintenance of cocaine self-administration in male, but not female, offspring of sires that self-administered cocaine. Brain-derived neurotrophic factor (Bdnf) mRNA and BDNF protein were increased in the medial prefrontal cortex (mPFC), and there was an increased association of acetylated histone H3 with Bdnf promoters in only the male offspring of cocaine-experienced sires. Administration of a BDNF receptor antagonist (the TrkB receptor antagonist ANA-12) reversed the diminished cocaine self-administration in male cocaine-sired rats. In addition, the association of acetylated histone H3 with Bdnf promoters was increased in the sperm of sires that self-administered cocaine. Collectively, these findings indicate that voluntary paternal ingestion of cocaine results in epigenetic reprogramming of the germline, having profound effects on mPFC gene expression and resistance to cocaine reinforcement in male offspring. © 2013 Nature America, Inc. All rights reserved.

Wong E.B.,Massachusetts General Hospital | Wong E.B.,KwaZulu Natal Research Institute for Tuberculosis and HIV | Cohen K.A.,KwaZulu Natal Research Institute for Tuberculosis and HIV | Bishai W.R.,KwaZulu Natal Research Institute for Tuberculosis and HIV
Trends in Microbiology | Year: 2013

The standard treatment for tuberculosis (TB) is lengthy, complex, and significantly toxic. Drug development for TB has stagnated for decades, but in recent years renewed commitment and coordinated research has generated a modest pipeline of new drugs that hold the potential to make treatment more effective, shorter, less complex, and less toxic in the near future. With a particular focus on bedaquiline (TMC207), the first anti-TB drug of a novel class to be approved by the US Food and Drug Administration (FDA) in 40 years, this review summarizes the recent evidence behind new developments in TB treatment. Novel drug classes, repurposed drugs, and host-directed therapies are reviewed. In parallel to these exciting developments in drug discovery, we propose that it is crucial to develop more rapid and comprehensive diagnostics that will allow the timely selection of the best regimen for individual patients. © 2013 Elsevier Ltd.

Warner J.,Beth Israel Deaconess Medical Center | Hochberg E.,Massachusetts General Hospital
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2012

Electronic health records (EHRs) have the potential to increase the quality and decrease the cost of cancer care. These twin goals can only be met by a fully functional oncology EHR, which includes at a minimum: searchable data repositories, clinical decision support (CDS), the ability to electronically order chemotherapeutic medications, and the ability to interface with patients via a patient portal. Such fully functional EHRs not only offer patients the best potential for high-quality care, they enable retrospective analysis to answer a wide variety of comparative effectiveness and quality improvement questions. The significant barriers of cost, time pressures, aversion to CDS, and interoperability will need to be overcome if EHRs are to be meaningfully used by the majority of oncologists. © JNCCN-Journal of the National Comprehensive Cancer Network.

Faje A.,Massachusetts General Hospital | Klibanski A.,Harvard University
Current Osteoporosis Reports | Year: 2012

The relationship between body composition and skeletal metabolism has received growing recognition. Low body weight is an established risk factor for fracture. The effect of obesity on skeletal health is less well defined. Extensive studies in patients with anorexia nervosa and obesity have illuminated many of the underlying biologic mechanisms by which body composition modulates bone mass. This review examines the relationship between body composition and bone mass through data from recent research studies throughout the weight spectrum ranging from anorexia nervosa to obesity. © Springer Science+Business Media, LLC 2012.

Baker K.,Harvard University | Baker K.,Massachusetts General Hospital
Anesthesiology | Year: 2010

Background: The literature is mixed on whether evaluation and feedback to clinical teachers improves clinical teaching. This study sought to determine whether resident-provided numerical evaluation and written feedback to clinical teachers improved clinical teaching scores. Methods: Anesthesia residents anonymously provided numerical scores and narrative comments to faculty members who provided clinical teaching. Residents returned 19,306 evaluations between December 2000 and May 2006. Faculty members received a quantitative summary report and all narrative comments every 6 months. Residents also filled out annual residency program evaluations in which they listed the best and worst teachers in the department. Results: The average teaching score for the entire faculty rose over time and reached a plateau with a time constant of approximately 1 yr. At first, individual faculty members had average teaching scores that were numerically diverse. Over time, the average scores became more homogeneous. Faculty members ranked highest by teaching scores were also most frequently named as the best teachers. Faculty members ranked lowest by teaching scores were most frequently named as the worst teachers. Analysis of ranks, differential improvement in scores, and a decrease in score diversity effectively ruled out simple score inflation as the cause for increased scores. An increase in teaching scores was most likely due to improved teaching. Conclusions: A combination of evaluation and feedback, including comments on areas for improvement, was related to a substantial improvement in teaching scores. Clinical teachers are able to improve by using feedback from residents. Copyright © 2010, the American Society of Anesthesiologists, Inc.

Hemphill L.C.,Massachusetts General Hospital
Journal of Clinical Lipidology | Year: 2010

Options for treatment of severe heterozygous and homozygous familial hypercholesterolemia prior to the statin era were limited by significant side effects and morbidity. The advent of both the statins and technology for the selective removal of LDL via apheresis have revolutionized management but challenges remain. © 2010 National Lipid Association. All rights reserved.

Sokol C.L.,Massachusetts General Hospital | Medzhitov R.,Howard Hughes Medical Institute
Current Opinion in Immunology | Year: 2010

Long appreciated for their role as Type-2 effector cells, basophils have recently come into the spotlight for their role in the initiation of Type-2 immunity. Via an assortment of different activation pathways, basophils produce cytokines such as IL-4 that promote Th2 differentiation. Furthermore, recent studies using different experimental systems have shown that basophils can act as antigen presenting cells both in vitro and in vivo. In addition, basophils shape the Type-2 immune response by guiding antibody production and the memory response.

Cutler C.,Dana-Farber Cancer Institute | Ballen K.K.,Massachusetts General Hospital
Blood Reviews | Year: 2012

Only 30% of patients who require an allogeneic hematopoietic cell transplant will have a HLA matched sibling donor. Many patients, particularly those patients with diverse racial and ethnic backgrounds, may not be able to identify a suitably matched unrelated donor. Over 25,000 umbilical cord blood transplant procedures have been performed in the last 25. years. Considerable challenges exist in defining the appropriate conditioning regimen and graft vs host disease prophylaxis, surmounting issues of cell dose and delayed engraftment, and improving immune recovery. In this review, we discuss strategies to improve umbilical cord blood transplant outcomes, focusing on cord blood unit selection, expansion, and homing efficiency. © 2012 Elsevier Ltd.

Rubin K.M.,Massachusetts General Hospital
Clinical Journal of Oncology Nursing | Year: 2012

Ipilimumab is a U.S. Food and Drug Administration-approved novel T-cell potentiator that improves survival in metastatic melanoma. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4, a negative regulator of the immune response, thus promoting T-cell activation and prolonging a patient's antitumor response. However, that action may produce a mechanism-related spectrum of immune-related adverse events (irAEs), which can become severe and life-threatening if left unrecognized and untreated. This article describes the clinical properties of ipilimumab, specifically in regard to its unique profile of irAEs. Guidelines to manage irAEs are reviewed with a particular emphasis on the contribution of nurses to patient care and education. The nurse's role in facilitating communication among the oncology team, primary practice team, patients, and caregivers is fundamental to early recognition and effective management of irAEs so that patients can continue on therapy. As a regular, ongoing presence in patient care, the oncology nurse is well placed to deliver information, assess patients' understanding of that information, and support them through their cancer experience. Checklists of irAE symptoms may be useful for patients and nurses alike. In addition, education on ipilimumab's mechanism of action and how it contributes to irAEs should form an integral part of the patient treatment plan. © Oncology Nursing Society.

Januzzi Jr. J.L.,Massachusetts General Hospital
Archives of Cardiovascular Diseases | Year: 2012

The care of patients with heart failure can be challenging, with few objective tools available to assist in therapy decision-making. Natriuretic peptides are powerfully prognostic biomarkers in patients with heart failure and may represent an objective target for therapy. Accordingly, the use of biomarker-guided care with either B-type natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) has been recently explored. Over the past few years, a number of studies with heterogeneous inclusion criteria, methods and results have been performed. We have reviewed the available literature, summarizing the results of biomarker-guided heart failure trials and deriving recommendations for optimal application of biomarker-guided heart failure care based on the experience gained. In general, positive studies had low BNP or NT-proBNP target concentrations (∼100 pg/mL and ∼1000 pg/mL, respectively) and achieved lower natriuretic peptide concentrations compared with standard care. Patients in the biomarker-guided arms of the studies typically received more aggressive heart failure care and had no excess adverse outcomes. In the recent ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study, patients treated with biomarker-guided care also had improved quality of life and significantly better reverse remodeling on echocardiography compared with patients who received standard care. In conclusion, heart failure therapy guided by a goal to reduce natriuretic peptide concentrations below prognostically-meaningful levels results in more aggressive heart failure care, is well tolerated and is associated with superior outcomes. © 2011 Elsevier Masson SAS. All rights reserved.

Seely E.W.,Brigham and Womens Hospital | Seely E.W.,Harvard University | Ecker J.,Harvard University | Ecker J.,Massachusetts General Hospital
New England Journal of Medicine | Year: 2011

A 35-year-old woman who has never been pregnant and who has a 5-year history of hypertension wants to become pregnant. She has stopped using contraception. Her only medication is lisinopril at a dose of 10 mg per day. Her blood pressure is 124/68 mm Hg, and her body-mass index (the weight in kilograms divided by the square of the height in meters) is 27. What would you advise?. Copyright © 2011 Massachusetts Medical Society.

Delaney T.F.,Massachusetts General Hospital
Frontiers of Radiation Therapy and Oncology | Year: 2011

The clinical advantage for proton radiotherapy over photon approaches is the marked reduction in integral dose to the patient, due to the absence of exit dose beyond the proton Bragg peak. The integral dose with protons is approximately 60% lower than that with any external beam photon technique. Pediatric patients, because of their developing normal tissues and anticipated length of remaining life, are likely to have the maximum clinical gain with the use of protons. Proton therapy may also allow treatment of some adult tumors to much more effective doses, because of normal tissue sparing distal to the tumor. Currently, the most commonly available proton treatment technology uses 3D conformal approaches based on (a) distal range modulation, (b) passive scattering of the proton beam in its x- and y-axes, and (c) lateral beam-shaping. It is anticipated that magnetic pencil beam scanning will become the dominant mode of proton delivery in the future, which will lower neutron scatter associated with passively scattered beam lines, reduce the need for expensive beam-shaping devices, and allow intensity-modulated proton radiotherapy. Proton treatment plans are more sensitive to variations in tumor size and normal tissue changes over the course of treatment than photon plans, and it is expected that adaptive radiation therapy will be increasingly important for proton therapy as well. While impressive treatment results have been reported with protons, their cost is higher than for photon IMRT. Hence, protons should ideally be employed for anatomic sites and tumors not well treated with photons. While protons appear cost-effective for pediatric tumors, their cost-effectiveness for treatment of some adult tumors, such as prostate cancer, is uncertain. Comparative studies have been proposed or are in progress to more rigorously assess their value for a variety of sites. The utility of proton therapy will be enhanced by technological developments that reduce its cost. Combinations of 3D protons with IMRT photons may offer improved treatment plans at lower cost than pure proton plans. Hypofractionation with proton therapy appears to be safe and cost-effective for many tumor sites, such as for selected liver, lung and pancreas cancers, and may yield significant reduction in the cost of a therapy course. Together, these offer practical strategies for expanding the clinical availability of proton therapy. Copyright © 2011 S. Karger AG, Basel.

Lefort K.,University of Lausanne | Dotto G.P.,University of Lausanne | Dotto G.P.,Massachusetts General Hospital
Cell | Year: 2011

Barrett's esophagus is an epithelial metaplasia associated with an increased risk for cancer, but its underlying mechanisms have been debated. Now Wang et al. (2011) suggest an intriguing explanation for this puzzle: a population of residual embryonic cells, lacking the transcription factor p63, migrates and repopulates a normal tissue damaged by inflammation or gastroesophageal reflux. © 2011 Elsevier Inc.

Patti J.A.,Massachusetts General Hospital
Journal of the American College of Radiology | Year: 2013

In this address, John A. Patti, MD, acknowledges the celebration and success that radiologists have experienced throughout their careers but also asks incisive questions about how they will face the future. Answers to those questions require an analysis of the past, an understanding of the present, serious and penetrating introspection, and engagement of a process for moving forward. An understanding of who we are and why we do what we do is essential to facilitate the changes that will be necessary if radiologists are to control the future, rather than having the future control radiologists. © 2013 American College of Radiology.

Shaw A.T.,Massachusetts General Hospital | Shaw A.T.,Massachusetts Institute of Technology | Solomon B.,Peter MacCallum Cancer Center
Clinical Cancer Research | Year: 2011

Several decades of cancer research have revealed a pivotal role for tyrosine kinases as key regulators of signaling pathways, controlling cell growth and differentiation. Deregulation of tyrosine kinase-mediated signaling occurs frequently in cancer and is believed to drive the initiation and progression of disease. Chromosomal rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) occur in a variety of human malignancies including non-small cell lung cancer (NSCLC), anaplastic large cell lymphomas, and inflammatory myofibroblastic tumors. The aberrant activation of ALK signaling leads to "oncogene addiction" and marked sensitivity to ALK inhibitors such as crizotinib (PF-02341066). This review focuses on ALK rearrangements in NSCLC, starting with the discovery of the EML4-ALK fusion oncogene, and culminating in the recent validation of ALK as a therapeutic target in patients with ALK-rearranged NSCLC. Current efforts seek to expand the role of ALK kinase inhibition in lung and other cancers and to address the molecular basis for the development of resistance. © 2011 American Association for Cancer Research.

Hunt J.L.,Harvard University | Hunt J.L.,Massachusetts General Hospital
Archives of Pathology and Laboratory Medicine | Year: 2011

Context.- Molecular testing in anatomic pathology is becoming standardized and can contribute valuable diagnostic, therapeutic, and prognostic information for the clinical management of patients. In head and neck pathology, recent advances in molecular testing have provided important targets in several different diagnostic areas, with particular emerging clinical applications in squamous and salivary gland pathology. In squamous mucosal-derived lesions, human papilloma virus has emerged as an important pathogenic etiology in a subset of oropharyngeal squamous cell carcinomas. Within the category of salivary gland tumors, 3 tumors have recently been recognized that contain oncogenic translocations. Objective.- To describe the current state of information about the molecular alterations in squamous lesions and in salivary gland tumors of the head and neck. Data Sources.- Published literature on squamous and salivary gland tumors of the head and neck. Conclusions.- The different approaches to identification of viral-associated tumors include assays using polymerase chain reaction, in situ hybridization, and immunohistochemistry. Most mucoepidermoid carcinomas harbor MECT1-MAML2 gene rearrangement. The MYB-NFIB translocations have recently been identified in adenoid cystic carcinomas. Finally, a newly described tumor of salivary gland, mammary analogue secretory carcinoma, harbors the ETV6-NTRK3 translocation. Although these translocations are just emerging as diagnostic targets, future roles mav evolve as potential therapeutic targets.

Sokol C.L.,Yale University | Medzhitov R.,Massachusetts General Hospital
Mucosal Immunology | Year: 2010

Basophils that were long thought to have a redundant role in mast cells in the effector response to allergens and parasites are now being recognized to have important roles in the regulation of adaptive immune responses. Recent data have revealed their role in the initiation of the T helper cell 2 (Th2)-mediated immune response. Not only do basophils guide the Th1-Th2 balance by providing an early source of crucial Th2-skewing cytokines, interleukin (IL)-4 and thymic stromal lymphopoietin, but recent findings have also illustrated their capacity to function as antigen-presenting cells. Thus, basophils activate and instruct naive CD4 T cells, and guide their development into Th2 cells. Not only do basophils directly interact with T cells, but new insights have illustrated that they may also directly guide antibody responses in both the primary and memory responses. These and other studies have illustrated the emerging role of basophils in the regulation of type 2 immunity. © 2010 Society for Mucosal Immunology.

Tanaka S.,Stephen d Catherine Pappas Center For Neuro Oncology | Louis D.N.,55 Fruit Street | Curry W.T.,55 Fruit Street | Batchelor T.T.,Massachusetts General Hospital | Dietrich J.,Stephen d Catherine Pappas Center For Neuro Oncology
Nature Reviews Clinical Oncology | Year: 2013

Glioblastomas are heterogeneous neoplasms that are driven by complex signalling pathways, and are among the most aggressive and challenging cancers to treat. Despite standard treatment with resection, radiation and chemotherapy, the prognosis of patients with glioblastomas remains poor. An increasing understanding of the molecular pathogenesis of glioblastomas has stimulated the development of novel therapies, including the use of molecular-targeted agents. Identification and validation of diagnostic, prognostic and predictive biomarkers has led to the advancement of clinical trial design, and identification of glioblastoma subgroups with a more-favourable prognosis and response to therapy. In this Review, we discuss common molecular alterations relevant to the biology of glioblastomas, targeted, antiangiogenic and immunotherapies that have impacted on the treatment of this disease, and the challenges and pitfalls associated with these therapies. In addition, we emphasize current biomarkers relevant to the management of patients with glioblastoma. © 2013 Macmillan Publishers Limited. All rights reserved.

Rigotti N.A.,Harvard University | Rigotti N.A.,Massachusetts General Hospital
The Lancet Respiratory Medicine | Year: 2013

Tobacco use is a leading cause of preventable death worldwide. Respiratory diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer, account for a large proportion of tobacco-related deaths. Smoking cessation benefits almost all smokers, irrespective of the age at which they quit, making smoking cessation a core component of prevention and treatment of respiratory diseases. Evidence shows that psychosocial counselling and pharmacotherapy are effective smoking cessation methods and are most effective when used together. The first-line drugs licensed to aid smoking cessation (nicotine replacement therapy, bupropion, and varenicline) are effective in patients with COPD. Efforts are underway to improve the efficacy of existing treatments and increase the proportion of smokers who try to quit, and who use treatment when doing so. However, existing smoking cessation counselling and drugs are among the most cost-effective clinical preventive services available. Incorporation of such treatment into routine clinical practice is essential for provision of high-quality care to all patients, especially those with respiratory disease. © 2013 Elsevier Ltd.

In order to personalize the communication of the CT risk, we need to describe the risk in the context of the clinical benefit of CT, which will generally be much higher, provided a CT scan has a well-established clinical indication. However as pediatric radiologists we should be careful not to overstate the benefit of CT, being aware that medico–legal pressures and the realities of health care economics have led to overutilization of the technology. And even though we should not use previously accumulated radiation dose to a child as an argument against conducting a clinically indicated scan (the “sunk-cost” bias), we should consider patients’ radiation history in the diagnostic decision process. As a contribution to future public health, it makes more sense to look for non-radiating alternatives to CT in the much larger group of basically healthy children who are receiving occasional scans for widely prevalent conditions such as appendicitis and trauma than to attempt lowering CT use in the smaller group of patients with chronic conditions with a limited life expectancy. When communicating the CT risk with individual patients and their parents, we should acknowledge and address their concerns within the framework of informed decision-making. When appropriate, we may express the individual radiation risk, based on estimates of summated absorbed organ dose, as an order of magnitude rather than as an absolute number, and compare this with the much larger natural cancer incidence over a child’s lifetime, and with other risks in medicine and daily life. We should anticipate that many patients cannot make informed decisions on their own in this complex matter, and we should offer our guidance while maintaining respect for patient autonomy. Proper documentation of the informed decision process is important for future reference. In concert with our referring physicians, pediatric radiologists are well-equipped to tackle the complexities associated with the communication of CT risk, a task that often falls upon us, and by becoming more involved in the diagnostic decision process we can add value to the health care system. © 2014, Springer-Verlag Berlin Heidelberg.

Durand M.L.,Massachusetts Eye and Ear Infirmary | Durand M.L.,Massachusetts General Hospital | Durand M.L.,Harvard University
Clinical Microbiology and Infection | Year: 2013

Endophthalmitis means bacterial or fungal infection inside the eye involving the vitreous and/or aqueous humors. Most cases are exogenous and occur after eye surgery, after penetrating ocular trauma, or as an extension of corneal infection. An increasing number of cases are occurring after intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications. Endophthalmitis may also be endogenous, arising from bacteraemic or fungaemic seeding of the eye. The infected eye never serves as a source of bacteraemia or fungaemia, however. The most common pathogens in endophthalmitis vary by category. Coagulase-negative staphylococci are the most common causes of post-cataract endophthalmitis, and these bacteria and viridans streptococci cause most cases of post-intravitreal anti-VEGF injection endophthalmitis, Bacillus cereus is a major cause of post-traumatic endophthalmitis, and Staphylococcus aureus and streptococci are important causes of endogenous endophthalmitis associated with endocarditis. In Taiwan and other East Asian nations, Klebsiella pneumoniae causes most cases of endogenous endophthalmitis, in association with liver abscess. Endogenous fungal endophthalmitis in hospitalized patients is usually caused by Candida species, particularly Candida albicans. Acute endophthalmitis is a medical emergency. The most important component of treatment is the intravitreal injection of antibiotics, along with vitrectomy in severe cases. Systemic antibiotics should be used in cases of endogenous endophthalmitis and exogenous fungal endophthalmitis, but their role in exogenous bacterial endophthalmitis is uncertain. Repeated intravitreal injections of antibiotics may be necessary if there is no response to the initial therapy. Many eyes that receive prompt and appropriate treatment will recover useful vision. © 2013 The Author Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

Ballen K.K.,Massachusetts General Hospital | Barker J.N.,Sloan Kettering Cancer Center
Current Opinion in Hematology | Year: 2013

Purpose of Review: We discuss outcomes after umbilical cord blood (UCB) transplantation (UCBT) for patients with acute myeloid leukemia (AML) and compare these outcomes to results after transplantation of other allogeneic graft sources. Recent Findings: Survival after UCBT has improved considerably over the past 10 years. Multiple retrospective studies using either myeloablative or reduced intensity conditioning have shown disease-free survival after UCBT that is comparable to that of matched related or unrelated donors. Improved unit selection, conditioning, graft manipulation, and supportive care are all emerging strategies to further improve outcomes, although disease status and center expertise remain key components of successful UCBT outcome. Summary: UCBT should be considered in all high-risk AML patients in whom allogeneic stem cell transplantation is indicated but who lack a matched related or unrelated donor. UCBT can thereby now be thought of as a 'mainstream' treatment of high-risk AML. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Bernstein A.S.,Center for Health and the Global Environment | Rice M.B.,Massachusetts General Hospital
Chest | Year: 2013

Climate change is a health threat no less consequential than cigarette smoking. Increased concentrations of greenhouse gases, and especially CO 2, in the earth's atmosphere have already warmed the planet substantially, causing more severe and prolonged heat waves, temperature variability, air pollution, forest fires, droughts, and floods, all of which put respiratory health at risk. These changes in climate and air quality substantially increase respiratory morbidity and mortality for patients with common chronic lung diseases such as asthma and COPD and other serious lung diseases. Physicians have a vital role in addressing climate change, just as they did with tobacco, by communicating how climate change is a serious, but remediable, hazard to their patients. © 2013 American College of Chest Physicians.

Cha T.D.,Massachusetts General Hospital | An H.S.,Rush University Medical Center
Nature Reviews Rheumatology | Year: 2013

The cervical spine can frequently become involved in patients with rheumatologic disorders, as a result of either the rheumatologic disease itself or age-associated degenerative processes that can also occur in the rest of the population. Awareness of the increased risk of cervical spine manifestations in patients with rheumatologic disorders enables early recognition and initiation of the appropriate treatment regimen. For example, patients with rheumatoid arthritis (RA) often have spinal instability which, if left untreated, can lead to neurological deficits. Biologic agents are effective in slowing the progression of the skeletal abnormality as well as for treating the RA, and this approach is often sufficient. However, early surgical intervention is recommended for patients with RA who develop neurologic deficits, as conservative approaches have limited effectiveness in this group. Spinal stability should be the primary surgical objective. For patients with ankylosing spondylitis, cervical spine surgery might be required either for fracture repair or to correct severe kyphosis. Understanding each condition's specific cervical spine manifestation and its natural history can help to clarify the appropriate indications for and timing of surgery to maximize patients' outcomes and limit complications. © 2013 Macmillan Publishers Limited. All rights reserved.

Saini N.,North Shore Medical Center | Mahindra A.,Massachusetts General Hospital
Expert Opinion on Investigational Drugs | Year: 2013

Introduction: The treatment options for patients with multiple myeloma (MM) remain limited. Immunomodulatory agents (IMiDs), such as thalidomide and lenalidomide, have changed the landscape in the treatment of patients with MM while newer IMiDs such as pomalidomide are showing promise in early clinical trials. Areas covered: This review focuses on the biologic rationales of IMiDs and the clinical results supporting their use in MM. It includes data on the new IMiD, pomalidomide and also explores the possible utility of combining IMiDs with other agents. A PubMed search and abstracts from oncology scientific meetings (ASCO and ASH) of articles related to IMiDs and MM was conducted. Expert opinion: IMiDs have shown clinical activity as single agents and in combination. Thalidomide was the first in class drug. Lenalidomide has a better toxicity profile than thalidomide. Pomalidomide may overcome resistance to lenalidomide indicating differences in their mechanisms of action and resistance. Molecular biomarkers may allow us to identify patients who will respond to IMiDs. © 2012 Informa UK, Ltd.

Aronin N.,University of Massachusetts Medical School | Difiglia M.,Massachusetts General Hospital
Movement Disorders | Year: 2014

The idea to lower mutant huntingtin is especially appealing in Huntington's disease (HD). It is autosomal dominant, so that expression of the mutant allele causes the disease. Advances in RNA and gene regulation provide foundations for the huntingtin gene (both normal and mutant alleles) and possibly the mutant allele only. There is much preclinical animal work to support the concept of gene and RNA silencing, but, to date, no clinical studies have been attempted in HD. Preventing expression of mutant huntingtin protein is at the cusp for a human trial. Antisense oligonucleotides delivered to patients with amyotrophic lateral sclerosis have been well tolerated; small RNAs administered to rodent and nonhuman primate brain knocked down huntingtin messenger RNA (mRNA); short-hairpin complementary DNA of microRNAs can be expressed in adeno-associated virus to provide long-term silencing of huntingtin mRNA and protein. We expect that these approaches will be ready for clinical studies in the near future, once safety has been validated. Our understanding of gene editing-changing the huntingtin gene itself-is rapidly progressing. Harnessing our knowledge of transcription and translation should push scientific creativity to new and exciting advances that overcome the lethality of the mutant gene in HD. © 2014 International Parkinson and Movement Disorder Society.

Kradin R.L.,Massachusetts General Hospital
Current Psychiatry Reports | Year: 2011

Placebo effects are a potentially inherent element in all treatment responses, and as such, they play a critical role in determining what is "therapeutic." However, the placebo response is also an area of substantial controversy. In the present review, the scientific issues that influence placebo effects are elucidated. The evolution of the concept of placebo and how this has affected its historical importance in therapeutics is considered. The importance of placebo responses in psychiatry and psychotherapy is specifically examined, and recent progress in determining the cognitive and neurobiological bases of placebo effects is reviewed. Finally, it is argued that the placebo response is a cardinal mind-body pathway that promotes salutogenesis and that evidence suggests its relationship to central nervous system activities that are responsible for the concomitant development of positive affects and somatic procedural memories that govern states of mind/body well-being during maternal-infant attachment. © 2010 Springer Science+Business Media, LLC.

Huber R.J.,Massachusetts General Hospital
Cellular and Molecular Life Sciences | Year: 2014

Cyclin-dependent kinases (Cdk) are a family of serine/threonine protein kinases that regulate eukaryotic cell cycle progression. Their ability to modulate the cell cycle has made them an attractive target for anti-cancer therapies. Cdk protein function has been studied in a variety of Eukaryotes ranging from yeast to humans. In the social amoebozoan Dictyostelium discoideum, several homologues of mammalian Cdks have been identified and characterized. The life cycle of this model organism is comprised of a feeding stage where single cells grow and divide mitotically as they feed on their bacterial food source and a multicellular developmental stage that is induced by starvation. Thus it is a valuable system for studying a variety of cellular and developmental processes. In this review I summarize the current knowledge of the Cdk protein family in Dictyostelium by highlighting the research efforts focused on the characterization of Cdk1, Cdk5, and Cdk8 in this model Eukaryote. Accumulated evidence indicates that each protein performs distinct functions during the Dictyostelium life cycle with Cdk1 being required for growth and Cdk5 and Cdk8 being required for processes that occur during development. Recent studies have shown that Dictyostelium Cdk5 shares attributes with mammalian Cdk5 and that the mammalian Cdk inhibitor roscovitine can be used to inhibit Cdk5 activity in Dictyostelium. Together, these results show that Dictyostelium can be used as a model system for studying Cdk protein function. © 2013 Springer Basel.

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.

Taylor C.E.,National Institute of Allergy and Infectious Diseases | Camargo Jr C.A.,Massachusetts General Hospital
Nutrition Reviews | Year: 2011

Several studies have documented the impact of vitamin D and other micronutrients on host responses to upper and lower respiratory tract infections, such as influenza and tuberculosis. These studies include observational as well as micronutrient intervention studies. Other studies have been conducted to understand the mechanisms by which micronutrients alter immune responses. However, critical information gaps and challenges remain. An immediate need exists for randomized controlled trials of vitamin D supplementation in high-risk populations, such as infants, children, and patients with immunocompromised health. Other important areas of research include vitamin D genetics, the impact of other micronutrient deficiencies on innate and adaptive immunity, the 25(OH)D threshold for insufficiency, the need for valuable reliable markers, standardization of assays to detect 25(OH)D, novel functional markers beyond serum 25(OH)D, and further development of in vitro and animal models that could be useful for preclinical studies. Lastly, a new systems biology approach is needed to address the complexity of micronutrient effects and regulation. © 2011 International Life Sciences Institute.

Barry M.J.,Massachusetts General Hospital
Journal of Ambulatory Care Management | Year: 2012

At the individual level, practicing high-quality medical care means doing the right thing for a patient as safely as possible. Some medical decisions have one optimal course of action, but most have multiple reasonable options with outcomes that will be valued differently by different people. For these preference-sensitive decisions, involving patients in a shared decision-making process is critical. Patient decision aids are tools that help make shared decision making practical. Policy changes at the federal and state level can help make shared decision making with the active participation of informed patients the rule rather than the exception. Copyright © 2012 Wolters Kluwer Health Lippincott Williams & Wilkins.

Shreffler W.G.,Harvard University | Shreffler W.G.,Massachusetts General Hospital
Journal of Allergy and Clinical Immunology | Year: 2011

The development of protein microarray-based immunoassays and the availability of recombinant allergens have, to a significant extent, emerged together over the past decade. Their long-anticipated wider application to allergy diagnosis has recently begun to accelerate. This review discusses some of the strengths and weaknesses of molecularly defined allergy testing and the microarray platform. Several recent applications of microarray assays to allergy testing are also summarized. Promising findings, particularly in the context of food and latex allergy, point to the potential for greater resolution between clinical reactivity and asymptomatic sensitization with this platform. © 2010 American Academy of Allergy, Asthma & Immunology.

McCarthy J.,Massachusetts General Hospital | Mc Millan S.,Our Lady of Lourdes Hospital
Orthopedic Clinics of North America | Year: 2013

Hip arthroscopy is a rapidly progressing field that has advanced in function and survivorship over the past decade. As increasing literature is published on outcomes of hip arthroscopy, a retrospective review has allowed for the identification of factors that affect survivorship. Within this review, the authors present the factors identified to date that affect survivorship after hip arthroscopy while raising questions about the future direction of the field. © 2013 Elsevier Inc.

BACKGROUND: TASK-1 and TASK-3 tandem pore potassium channel subunits provide a constitutive acidic pH- and hypoxia-inhibited potassium conductance. TASK channels are expressed in a number of tissues involved in regulation of breathing, and the TASK-1/TASK-3 heterodimer provides the predominant hypoxia-sensitive potassium conductance in carotid body type 1 glomus chemosensing cells. The carotid bodies have an important role in regulation of breathing. Doxapram is a potent TASK-1 and TASK-3 potassium channel antagonist and a carotid body and breathing stimulant. PK-THPP and A1899 are potent and selective TASK-1 and TASK-3 antagonists. I hypothesized PK-THPP and A1899 are, like doxapram, breathing stimulants. METHODS: I studied rat TASK-3 potassium channel function by Ussing chamber using Fischer rat thyroid monolayers. To quantify breathing effects, I studied male Sprague-Dawley rats spontaneously breathing 1.5% isoflurane in room air by noninvasive plethysmography and by arterial blood gas analysis. RESULTS: PK-THPP, A1899, and doxapram inhibit rat TASK-3 potassium channel function with IC50s of 42 nM (33-52), 1.6 μm (0.8-3.3), and 22 μm (18-28) (n = 4-6; 95% confidence limits). IV PK-THPP, A1899, and doxapram stimulated breathing by plethysmography with a peak change in minute ventilation relative to baseline of 84% ± 19% and 226% ± 56% (for PK-THPP at 0.5 and 5 mg/kg; mean ± SEM; n = 3-4; P < 0.05 and P < 0.001, respectively, relative to vehicle); 46% ± 2% and 236% ± 48% (for A1899 at 5 and 25 mg/kg; n = 3-4; P > 0.05 and P < 0.001, respectively); 103% ± 20% (for doxapram at 25 mg/kg; n = 4), and 33% ± 9% (for dimethylsulfoxide vehicle at 1 mL/kg; n = 4). PK-THPP and A1899, unlike doxapram, induced a profound and lasting respiratory alkalosis by arterial blood gas analysis. Thirty minutes after IV drug administration, I observed an arterial pH and carbon dioxide partial pressure of 7.62 ± 0.02 and 23 ± 0.8 mm Hg (for PK-THPP after 5 mg/kg; n = 4; P < 0.001 for both relative to vehicle), 7.49 ± 0.02 and 31 ± 2 mm Hg (for A1899 at 25 mg/kg; n = 6; P < 0.05 and 0.001, respectively), 7.43 ± 0.03 and 39 ± 4 mm Hg (for doxapram after 25 mg/kg; n = 4; P > 0.05 for both), and 7.38 ± 0.03 and 48 ± 4 mm Hg (for dimethylsulfoxide vehicle after 1 mL/kg; n = 3). CONCLUSIONS: PK-THPP and A1899 are potent rat TASK-3 antagonists and effective breathing stimulants. PK-THPP and A1899 effects on breathing were of greater magnitude and/or duration relative to that of doxapram. PK-THPP and A1899 or related compounds may have therapeutic potential for treating breathing disorders. Copyright © 2013 International Anesthesia Research Society.

Smoller J.W.,Massachusetts General Hospital
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2013

Over the past century, the definition and classification of psychiatric disorders has evolved through a combination of historical trends, clinical observations, and empirical research. The current nosology, instantiated in the DSM-5 and ICD-10, rests on descriptive criteria agreed upon by a consensus of experts. While the development of explicit criteria has enhanced the reliability of diagnosis, the validity of the current diagnostic categories has been the subject of debate and controversy. Genetic studies have long been regarded as a key resource for validating the boundaries among diagnostic categories. Genetic epidemiologic studies have documented the familiality and heritability of clinically defined psychiatric disorders and molecular genetic studies have begun to identify specific susceptibility variants. At the same time, there is growing evidence from family, twin and genomic studies that genetic influences on psychiatric disorders transcend clinical boundaries. Here I review this evidence for cross-disorder genetic effects and discuss the implications of these findings for psychiatric nosology. Psychiatric genetic research can inform a bottom-up reappraisal of psychopathology that may help the field move beyond a purely descriptive classification and toward an etiology-based nosology. © 2013 Wiley Periodicals, Inc.

Janne P.A.,Belfer Institute for Applied Cancer Science | Shaw A.T.,Massachusetts General Hospital | Pereira J.R.,Instituto Brasileiro Of Cancerologia Toracica | Jeannin G.,Service de pneumologie | And 8 more authors.
The Lancet Oncology | Year: 2013

Background: No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC. Methods: Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m2 on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825. Findings: Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group). Interpretation: Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC. Funding: AstraZeneca. © 2013 Elsevier Ltd.

Barnett M.L.,Harvard University | Hsu J.,Brigham and Womens Hospital | Hsu J.,Massachusetts General Hospital | Michael McWilliams J.,Harvard University
JAMA Internal Medicine | Year: 2015

IMPORTANCE Medicare penalizes hospitals with higher than expected readmission rates by up to 3%of annual inpatient payments. Expected rates are adjusted only for patients' age, sex, discharge diagnosis, and recent diagnoses. OBJECTIVE To assess the extent to which a comprehensive set of patient characteristics accounts for differences in hospital readmission rates. DESIGN, SETTING, AND PARTICIPANTS Using survey data from the nationally representative Health and Retirement Study (HRS) and linked Medicare claims for HRS participants enrolled in Medicare who were hospitalized from 2009 to 2012 (n = 8067 admissions), we assessed 29 patient characteristics from survey data and claims as potential predictors of 30-day readmission when added to standard Medicare adjustments of hospital readmission rates.We then compared the distribution of these characteristics between participants admitted to hospitals with higher vs lower hospital-wide readmission rates reported by Medicare. Finally, we estimated differences in the probability of readmission between these groups of participants before vs after adjusting for the additional patient characteristics. MAIN OUTCOMES AND MEASURES All-cause readmission within 30 days of discharge. RESULTS Of the additional 29 patient characteristics assessed, 22 significantly predicted readmission beyond standard adjustments, and 17 of these were distributed differently between hospitals in the highest vs lowest quintiles of publicly reported hospital-wide readmission rates (P .04 for all comparisons). Almost all of these differences (16 of 17) indicated that participants admitted to hospitals in the highest quintile of readmission rates were more likely to have characteristics that were associated with a higher probability of readmission. The difference in the probability of readmission between participants admitted to hospitals in the highest vs lowest quintile of hospital-wide readmission rates was reduced by 48%from 4.41 percentage points with standard adjustments used by Medicare to 2.29 percentage points after adjustment for all patient characteristics assessed (reduction in difference: 2.12; 95%CI, 3.33 to 0.67; P = .003). CONCLUSIONS AND RELEVANCE Patient characteristics not included in Medicare's current risk-adjustment methods explained much of the difference in readmission risk between patients admitted to hospitals with higher vs lower readmission rates. Hospitals with high readmission ratesmay be penalized to a large extent based on the patients they serve. Copyright © 2015 American Medical Association. All rights reserved.

Seddon J.M.,Tufts University | Reynolds R.,Tufts University | Yu Y.,Tufts University | Daly M.J.,Massachusetts General Hospital | Rosner B.,Harvard University
Ophthalmology | Year: 2011

Purpose: To expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status. Design: Prospective, longitudinal study. Participants: We included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up. Methods: Cox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables. Main Outcome Measures: Progression to advanced AMD, including geographic atrophy and neovascular disease. Results: In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered. Conclusions: Factors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. © 2011 American Academy of Ophthalmology.

Ballen K.K.,Massachusetts General Hospital | Verter F.,Parents Guide to Cord Blood Foundation | Kurtzberg J.,Duke University
Bone Marrow Transplantation | Year: 2015

Umbilical cord blood (UCB) is a graft source for patients with malignant or genetic diseases who can be cured by allogeneic hematopoietic cell transplantation (HCT), but who do not have an appropriately HLA-matched family or volunteer unrelated adult donor. Starting in the 1990s, unrelated UCB banks were established, accepting donations from term deliveries and storing UCB units for public use. An estimated 730 000 UCB units have been donated and stored to date and ∼35 000 UCB transplants have been performed worldwide. Over the past 20 years, private and family banks have grown rapidly, storing ∼4 million UCB units for a particular patient or family, usually charging an up-front and yearly storage fee; therefore, these banks are able to be financially sustainable without releasing UCB units. Private banks are not obligated to fulfill the same regulatory requirements of the public banks. The public banks have released ∼30 times more UCB units for therapy. Some countries have transitioned to an integrated banking model, a hybrid of public and family banking. Today, pregnant women, their families, obstetrical providers and pediatricians are faced with multiple choices about the disposition of their newborn's cord blood. In this commentary, we review the progress of UCB banking technology; we also analyze the current data on pediatric and adult unrelated UCB, including the recent expansion of interest in transplantation for hemoglobinopathies, and discuss emerging studies on the use of autologous UCB for neurologic diseases and regenerative medicine. We will review worldwide approaches to UCB banking, ethical considerations, criteria for public and family banking, integrated banking ideas and future strategies for UCB banking. © 2015 Macmillan Publishers Limited.

Bhan I.,Massachusetts General Hospital
Current Opinion in Nephrology and Hypertension | Year: 2014

Purpose of review The review focuses on the rationale and evidence behind management strategies for hyperphosphatemia in patients with chronic kidney disease (CKD). Recent findings Optimal management of phosphate in CKD remains an area of uncertainty, but multiple studies now point to a clinical benefit from the use of phosphate binders. Evidence of improved survival is particularly strong with sevelamer, though it remains unclear whether the absence of calcium or other properties of sevelamer are responsible for this relationship. Newer agents, such as iron-based binders or niacin compounds to inhibit phosphorus absorption, may have additional benefits which will be better defined with additional experience. A reduced pill count may be a particularly beneficial characteristic of newer agents, and has been associated with improved response to therapy. Increased use of frequent, nocturnal hemodialysis is an additional tool to help ameliorate phosphate control. Data on the reduction of fibroblast growth factor 23 through use of phosphate binders remain weak. Summary An improved understanding of phosphate regulation and the development of new therapeutic agents have reinvigorated a once stagnant field, but significant changes to practice cannot yet be justified. There is increasing support for using sevelamer in place of calcium-based binders, though economic practicability remains challenging. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Gardella T.J.,Massachusetts General Hospital | Vilardaga J.-P.,University of Pittsburgh
Pharmacological Reviews | Year: 2015

The type-1 parathyroid hormone receptor (PTHR1) is a family B G protein–coupled receptor (GPCR) that mediates the actions of two polypeptide ligands; parathyroid hormone (PTH), an endocrine hormone that regulates the levels of calcium and inorganic phosphate in the blood by acting on bone and kidney, and PTHrelated protein (PTHrP), a paracrine-factor that regulates cell differentiation and proliferation programs in developing bone and other tissues. The type-2 parathyroid hormone receptor (PTHR2) binds a peptide ligand, called tuberoinfundibular peptide-39 (TIP39), and while the biologic role of the PTHR2/TIP39 system is not as defined as that of the PTHR1, it likely plays a role in the central nervous systemaswell as in spermatogenesis.Mechanisms of action at these receptors have been explored through a variety of pharmacological and biochemical approaches, and the data obtained support a basic “two-site” mode of ligand binding now thought to be used by each of the family B peptide hormone GPCRs. Recent crystallographic studies on the family B GPCRs are providing new insights that help to further refine the specifics of the overall receptor architecture and modes of ligand docking. One intriguing pharmacological finding for the PTHR1 is that it can form surprisingly stable complexes with certain PTH/PTHrP ligand analogs and thereby mediate markedly prolonged cell signaling responses that persist even when the bulk of the complexes are found in internalized vesicles. The PTHR1 thus appears to be able to activate the Gas/cAMP pathway not only from the plasma membrane but also from the endosomal domain. The cumulative findings could have an impact on efforts to develop new drug therapies for the PTH receptors. © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Baselga J.,Massachusetts General Hospital
Annals of Oncology | Year: 2010

The HER family of receptors consists of four closely related type 1 transmembrane TK receptors: HER1 (EGFR), HER2, HER3 and HER4. Signalling via the HER family of receptors underpins the majority of the intricate array of cellular activities on which cell survival and functionality depend. Aberrant HER2 expression and/or functionality have been implicated in the evolution of breast cancer and this receptor has proved to be a potent target for anticancer therapies, including antibody-based therapies to prevent ligand binding, dimer formation or the recruitment of antibody-dependent cell-mediated cytotoxicity, and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners. Novel strategies against HER2 include HER tyrosine kinase inhibitors, HSP90 inhibitors and antibody-chemotherapy conjugates. This latter approach is exemplified by T-DM1, a potent antibody that has a good safety profile and that has shown remarkable activity in patients with advanced disease. In addition, pertuzumab, an mAb that directly inhibits the formation of HER2 dimers including the HER2:HER3 dimer, offers a unique mechanism of HER3 inhibition. All these approaches have shown substantial clinical activity in patients refractory to trastuzumab. It is anticipated that with the increased availability of novel anti-HER2 agents together with a better understanding of the mechanisms of resistance to anti-HER2 agents we should be able to further improve the outcome of patients with HER2 breast cancer. There will also be an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Darcy K.M.,Roswell Park Cancer Institute | Birrer M.J.,Massachusetts General Hospital
Gynecologic Oncology | Year: 2010

Objectives: To review the translational research (TR) performed in the Gynecologic Oncology Group (GOG) to evaluate ovarian cancer markers, profiles and novel therapies. Methods: Prospective trials with stand alone or embedded TR objectives involving patient and specimen accrual as well as retrospective studies using banked specimens and resources were and continue to be performed in the GOG. Appropriate statistical methods are employed to evaluate associations with clinical characteristics and outcomes including tumor response, adverse events, progression free survival and overall survival. Results: Highlights are presented for some of the collaborative and multidisciplinary TR conducted with the GOG to evaluate markers, pathway and novel therapeutics in epithelial ovarian, primary peritoneal and/or fallopian tube cancer. For example, in GOG 111, high immunohistochemical (IHC) expression of cyclin E was associated with a shorter median survival (29 versus 35 months) and an increased risk of death (hazard ratio [HR]=1.4, 95% confidence interval [CI]=1.0-2.1, p=0.05). In GOG 114/132, non-detectable immunoblot expression of maspin was associated with debulking status (p=0.034) and an increased risk of disease progression (HR=1.89, 95% CI=1.04-3.45, p=0.038) and death (HR=1.99, 95% CI=1.07-3.69, p=0.030) while high CD105-microvessel density (MVD), but not CD31-MVD in tumor was associated with increased risk of disease progression (HR=1.873, 95% CI=1.102-3.184, p=0.020) but not death. In GOG 172, low IHC expression of BRCA1 was associated with advanced stage (p<0.001), serous histology (p<0.001) and a reduced risk of disease progression (HR=0.64, 95% CI=0.42-0.96) and death (HR=0.51, 95% CI=0.32-0.83) while the CA/AA versus CC genotypes in C8092A in ERCC1 were associated with an increased risk of disease progression (HR=1.44, 95% CI=1.06-1.94, p=0.018) and death (HR=1.50, 95% CI=1.07-2.09, p=0.018). Conclusions: The GOG has an extensive TR program that provides clues regarding the molecular and biochemical mechanisms of disease, treatments and outcomes in women with or at risk for a gynecologic malignancy. © 2010 Elsevier Inc. All rights reserved.

Misdraji J.,Massachusetts General Hospital
Archives of Pathology and Laboratory Medicine | Year: 2010

Low grade appendiceal mucinous neoplasms can spread to the peritoneum as pseudomyxoma peritonei even though they are not obviously invasive in the appendix. During the past several decades, several problematic issues surrounding this enigmatic tumor have been debated in the literature, including appropriate nomenclature for the appendiceal tumors and their peritoneal metastases. In this article, the most contentious issues in the area of appendiceal mucinous tumors are examined. First, the classification systems that have been proposed for these tumors are compared in the context of whether the appendiceal mucinous tumors are ruptured adenomas or invasive carcinomas. The controversy about the nature of pseudomyxoma peritonei and its classification systems is discussed in the following section. A brief discussion follows that examines the issue of localized pseudomyxoma peritonei and its clinical significance. Next reviewed is the largely resolved controversy about whether ovarian mucinous tumors in this setting are separate primaries or are metastases from the appendiceal tumor. Finally, the controversy about the most effective treatment of patients with pseudomyxoma peritonei is discussed.

Bouley R.,Massachusetts General Hospital
Kidney International | Year: 2012

The protease corin generates atrial natriuretic peptide and affects blood pressure and salt-water homeostasis. Under dietary salt challenge, corin knockout mice show blood pressure exacerbation and significant weight gain due to water and salt retention. This phenotype involves the epithelial sodium channel but is independent of the renin-angiotensin-aldosterone system. This suggests that corin has an important role in a new adaptive mechanism of the response to variations of salt in the diet.

Kumar A.T.N.,Massachusetts General Hospital
Optics Letters | Year: 2012

We show that a multiexponential model for time-resolved fluorescence allows the use of an absorption-perturbation Monte Carlo (MC) approach based on stored photon path histories. This enables the rapid fitting of fluorescence yield, lifetimes, and background tissue absorptions in complex heterogeneous media within a few seconds, without the need for temporal convolutions or MC recalculation of photon path lengths. We validate this method using simulations with both a slab and a heterogeneous model of the mouse head. © 2012 Optical Society of America.

Blinderman C.D.,Massachusetts General Hospital
Journal of Pain and Symptom Management | Year: 2010

The safety of patients in U.S. hospitals is a serious problem, with adverse events because of medical error affecting a significant proportion of hospitalized patients. Patients at the end of life are particularly vulnerable and are at risk of potential adverse events. This article presents a case in which opioids were rapidly titrated to neurotoxic doses in a patient who was terminally extubated. The patient was profoundly sedated and was noted to have Cheyne-Stokes breathing. The possibility of opioid-related iatrogenic harm is raised, and a discussion of what counts as medical error in these circumstances is explored. Palliative care specialists have a unique responsibility to provide guidance and establish a standard of care that clinicians should adhere to. Prevention of harm in dying patients should be a priority in the hospital setting. © 2010 U.S. Cancer Pain Relief Committee.

Meltzer E.O.,Allergy and Asthma Medical Group and Research Center | Hamilos D.L.,Massachusetts General Hospital
Mayo Clinic Proceedings | Year: 2011

Rhinosinusitis (RS) affects approximately 1 in 7 adults in the United States, and its effect on quality of life, productivity, and finances is substantial. During the past 10 years, several expert panels from authoritative bodies have published evidence-based guidelines for the diagnosis and management of RS and its subtypes, including acute viral RS, acute bacterial RS, chronic RS (CRS) without nasal polyposis, CRS with nasal polyposis, and allergic fungal RS. This review examines and compares the recommendations of the Rhinosinusitis Initiative, the Joint Task Force on Practice Parameters, the Clinical Practice Guideline: Adult Sinusitis, the European Position Paper on Rhinosinusitis and Nasal Polyps 2007, and the British Society for Allergy and Clinical Immunology. Points of consensus and divergent opinions expressed in these guidelines regarding classification, diagnosis, and management of adults with acute RS (ARS) and CRS and their various subtypes are highlighted for the practicing clinician. Key points of agreement regarding therapy in the guidelines for ARS include the efficacy of symptomatic treatment, such as intranasal corticosteroids, and the importance of reducing the unnecessary use of antibiotics in ARS; however, guidelines do not agree precisely regarding when antibiotics should be considered as a reasonable treatment strategy. Although the guidelines diverge markedly on the management of CRS, the diagnostic utility of nasal airway examination is acknowledged by all. Important and relevant data from MEDLINE-indexed articles published since the most recent guidelines were issued are also considered, and needs for future research are discussed. © 2011 Mayo Foundation for Medical Education and Research.

Manion S.C.,Massachusetts General Hospital | Brennan T.J.,University of Iowa
Anesthesiology | Year: 2011

Thoracic epidural analgesia, using local anesthetic and opioid combinations, remains a key tool for acute pain management in patients undergoing thoracic and upper abdominal surgery. TEA is beneficial by providing superior perioperative analgesia compared with parenteral opioids, decreasing pulmonary complications and duration of mechanical ventilation, decreasing postoperative catabolism, and decreasing the duration of postoperative ileus after abdominal surgery. In addition, TEA likely reduces morbidity and mortality in patients incurring multiple rib fractures. Complications associated with TEA appear to be rare. Thus, it continues to be imperative that anesthesiologists use TEA in selected patients for acute pain management. Copyright © 2011, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.

Forman S.A.,Harvard University | Forman S.A.,Massachusetts General Hospital
Anesthesiology | Year: 2011

This review focuses on the unique clinical and molecular pharmacologic features of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single-bolus administration. It also produces a unique toxicity among anesthetic drugs: inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific γ-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis. © 2011 American Society of Anesthesiologists, Inc.

Leffler D.A.,Beth Israel Deaconess Medical Center | Green P.H.R.,Columbia University | Fasano A.,Massachusetts General Hospital
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Coeliac disease is a common disorder that can arise at any age and typically presents with a broad spectrum of symptoms. The disease is thought to be underdiagnosed, in part owing to the fact that coeliac disease is often characterized by associated conditions and extraintestinal manifestations that can misdirect and impede diagnosis. Some of these manifestations are direct consequences of autoimmunity, such as dermatitis herpetiformis or gluten ataxia, whereas others are indirectly related to inflammation and/or malabsorption including anaemia, osteoporosis, short stature and delayed puberty. Any organ from the central nervous system to joints, liver or teeth can be affected. In some cases, extraintestinal symptoms are the only clinical manifestations of coeliac disease or occur in conjunction with diarrhoea and malabsorptive symptoms. An increased awareness among medical practitioners of the variety of extraintestinal manifestations of coeliac disease is essential to improve diagnosis and treatment. © 2015 Macmillan Publishers Limited. All rights reserved.

Ballen K.,Massachusetts General Hospital
Stem Cell Reviews and Reports | Year: 2010

Twenty years has passed since the first report of a successful cord blood transplant was reported in 1989 in a child with Fanconi's anemia. During these 20 years, the cord blood field has had dramatic growth, with over 400,000 cord blood units donated and stored worldwide for unrelated use. Approximately, 14,000 unrelated cord blood transplants have been performed to date for patients with hematologic malignancies and bone marrow disorders, and who do not have matched family or unrelated donors. In contrast, about 900,000 cord blood units have been stored privately for personal use, with about 100 autologous transplants performed. Twenty years ago, due to the low cell dose, cord blood transplants were only performed in children. Today, with the use of better banking techniques, reduced intensity transplants, and double cord blood transplantation, the majority of cord blood transplants are being performed in adults. In this chapter, we review the scientific basis for cord blood transplantation, and outcome data in both pediatric and adult transplantation. We will then focus on the recent concerns regarding private and public cord blood banking. Finally, we discuss the future of cord blood transplantation, and the exciting work beginning outside of oncology. © Springer Science+Business Media, LLC 2009.

Padmanabhan S.,University of Glasgow | Newton-Cheh C.,Massachusetts General Hospital | Dominiczak A.F.,University of Glasgow
Trends in Genetics | Year: 2012

Blood pressure (BP) is a complex trait regulated by an intricate network of physiological pathways involving extracellular fluid volume homeostasis, cardiac contractility and vascular tone through renal, neural or endocrine systems. Untreated high BP, or hypertension (HTN), is associated with increased mortality, and thus a better understanding of the pathophysiological and genetic underpinnings of BP regulation will have a major impact on public health. However, identifying genes that contribute to BP and HTN has proved challenging. In this review we describe our current understanding of the genetic architecture of BP and HTN, which has accelerated over the past five years primarily owing to genome-wide association studies (GWAS) and the continuing progress in uncovering rare gene mutations, epigenetic markers and regulatory pathways involved in the physiology of BP. We also look ahead to future studies characterizing novel pathways that affect BP and HTN and discuss strategies for translating current findings to the clinic. © 2012 Elsevier Ltd.

Higgins M.J.,Massachusetts General Hospital | Stearns V.,Sidney Kimmel Comprehensive Cancer Center
Annual Review of Medicine | Year: 2011

The selective estrogen receptor modulator tamoxifen has been used for more than three decades for the treatment, and more recently prevention, of breast cancer in women of all ages. The conversion of tamoxifen to active metabolites involves several cytochrome P450 (CYP) enzymes. CYP2D6 is the key enzyme responsible for the conversion of N-desmethyl tamoxifen to endoxifen. Single nucleotide polymorphisms in the CYP2D6 gene are not uncommon, and some alleles code for enzymes with reduced, null, or increased activity. Multiple studies suggest that women who carry one or two variant CYP2D6 alleles that encode enzymes with null or reduced activity may have an inferior breast cancer outcome when treated with tamoxifen in the adjuvant setting compared to women carrying two alleles encoding an enzyme with normal activity. Unfortunately, the data are not uniformly concordant, and definitive evidence that would change routine clinical practice is not yet available. CYP2D6 activity can also be reduced by concomitant use of drugs that inhibit the enzyme, including antidepressants used for psychiatric conditions or to relieve hot flashes, and these should be avoided in tamoxifen users whenever possible. Emerging data suggest that host factors may also predict interpatient variability in response to aromatase inhibitors. © 2011 by Annual Reviews. All rights reserved.

Wright C.D.,Massachusetts General Hospital | Wright C.D.,U.S. National Cancer Institute
Journal of Thoracic Oncology | Year: 2010

Almost all series reporting on the results of resection in thymic tumors indicate that the performance of a complete resection is probably the most important prognostic factor. This issue is not a factor in Masaoka stage I and II tumors that are almost always easily completely resected and have an excellent prognosis. Masaoka stage III tumors that invade the pericardium, lungs, or great vessels have relatively higher incomplete resection rates, significantly higher recurrence rates, and thus a worse prognosis. There are several small reports on the efficacy of resection of the great veins when involved by a thymic malignancy with low morbidity and meaningful long-term survival. Superior vena cava reconstruction is commonly performed by a polytetrafluroethylene, venous, or pericardial graft. These cases can usually be identified preoperatively and, thus, considered for induction therapy. Because these types of cases are almost always of marginal respectability in terms of obtaining a true en bloc resection, there is an increasing enthusiasm for offering induction therapy in an effort to enhance resectability. Preliminary results suggest increased R0 resection rates and improved survival with induction therapy for locally advanced tumors. The optimal induction treatment is unknown. The ultimate extended surgery for advanced thymic tumors is an extrapleural pneumonectomy performed for extensive pleural disease (Masaoka stage IVA). These rarely performed operations are done for IVA disease found at initial presentation and for recurrent disease as a salvage procedure. Again these advanced patients are probably best managed by induction chemotherapy followed by resection. © 2010 by the International Association for the Study of Lung Cancer.

Ballen K.K.,Massachusetts General Hospital | Gluckman E.,University Paris Diderot | Broxmeyer H.E.,Indiana University
Blood | Year: 2013

Umbilical cord blood is an alternative hematopoietic stem cell source for patients with hematologic diseases who can be cured by allogeneic hematopoietic cell transplantation. Initially, umbilical cord blood transplantation was limited to children, given the low cell dose infused. Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders and metabolic storage diseases in the pediatric setting. The results for adult umbilical cord blood transplantation have improved, with greater emphasis on cord blood units of sufficient cell dose and human leukocyte antigen match and with the use of double umbilical cord blood units and improved supportive care techniques. Cord blood expansion trials have recently shown improvement in time to engraftment. Umbilical cord blood is being compared with other graft sources in both retrospective and prospective trials. The growth of the field over the last 25 years and the plans for future exploration are discussed. Copyright © 2011 by The American Society of Hematology; all rights reserved.

Woythaler M.A.,Massachusetts General Hospital | McCormick M.C.,Beth Israel Deaconess Medical Center | McCormick M.C.,Harvard University | Smith V.C.,Beth Israel Deaconess Medical Center
Pediatrics | Year: 2011

BACKGROUND: Late preterm infants (34-37 weeks' gestation) are often perceived at similar risks for morbidity and mortality as term infants. OBJECTIVE: To compare the neurodevelopmental outcomes of late preterm to term infants. METHODS: Our study sample of 6300 term and 1200 late preterm infants came from the Early Childhood Longitudinal Study-Birth Cohort. We used general estimating equations to get weighted odds of having developmental delay, mental index scores (MDI) or psychomotor index scores (PDI) < 70, at 24 months of age. RESULTS: Late preterm infants compared with term infants had lower MDI (85 vs 89) and PDI (88 vs 92), both P < .0001, respectively. A higher proportion of late preterm infants compared with term infants had an MDI <0 (21% vs 16%; P < .0001). An equal number had PDIs <70 (6.1% vs 6.5%). After controlling for statistically significant and clinically relevant descriptive characteristics, late preterm infants still had higher odds of mental (odds ratio: 1.52 [95% confidence interval: 1.26-1.82] P < .0001) or physical (odds ratio: 1.56 [95% confidence interval: 1.30-1.89] P < .0001) developmental delay. CONCLUSIONS: Late preterm infants have poorer neurodevelopmental outcomes than term infants and have increased odds to have a mental and/or physical developmental delay. Copyright © 2011 by the American Academy of Pediatrics.

Zinman L.,Sunnybrook Health science Center | Cudkowicz M.,Massachusetts General Hospital
The Lancet Neurology | Year: 2011

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that is currently untreatable. Many compounds have been tested in laboratory-based models and in patients with ALS, but so far only one drug, riluzole, has shown efficacy, yet it only slightly slows disease progression. Several new insights into the causes of motor neuron death have led to the identification of some important novel targets for intervention. At no time have studies involved such a wide range of innovations and such advanced technologies. Many promising studies are underway to test potential targets that will hopefully translate into meaningful therapeutics for patients with ALS. © 2011 Elsevier Ltd.

Barrett L.F.,Northeastern University | Barrett L.F.,Massachusetts General Hospital | Simmons W.K.,Laureate Institute for Brain Research | Simmons W.K.,University of Tulsa
Nature Reviews Neuroscience | Year: 2015

Intuition suggests that perception follows sensation and therefore bodily feelings originate in the body. However, recent evidence goes against this logic: interoceptive experience may largely reflect limbic predictions about the expected state of the body that are constrained by ascending visceral sensations. In this Opinion article, we introduce the Embodied Predictive Interoception Coding model, which integrates an anatomical model of corticocortical connections with Bayesian active inference principles, to propose that agranular visceromotor cortices contribute to interoception by issuing interoceptive predictions. We then discuss how disruptions in interoceptive predictions could function as a common vulnerability for mental and physical illness. © 2015 Macmillan Publishers Limited.

Tsai A.C.,Harvard University | Tsai A.C.,Massachusetts General Hospital | Hung K.J.,Beth Israel Deaconess Medical Center | Weiser S.D.,San Francisco General Hospital
PLoS Medicine | Year: 2012

Background: Understanding how food insecurity among women gives rise to differential patterning in HIV risks is critical for policy and programming in resource-limited settings. This is particularly the case in Brazil, which has undergone successive changes in the gender and socio-geographic composition of its complex epidemic over the past three decades. We used data from a national survey of Brazilian women to estimate the relationship between food insecurity and HIV risk. Methods and Findings: We used data on 12,684 sexually active women from a national survey conducted in Brazil in 2006-2007. Self-reported outcomes were (a) consistent condom use, defined as using a condom at each occasion of sexual intercourse in the previous 12 mo; (b) recent condom use, less stringently defined as using a condom with the most recent sexual partner; and (c) itchy vaginal discharge in the previous 30 d, possibly indicating presence of a sexually transmitted infection. The primary explanatory variable of interest was food insecurity, measured using the culturally adapted and validated Escala Brasiliera de Segurança Alimentar. In multivariable logistic regression models, severe food insecurity with hunger was associated with a reduced odds of consistent condom use in the past 12 mo (adjusted odds ratio [AOR] = 0.67; 95% CI, 0.48-0.92) and condom use at last sexual intercourse (AOR = 0.75; 95% CI, 0.57-0.98). Self-reported itchy vaginal discharge was associated with all categories of food insecurity (with AORs ranging from 1.46 to 1.94). In absolute terms, the effect sizes were large in magnitude across all outcomes. Underweight and/or lack of control in sexual relations did not appear to mediate the observed associations. Conclusions: Severe food insecurity with hunger was associated with reduced odds of condom use and increased odds of itchy vaginal discharge, which is potentially indicative of sexually transmitted infection, among sexually active women in Brazil. Interventions targeting food insecurity may have beneficial implications for HIV prevention in resource-limited settings. © 2012 Tsai et al.

Hirshfeld-Becker D.R.,Massachusetts General Hospital
New directions for child and adolescent development | Year: 2010

Social anxiety disorder (SAD) is a common disorder that can lead to significant impairment. In this chapter, the author provides background on the disorder and reviews hypothesized familial and temperamental risk factors. In particular, it highlights the Massachusetts General Hospital (MGH) Longitudinal Study of Children at Risk for Anxiety, now in its fifteenth year, and describes how this study has identified some factors that contribute to risk for SAD.

Lucas M.R.,Massachusetts General Hospital
Journal of Neuroscience Nursing | Year: 2010

The purpose of this article was to explore the psychosocial implications of being diagnosed with a high-grade glioma, World Health Organization III/IV and IV/IV, to better inform healthcare providers and researchers of the patient experience. The information is the cumulative data collected from hundreds of patient interviews in a large metropolitan brain tumor clinic over a 7-year period. Three themes of loss emergedVloss of independence, loss of self, and loss of relationships. This information is presented on behalf of the patients for acknowledgement of their experience and for identification of the need for increased psychological and concrete services to better serve this population. Copyright © 2010 American Association of Neuroscience Nurses.

Dowdy D.W.,Johns Hopkins University | Basu S.,Stanford University | Basu S.,London School of Hygiene and Tropical Medicine | Andrews J.R.,Massachusetts General Hospital
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Rationale: Tuberculosis (TB) is characterized by a subclinical phase (symptoms absent or not considered abnormal); prediagnostic phase (symptoms noticed but diagnosis not pursued); and clinical phase (care actively sought). Diagnostic capacity during these phases is limited. Objectives: To estimate the population-level impact of TB casefinding strategies in the presence of subclinical and prediagnostic disease. Methods: We created a mathematical epidemic model of TB, calibrated to global incidence. We then introduced three prototypical diagnostic interventions: increased sensitivity of diagnosis in the clinical phase by 20% ("passive"); early diagnosis during the prediagnostic phase at a rate of 10% per year ("enhanced"); and population-based diagnosis of 5% of undiagnosed prevalent cases per year ("active"). Measurements and Main Results: If the subclinical phase was ignored, as in most models, the passive strategy was projected to reduce TB incidence by18%(90% uncertainty range [UR], 11-32%) by year 10, compared with 23% (90% UR, 14-35%) for the enhanced strategy and 18% (90% UR, 11-28%) for the active strategy. After incorporating a subclinical phase into the model, consistent with population-based prevalence surveys, the active strategy still reduced 10-year TB incidence by 16% (90% UR, 11-28%), but the passive and enhanced strategies' impact was attenuated to 11% (90% UR, 8-25%) and 6% (90% UR, 4-13%), respectively. The degree of attenuation depended strongly on the transmission rate during the subclinical phase. Conclusions: Subclinical disease may limit the impact of current diagnostic strategies for TB. Active detection of undiagnosed prevalent casesmay achieve greater population-level TB control than increasing passive case detection. Copyright © 2013 by the American Thoracic Society.

Vishwanath R.,Genzyme | Hemphill L.C.,Massachusetts General Hospital
Journal of Clinical Lipidology | Year: 2014

Familial hypercholesterolemia (FH), an autosomal-dominant inherited disorder, can occur in either the heterozygous (HeFH) or homozygous (HoFH) state, and is characterized by high levels of serum low-density lipoprotein cholesterol (LDL-C). Although potent statins and maximally tolerated lipid-lowering therapy (LLT) have greatly reduced the risk of premature coronary heart disease (CHD) and death, all patients with HoFH and many with severe HeFH remain far from treatment goals and are thus at risk of cardiovascular disease. LDL apheresis is the treatment of choice for these patients but remains underutilized. No formal studies or epidemiologic data have estimated the prevalence of HoFH. An HeFH prevalence of 1:500 and a simplified Hardy-Weinberg equilibrium model was used to determine the probability of finding HoFH as 1:1 million in the general population. A US population of approximately 314.8 million was used to determine the number of cases of HoFH and HeFH. The following key parameters were used to estimate the prevalence of severe HeFH: baseline pretreatment LDL-C level and distribution of patients with FH, posttreatment LDL-C level and distribution after maximally tolerated LLT, and baseline percentage of patients with HeFH who have CHD. We assumed an HeFH prevalence of 1:500 and used statistics for a Gaussian distribution after the posttreatment means and standard deviations of LDL-C levels in patients with HeFH receiving maximally tolerated LLT, as has been documented by data from clinical trials and cross-sectional studies. These estimates do not include the statin-intolerant population. The objective of this analysis was to determine the prevalence of the US population with severe HeFH with or without CHD who still will be eligible for LDL apheresis despite maximally tolerated LLT. We estimated that there are 315 US patients with HoFH and 650,000 with HeFH. The estimated prevalence of the severe HeFH population eligible for apheresis is approximately 1:20,000 (range, 1:11,700-1:62,500). This estimate suggests that, based on the efficacy of maximally tolerated LLT and CHD status, approximately 15,000 (approximately 2.4%) of the 625,000 patients with HeFH who are maximally treated will still be eligible for LDL apheresis. © 2014 National Lipid Association. All rights reserved.

Bracco P.,University of Turin | Oral E.,Massachusetts General Hospital
Clinical Orthopaedics and Related Research | Year: 2011

Background: Osteolysis due to wear of UHMWPE limits the longevity of joint arthroplasty. Oxidative degradation of UHMWPE gamma-sterilized in air increases its wear while decreasing mechanical strength. Vitamin E stabilization of UHMWPE was proposed to improve oxidation resistance while maintaining wear resistance and fatigue strength. Questions/purposes: We reviewed the preclinical research on the development and testing of vitamin E-stabilized UHMWPE with the following questions in mind: (1) What is the rationale behind protecting irradiated UHMWPE against oxidation by vitamin E? (2) What are the effects of vitamin E on the microstructure, tribologic, and mechanical properties of irradiated UHMWPE? (3) Is vitamin E expected to affect the periprosthetic tissue negatively? Methods: We performed searches in PubMed, Scopus, and Science Citation Index to review the development of vitamin E-stabilized UHMWPEs and their feasibility as clinical implants. Results: The rationale for using vitamin E in UHMWPE was twofold: improving oxidation resistance of irradiated UHMWPEs and fatigue strength of irradiated UHMWPEs with an alternative to postirradiation melting. Vitamin E-stabilized UHMWPE showed oxidation resistance superior to that of irradiated UHMWPEs with detectable residual free radicals. It showed equivalent wear and improved mechanical strength compared to irradiated and melted UHMWPE. The biocompatibility was confirmed by simulating elution, if any, of the antioxidant from implants. Conclusions: Vitamin E-stabilized UHMWPE offers a joint arthroplasty technology with good mechanical, wear, and oxidation properties. Clinical Relevance: Vitamin E-stabilized, irradiated UHMWPEs were recently introduced clinically. The rationale behind using vitamin E and in vitro tests comparing its performance to older materials are of great interest for improving longevity of joint arthroplasties. © 2010 The Association of Bone and Joint Surgeons®.

Stephan M.T.,Massachusetts Institute of Technology | Irvine D.J.,Massachusetts Institute of Technology | Irvine D.J.,Massachusetts General Hospital | Irvine D.J.,Howard Hughes Medical Institute
Nano Today | Year: 2011

Therapeutic treatments based on the injection of living cells are in clinical use and preclinical development for diseases ranging from cancer to cardiovascular disease to diabetes. To enhance the function of therapeutic cells, a variety of chemical and materials science strategies are being developed that engineer the surface of therapeutic cells with new molecules, artificial receptors, and multifunctional nanomaterials, synthetically endowing donor cells with new properties and functions. These approaches offer a powerful complement to traditional genetic engineering strategies for enhancing the function of living cells. © 2011 Elsevier Ltd. All rights reserved.

Walker L.M.,Scripps Research Institute | Burton D.R.,Scripps Research Institute | Burton D.R.,Massachusetts General Hospital
Current Opinion in Immunology | Year: 2010

Many antiviral vaccines elicit neutralizing antibodies as a correlate of protection. For HIV, given the huge variability of the virus, it is widely believed that the induction of a broadly neutralizing antibody (bNAb) response will be crucial in a successful vaccine against the virus. Unfortunately, despite many efforts, the development of an immunogen that elicits bNAbs remains elusive. However, recent structural studies of HIV-1 Env proteins, generation of novel bNAbs, maturation of technologies for the isolation of further antibodies, insights into the requirements for antibody-mediated protection, and novel vaccination approaches are providing grounds for renewed optimism. © 2010 Elsevier Ltd.

Isakoff S.J.,Massachusetts General Hospital
Cancer Journal | Year: 2010

Cytotoxic chemotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC) despite the promise of new targeted and biologic agents. Many studies have shown significant benefit of chemotherapy in the neoadjuvant, adjuvant, and metastatic treatment of TNBC. Neoadjuvant chemotherapy studies have consistently reported higher response rates in TNBC than non-TNBC, and pathologic complete response has been shown to predict improved long-term outcomes for TNBC. Although the specific adjuvant regimens that may be most effective for TNBC are still being determined, third-generation chemotherapy regimens using dose dense or metronomic polychemotherapy are among the most effective tools presently available. The role of specific chemotherapy agents in the treatment of TNBC remains incompletely defined and warrants careful review to ensure that the most effective therapy is delivered while minimizing unnecessary toxicity. Platinum agents have seen renewed interest in TNBC based on a growing body of preclinical and clinical data suggesting encouraging activity. Taxanes and anthracyclines are active in TNBC and remain important agents but have not shown specific benefit over non-TNBC. Capecitabine has limited reported data in TNBC, but some reports suggest differential activity in TNBC compared with hormone receptor-positive breast cancer. TNBC is itself a heterogeneous group in which subgroups such as BRCA1 mutation carriers may have particular sensitivity to platinum agents and relatively less sensitivity to taxanes. Therefore, the identification of additional molecular biomarkers to predict response to specific chemotherapy is required to further improve treatment strategies with the current menu of chemotherapy options and future combinations with targeted therapies. © 2010 Lippincott Williams & Wilkins, Inc.

Rosenquist J.N.,Massachusetts General Hospital
Current Opinion in Psychiatry | Year: 2011

Purpose of Review: This study presents an overview of the rapidly expanding field of social network analysis, with an emphasis placed on work relevant to behavioral health clinicians and researchers. I outline how social network analysis is a distinct empirical methodology within the social sciences that has the potential to deepen our understanding of how mental health and addiction are influenced by social environmental factors. Recent Findings: Whereas there have been a number of recent studies in the mental health literature that discuss social influences on mental illness and addiction, and a number of studies looking at how social networks influence health and behaviors, there are still relatively few studies that combine the two. Those that have suggest that mood symptoms as well as alcohol consumption are clustered within, and may travel along, social networks. Summary: Social networks appear to have an important influence on a variety of mental health conditions. This avenue of research has the potential to influence both clinical practice and public policy. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

See K.C.,National University Hospital Singapore | See K.C.,Harvard University | Christiani D.C.,Harvard University | Christiani D.C.,Massachusetts General Hospital
Chest | Year: 2013

Background: Elevated fractional excretion of exhaled nitric oxide (FENO) reflects airway inflammation, but few studies have established its normal values. This study aims to establish the normal values and thresholds for the clinical interpretation of FENO in the US general population. Methods: Thirteen thousand two hundred seventy-five subjects aged 6 to 80 years sampled for the National Health and Nutrition Examination Survey (NHANES) 2007-2010 underwent interviews, physical examination, and FENO analysis at 50 mL/s using an online chemiluminescence device according to American Thoracic Society/European Respiratory Society guidelines. After excluding subjects with self-reported asthma and subjects with wheeze in the prior 12 months, prediction equations for the natural logarithm (ln) of FENO were constructed using age, sex, ethnicity, height, BMI, active/passive smoke exposure, and hay fever episodes as covariates. Results: The fifth to 95th percentile values of FENO were 3.5 to 36.5 parts per billion (ppb) for children < 12 years of age and 3.5 to 39 ppb for subjects 12 to 80 years of age. Using multiple linear regression, prediction equations explained only 10.3% to 15.7% of the variation in the general population. In the general population, 39% to 45% had ln(FENO) levels > 2 SD of the predicted means. When applied to the general population inclusive of subjects who reported asthma but who did not have attacks within the past year, nearly identical results were obtained. Conclusions: Assuming 95% of the healthy US general population had no clinically significant airway inflammation as assessed by FENO, values exceeding the 95th percentiles indicated abnormality and a high risk of airway inflammation. A large variation of normal FENO values existed in the general population, which was poorly predicted by multiple linear regression models. © 2013 American College of Chest Physicians.

Ceranoglu T.A.,Massachusetts General Hospital
Academic Psychiatry | Year: 2010

Objective: Video games are used in medical practice during psycho-education in chronic disease management, physical therapy, rehabilitation following traumatic brain injury, and as an adjunct in pain management during medical procedures or cancer chemotherapy. In psychiatric practice, video games aid in social skills training of children with developmental delays and in cognitive behavioral therapy (CBT). This most popular children's toy may prove a useful tool in dynamic psychotherapy of youth. Methods: The author provides a framework for using video games in psychotherapy by considering the characteristics of video games and describes the ways their use has facilitated various stages of therapeutic process. Results: Just as other play techniques build a relationship and encourage sharing of emotional themes, sitting together in front ofa console and screen facilitates a relationship and allows a safe path for the patient's conflict to emerge. Conclusion: During video game play, the therapist may observe thought processes, impulsivity, temperament, decision-making, and sharing, among other aspects of a child's clinical presentation. Several features inherent to video games require a thoughtful approach as resistance and transference in therapy may be elaborated differently in comparison to more traditional toys. Familiarity with the video game content and its dynamics benefits child mental health clinicians in their efforts to help children and their families. Copyright © 2010 Academic Psychiatry.

Helman E.,Harvard-MIT Division of Health Sciences and Technology | Naxerova K.,Massachusetts General Hospital | Kohane I.S.,Harvard-MIT Division of Health Sciences and Technology
Oncogene | Year: 2012

Aberrant DNA hypermethylation of tumor suppressor genes is thought to be an early event in tumorigenesis. Many studies have reported the methylation status of individual genes with known involvement in cancer, but an unbiased assessment of the biological function of the collective of hypermethylated genes has not been conducted so far. Based on the observation that a variety of human cancers recapitulate developmental gene expression patterns (that is activate genes normally expressed in early development and suppress late developmental genes), we hypothesized that the silencing of differentiation-associated genes in cancer could be attributed in part to DNA hypermethylation. To this end, we investigated the developmental expression patterns of genes with hypermethylated CpG islands in primary human lung carcinomas and lung cancer cell lines. We found that DNA hypermethylation primarily affects genes that are expressed in late stages of murine lung development. Gene ontology characterization of these genes shows that they are almost exclusively involved in morphogenetic differentiation processes. Our results indicate that DNA hypermethylation in cancer functions as a selective silencing mechanism of genes that are required for the maintenance of a differentiated state. The process of cellular de-differentiation that is evident on both the microscopic and transcriptional level in cancer might at least partly be mediated by these epigenetic events. Our observations provide a mechanistic explanation for induction of differentiation upon treatment with DNA methyltransferase inhibitors. © 2012 Macmillan Publishers Limited All rights reserved.

Hamilos D.L.,Massachusetts General Hospital
American Journal of Rhinology and Allergy | Year: 2016

This problem-based learning case focused on the approach to evaluation and management of a 5-year old girl who was "always sick" with sinus infections. The discussion unfolds in a "real life" scenario, i.e., based on information available to the clinician initially and after the acquisition of laboratory data, and, ultimately, after sinus surgery. Emphasis is placed on the differential diagnosis of the patient's symptoms, discussion of the initial management strategy for chronic rhinosinusitis (CRS), evolution from acute rhinosinusitis to CRS, the prevalence of and differential diagnosis of nasal polyps in children, treatment considerations specific for CRS with nasal polyps, the significance of Pseudomonas aeruginosa sinus infection, the significance of an abnormal sweat chloride test in a young child with nasal polyposis, special considerations in children with CRS who have cystic fibrosis, treatment considerations after endoscopic sinus surgery, and, finally, prognostic factors that impact the outcomes of endoscopic sinus surgery. This problem-based learning case highlights many facets of managing refractory CRS in children. © Copyright 2016, OceanSide Publications, Inc., U.S.A.

Lucas M.R.,Massachusetts General Hospital
Journal of Psychosocial Oncology | Year: 2011

A private ListServ was created as a psychosocial intervention for the caregivers of the brain tumor patients in a large metropolitan cancer center. Caring for someone with a brain tumor can be quite challenging, and the day-to-day responsibilities restrict the amount of discretionary time allotted the caregiver. Consequently, they can become isolated and overwhelmed. It was conceived that, for convenience sake, a ListServ might be the solution to best serve this population. The hope being that sharing with their peers would lessen the isolation and validate their own experience, decreasing their fear and anxiety. This was all possible for less than a dollar a day. Copyright © Taylor & Francis Group, LLC.

Smith E.E.,University of Calgary | Schwamm L.H.,Massachusetts General Hospital
Stroke | Year: 2015

Endovascular acute ischemic stroke therapy is now proven by randomized controlled trials to produce large, clinically meaningful benefits. In response, stroke systems of care must change to increase timely and equitable access to this therapy. In this review, we provide a North American perspective on implications for stroke systems, focusing on the United States and Canada, accompanied by initial recommendations for changes. Most urgently, every community must create access to a hospital that can safely and quickly provide intravenous tissue-type plasminogen activator and immediately transfer appropriate patients onward to a more capable center as required. Safe and effective therapy in the community setting will be ensured by certification programs, performance measurement, and data entry into registries. © 2015 American Heart Association, Inc.

Gardiner S.,Addenbrookes Hospital | Hartzell T.L.,Massachusetts General Hospital
Journal of Plastic, Reconstructive and Aesthetic Surgery | Year: 2012

Background: Telemedicine is a rapidly expanding technology involving the exchange of medical information to assist diagnosis and treatment at a distance. Within the field of plastic surgery, where visual examination contributes heavily to patient management decision-making, telemedicine has great potential. However, privacy and medico-legal issues must be considered when using electronic communication to assist our clinical practice. Methods: A comprehensive literature review of manuscripts published on telemedicine was performed. Articles were selected for relevance to plastic and reconstructive surgery and reviewed for applications, benefits and complications of telemedicine. In addition, the manuscripts were reviewed for conforming to current legal guidelines for the electronic transfer of patient information. Results: Twenty-nine articles met the inclusion criteria (11 trauma and burns, 4 hand, 5 wound-care, 5 maxillofacial, 1 digital replantation, 2 free-flap monitoring, and 1 technical application). Twenty-eight (96%) manuscripts reported a benefit of telemedicine (commonly including increased access to expertise and costs saved through reduction of unnecessary transfers). However only five (17%) reported a statistical benefit compared to a standard treatment cohort (face-to-face interactions). Fifteen (51%) reported on adverse effects, which included misdiagnosis, time consumption, training, technical and cost issues. Only four manuscripts (14%) discussed conforming to legal guidelines within their institution. Conclusions: Telemedicine can improve access to the specialty of plastic surgery by facilitating the provision of expertise at remote sites. Its application can be used in many situations and between a variety of healthcare professionals. However, there is little critical analysis on the benefits and risks of telemedicine. In addition, its legal implications need to be carefully considered if it is to be safely integrated into our daily practice. © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Leffert L.R.,Massachusetts General Hospital
International Journal of Obstetric Anesthesia | Year: 2015

Recent advances in the diagnosis, pathogenesis, and understanding of preeclampsia-related morbidity provide opportunities to optimize clinical management of the mother and fetus. These discoveries are timely, as contemporary data suggest that the prevalence of preeclampsia, affecting 7.5% of pregnancies globally and 2-5% in the USA, has increased by up to 30% over the last decade. Managing pregnant patients with preeclampsia can be challenging for all members of the obstetric care team due to the disease's multi-organ system maternal and fetal effects. This review presents recent updates in the definition of preeclampsia, etiology, comorbidities and therapeutic interventions and discusses how they impact the care of these high-risk patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tambouret R.,Massachusetts General Hospital
Archives of Pathology and Laboratory Medicine | Year: 2013

Context.-Cervical cancer remains the most common malignancy in women living in low- and middle-income countries, despite the decline of the disease in countries where cervical cytology screening programs have been implemented. Objectives.-To review the current incidence of cervical cancer in low-resource countries, the availability and types of screening programs, and the treatment options. Data Sources.-Literature review through PubMed, Internet search, and personal communication. Conclusions.-Although data are incomplete, available figures confirm that the rate of cervical cancer deaths and the availability of cervical cancer screening programs are inversely proportional and vary, in general, by the wealth of the nation. Despite the success of cervical cytology screening, many major health care organizations have abandoned screening by cytology in favor of direct visualization methods with immediate treatment of lesions by cryotherapy provided by trained, nonmedical personnel.

Cote C.J.,Massachusetts General Hospital
Current Opinion in Anaesthesiology | Year: 2015

Purpose of review To summarize recent evidence-based data regarding outcomes associated with children who have obstructive sleep apnea (OSA). Recent findings Internet surveys conducted by pediatric otolaryngologists and pediatric anesthesiologists have reported a disturbing number of deaths within 24h of tonsillectomy attributed to postsurgical/anesthesia apnea. Several occurred in the post anesthesia care unit after routine monitors had been removed. In addition, a number of deaths also have been attributed to children who have duplicated cytochromes allowing the rapid conversion of codeine to morphine, thus producing a relative drug overdose. Finally, there is some human and animal evidence suggesting that repeated episodes of hypoxemia result in altered opioid receptors causing relative opioid sensitivity. These factors have important clinical implications. Summary Perioperative deaths in children with OSA occur at a low frequency. Hypoxia-induced opioid sensitivity combined with an approximate 1-2% incidence of rapid conversion of codeine to morphine suggest the need for new approaches for providing preoperative assessment of risk, extended postoperative observation and the need for alternative opioids to codeine. Additionally, new less painful surgical approaches may help to reduce postoperative opioid requirements and therefore perhaps less risk for opiate-induced apnea in this vulnerable population. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Corey K.E.,Massachusetts General Hospital | Chalasani N.,Indiana University
Clinical Gastroenterology and Hepatology | Year: 2014

Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the United States and is associated with an increased risk of cardiovascular disease (CVD) and cardiovascular (CV) mortality, independent of traditional cardiovascular risk factors. CVD is one of the most common causes of death among individuals with NAFLD and management of NAFLD must extend beyond liver disease to include CVD risk modification. Clinicians should assess CVD risk with the Framingham Risk Score and screen for CVD risk factors including dyslipidemia, diabetes mellitus, hypertension, tobacco use, and the metabolic syndrome. CVD risk factors, particularly dyslipidemia, require aggressive medical management to reduce the high risk of CVD events and death in individuals with NAFLD. © 2014 AGA Institute.

Background Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specifi c variants underlying genetic eff ects shared between the fi ve disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention defi cit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. Methods We analysed genome-wide single-nucleotide polymorphism (SNP) data for the fi ve disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic eff ects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fi tting model of relations between genotype and phenotype. We examined cross-disorder eff ects of genome-wide signifi cant loci previously identifi ed for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such eff ects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the fi ve disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. Findings SNPs at four loci surpassed the cutoff for genome-wide signifi cance (p< 5×10-8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported eff ects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specifi city. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all fi ve disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. Interpretation Our fi ndings show that specifi c SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic eff ects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

Cherayil B.J.,Massachusetts General Hospital
Gut Microbes | Year: 2010

Recent publications from my laboratory have highlighted the important influence of altered iron homeostasis on the inflammatory response to intestinal bacteria. Here, I provide commentary on one of those papers, "Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice", which was published in the Journal of Clinical Investigation in November, 2009. It describes experiments that point to a previously unappreciated role for intracellular iron in the regulation of Toll-like receptor 4 signaling, and also demonstrates the potential therapeutic application of this information in a novel anti-inflammatory strategy based on manipulating iron balance. Our findings indicate that further investigation of the cross-talk between iron homeostasis and inflammation will yield new insights into the pathogenesis of chronic inflammatory diseases and may suggest new treatment approaches for these conditions. © 2010 Landes Bioscience.

Nierenberg A.A.,Massachusetts General Hospital
Primary Care Companion to the Journal of Clinical Psychiatry | Year: 2010

Recovery-the absence of all abnormal mood symptoms-is the goal of treatment for bipolar disorder. Unfortunately, a minority of people suffering from bipolar disorder achieve sustained recovery. Improving recovery rates for this population will require clinicians in the primary care setting to be familiar with appropriate treatments for acute bipolar mania and depression and for the maintenance phase. Efficacy and tolerability of pharmacotherapeutic and psychotherapeutic options for all phases of treatment and each type of mood episode are discussed. Primary care physicians are encouraged to avoid prescribing antidepressant monotherapy for any patient with depression and a history of mania or hypomania. © 2010 Physicians Postgraduate Press, Inc.

Delahanty L.M.,Massachusetts General Hospital
Journal of Human Nutrition and Dietetics | Year: 2010

The demand for clinical trials targeting lifestyle intervention has increased as a result of the escalation in obesity, diabetes mellitus and cardiovascular disease. Little is published about the strategies that dietitians have used to successfully screen potential study volunteers, implement interventions and maximise adherence and retention in large multicentre National Institutes of Health funded nutrition and lifestyle intervention clinical trials. This paper discusses an expanded role for the contributions of dietitians as members of an interdisciplinary team based on research experiences in the Diabetes Control and Complications Trial, Diabetes Prevention Program and Look AHEAD (Action for Health in Diabetes). Many of the strategies and insights discussed are also relevant to effective clinical practice. Dietitians need to broaden their scope of practice so that they are integrated proactively into the screening and intervention phases of large clinical trials to maximise retention and adherence to assigned nutrition, lifestyle and behavioural interventions. The skills of dietitians are a unique fit for this work and it is important that investigators and project managers consider including them in both the screening and intervention phases of such clinical trials to maximise retention results. © 2010 The Author. Journal compilation © 2010 The British Dietetic Association Ltd.

Tilly J.L.,Massachusetts General Hospital | Tilly J.L.,Harvard University | Sinclair D.A.,Harvard University | Sinclair D.A.,University of New South Wales
Cell Metabolism | Year: 2013

The role of metabolism in ovarian aging is poorly described, despite the fact that ovaries fail earlier than most other organs. Growing interest in ovarian function is being driven by recent evidence that mammalian females routinely generate new oocytes during adult life through the activity of germline stem cells. In this perspective, we overview the female reproductive system as a powerful and clinically relevant model to understand links between aging and metabolism, and we discuss new concepts for how oocytes and their precursor cells might be altered metabolically to sustain or increase ovarian function and fertility in women. © 2013 Elsevier Inc.

Genevay S.,University of Geneva | Atlas S.J.,Massachusetts General Hospital
Best Practice and Research: Clinical Rheumatology | Year: 2010

Lumbar spinal stenosis (LSS) is most commonly due to degenerative changes in older individuals. LSS is being more commonly diagnosed and may relate to better access to advanced imaging and to an ageing population. This review focusses on radicular symptoms related to degenerative central and lateral stenosis and updates knowledge of LSS pathophysiology, diagnosis and management. Since patients with anatomic LSS can range from asymptomatic to severely disabled, the clinical diagnosis focusses on symptoms and examination findings associated with LSS. Imaging findings are helpful for patients with persistent, bothersome symptoms in whom invasive treatments are being considered. There is limited information from high-quality studies about the relative merits and demerits of commonly used treatments. Interpreting and comparing results of available research are limited by a lack of consensus about the definition of LSS. Nevertheless, evidence supports decompressive laminectomy for patients with persistent and bothersome symptoms. Recommendations favour a shared decision-making approach due to important trade-offs between alternative therapies and differences among patients in their preferences and values. © 2009 Elsevier Ltd. All rights reserved.

Hilgendorf I.,Albert Ludwigs University of Freiburg | Swirski F.K.,Massachusetts General Hospital | Robbins C.S.,University of Toronto
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015

Monocytes and their descendant macrophages are essential to the development and exacerbation of atherosclerosis, a lipid-driven inflammatory disease. Lipid-laden macrophages, known as foam cells, reside in early lesions and advanced atheromata. Our understanding of how monocytes accumulate in the growing lesion, differentiate, ingest lipids, and contribute to disease has advanced substantially over the last several years. These cells' remarkable phenotypic and functional complexity is a therapeutic opportunity: in the future, treatment and prevention of cardiovascular disease and its complications may involve specific targeting of atherogenic monocytes/macrophages and their products. © 2014 American Heart Association, Inc.

Hasegawa K.,Harvard University | Hiraide A.,Kinki University | Chang Y.,Massachusetts General Hospital | Brown D.F.M.,Harvard University
JAMA - Journal of the American Medical Association | Year: 2013

Importance: It is unclear whether advanced airway management such as endotracheal intubation or use of supraglottic airway devices in the prehospital setting improves outcomes following out-of-hospital cardiac arrest (OHCA) compared with conventional bag-valve-mask ventilation. Objective: To test the hypothesis that prehospital advanced airway management is associated with favorable outcome after adult OHCA. Design, Setting, and Participants: Prospective, nationwide, population-based study (All-Japan Utstein Registry) involving 649 654 consecutive adult patients in Japan who had an OHCA and in whom resuscitation was attempted by emergency responders with subsequent transport to medical institutions from January 2005 through December 2010. Main Outcome Measures: Favorable neurological outcome 1 month after an OHCA, defined as cerebral performance category 1 or 2. Results: Of the eligible 649 359 patients with OHCA, 367 837 (57%) underwent bag-valve-mask ventilation and 281 522 (43%) advanced airway management, including 41 972 (6%) with endotracheal intubation and 239 550 (37%) with use of supraglottic airways. In the full cohort, the advanced airway group incurred a lower rate of favorable neurological outcome compared with the bag-valve-mask group (1.1% vs 2.9%; odds ratio [OR], 0.38; 95% CI, 0.36-0.39). In multivariable logistic regression, advanced airway management had an OR for favorable neurological outcome of 0.38 (95% CI, 0.37-0.40) after adjusting for age, sex, etiology of arrest, first documented rhythm, witnessed status, type of bystander cardiopulmonary resuscitation, use of public access automated external defibrillator, epinephrine administration, and time intervals. Similarly, the odds of neurologically favorable survival were significantly lower both for endotracheal intubation (adjusted OR, 0.41; 95% CI, 0.37-0.45) and for supraglottic airways (adjusted OR, 0.38; 95% CI, 0.36-0.40). In a propensity score-matched cohort (357 228 patients), the adjusted odds of neurologically favorable survival were significantly lower both for endotracheal intubation (adjusted OR, 0.45; 95% CI, 0.37-0.55) and for use of supraglottic airways (adjusted OR, 0.36; 95% CI, 0.33-0.39). Both endotracheal intubation and use of supraglottic airways were similarly associated with decreased odds of neurologically favorable survival. Conclusion and Relevance: Among adult patients with OHCA, any type of advanced airway management was independently associated with decreased odds of neurologically favorable survival compared with conventional bag-valve-mask ventilation. ©2013 American Medical Association. All rights reserved.

McKinsey J.F.,Cornell University | Zeller T.,Universitats Herzzentrum Freiburg Bad Krozingen | Rocha-Singh K.J.,Prairie Heart Institute At St Johns Hospital | Jaff M.R.,Massachusetts General Hospital | Garcia L.A.,Tufts University
JACC: Cardiovascular Interventions | Year: 2014

Objectives The aim of this study was to assess the safety and effectiveness of directional atherectomy (DA) for endovascular treatment of peripheral arterial disease (PAD) in infrainguinal arteries in patients with claudication or critical limb ischemia. Background To date, no prospective, multicenter, independently-adjudicated study has evaluated the effectiveness and durability of DA in the treatment of PAD. Previous DA studies have not been prospectively powered to evaluate any differences in outcomes in patients with and without diabetes. Methods DEFINITIVE LE (Determination of EFfectiveness of the SilverHawk® PerIpheral Plaque ExcisioN System (SIlverHawk Device) for the Treatment of Infrainguinal VEssels / Lower Extremities) prospectively enrolled subjects at 47 multinational centers with an infrainguinal lesion length up to 20 cm. Primary endpoints were defined as primary patency at 12 months for claudicants and freedom from major unplanned amputation for critical limb ischemia (CLI) subjects. A pre-specified statistical hypothesis evaluated noninferiority of primary patency in diabetic versus nondiabetic claudicants. Independent angiographic and sonographic core laboratories assessed outcomes, and events were adjudicated by a clinical events committee. Results A total of 800 subjects were enrolled. The 12-month primary patency was 78% (95% confidence interval: 74.0% to 80.6%) in claudicants, with a 77% rate in the diabetic subgroup versus 78% in the nondiabetic subgroup (noninferior, p < 0.001). The rate of freedom from major unplanned amputation of the target limb at 12 months in CLI subjects was 95% (95% confidence interval: 90.7% to 97.4%). Periprocedural adverse events included embolization (3.8%), perforation (5.3%), and abrupt closure (2.0%). The bail-out stent rate was 3.2%. Conclusions The DEFINITIVE LE study demonstrated that DA is a safe and effective treatment modality at 12 months for a diverse patient population with either claudication or CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with those without diabetes. (Study of SilverHawk/TurboHawk in Lower Extremity Vessels [DEFINITIVE LE]; NCT00883246). © 2014 by the American College of Cardiology Foundation.

Kingston R.E.,Massachusetts General Hospital | Tamkun J.W.,University of California at Santa Cruz
Cold Spring Harbor Perspectives in Biology | Year: 2014

The trithorax group of genes (trxG) was identified in mutational screens that examined developmental phenotypes and suppression of Polycomb mutant phenotypes. The protein products of these genes are primarily involved in gene activation, although some can also have repressive effects. There is no central function for these proteins. Some move nucleosomes about on the genome in an ATP-dependent manner, some covalently modify histones such as methylating lysine 4 of histone H3, and some directly interact with the transcription machinery or are a part of that machinery. It is interesting to consider why these specific members of large families of functionally related proteins have strong developmental pheno-types. © 2014 Cold Spring Harbor Laboratory Press; All rights reserved.

Firth P.G.,Massachusetts General Hospital
Anesthesiology | Year: 2016

Although Ernest Shackleton's Endurance Antarctic expedition of 1914 to 1916 is a famous epic of survival, the medical achievements of the two expedition doctors have received little formal examination. Marooned on Elephant Island after the expedition ship sank, Drs. Macklin and McIlroy administered a chloroform anesthetic to crew member Perce Blackborow to amputate his frostbitten toes. As the saturated vapor pressure of chloroform at 0°C is 71.5 mmHg and the minimum alveolar concentration is 0.5% of sea-level atmospheric pressure (3.8 mmHg), it would have been feasible to induce anesthesia at a low temperature. However, given the potentially lethal hazards of a light chloroform anesthetic, an adequate and constant depth of anesthesia was essential. The pharmacokinetics of the volatile anesthetic, administered via the open-drop technique in the frigid environment, would have been unfamiliar to the occasional anesthetist. To facilitate vaporization of the chloroform, the team burned penguin skins and seal blubber under overturned lifeboats to increase the ambient temperature from -0.5° to 26.6°C. Chloroform degrades with heat to chlorine and phosgene, but buildup of these poisonous gases did not occur due to venting of the confined space by the stove chimney. The anesthetic went well, and the patient - and all the ship's crew - survived to return home.

Barton J.P.,Massachusetts Institute of Technology | Barton J.P.,Massachusetts General Hospital | Sontag E.D.,Rutgers University
Biophysical Journal | Year: 2013

Complex networks of biochemical reactions, such as intracellular protein signaling pathways and genetic networks, are often conceptualized in terms of modules-semiindependent collections of components that perform a welldefined function and which may be incorporated in multiple pathways. However, due to sequestration of molecular messengers during interactions and other effects, collectively referred to as retroactivity, real biochemical systems do not exhibit perfect modularity. Biochemical signaling pathways can be insulated from impedance and competition effects, which inhibit modularity, through enzymatic futile cycles that consume energy, typically in the form of ATP. We hypothesize that better insulation necessarily requires higher energy consumption. We test this hypothesis through a combined theoretical and computational analysis of a simplified physical model of covalent cycles, using two innovative measures of insulation, as well as a possible new way to characterize optimal insulation through the balancing of these two measures in a Pareto sense. Our results indicate that indeed better insulation requires more energy. While insulation may facilitate evolution by enabling a modular plug-and-play interconnection architecture, allowing for the creation of new behaviors by adding targets to existing pathways, our work suggests that this potential benefit must be balanced against the metabolic costs of insulation necessarily incurred in not affecting the behavior of existing processes. © 2013 by the Biophysical Society.

Durante M.,Helmholtz Center for Heavy Ion Research | Loeffler J.S.,Massachusetts General Hospital
Nature Reviews Clinical Oncology | Year: 2010

Radiotherapy is one of the most common and effective therapies for cancer. Generally, patients are treated with X-rays produced by electron accelerators. Many years ago, researchers proposed that high-energy charged particles could be used for this purpose, owing to their physical and radiobiological advantages compared with X-rays. Particle therapy is an emerging technique in radiotherapy. Protons and carbon ions have been used for treating many different solid cancers, and several new centers with large accelerators are under construction. Debate continues on the cost: benefit ratio of this technique, that is, on whether the high costs of accelerators and beam delivery in particle therapy are justified by a clear clinical advantage. This Review considers the present clinical results in the field, and identifies and discusses the research questions that have resulted with this technique. © 2009 Macmillan Publishers Limited. All rights reserved.

Dekker J.P.,Massachusetts General Hospital
Point of Care | Year: 2012

Point-of-care (POC) testing plays an essential role in the diagnosis of infectious disease in diverse settings, from the pediatrician's office to the obstetrics ward. The faster turnaround times afforded by POC tests have many potential clinical benefits, including the prompter initiation of directed antimicrobial therapy and the more efficient triage of patients. In addition, the menu of available POC tests for infectious diseases continues to expand, creating new opportunities for POC microbiology to improve operations in a variety of care settings. This review covers selected US Food and Drug Administration-approved POC tests used to diagnose common bacterial and viral infections in outpatient and acute care settings in the United States. © 2012 Lippincott Williams & Wilkins.

Ndung'U T.,University of KwaZulu - Natal | Ndung'U T.,Massachusetts General Hospital | Weiss R.A.,University College London
AIDS | Year: 2012

HIV type 1 (HIV-1) displays a greater degree of genetic and antigenic variability than any other virus studied. This diversity reflects a high mutation rate during viral replication with a large turnover of virus, and a high tolerance of variation while maintaining reproductive capacity. Generation of diversity is a common property of lentiviruses such as HIV. Differences in virulence and in transmissibility are seen between different HIV-1 strains which may have clinical implications. The great degree of HIV diversity presents challenges to maintaining sensitivity to antiretroviral therapy and to the development of preventive strategies such as microbicides and vaccines. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Kimberly W.T.,Massachusetts General Hospital
Neurotherapeutics | Year: 2012

The gold standard for assessing neurological function is the bedside clinical examination. However, in neurocritical patients, the signs and symptoms related to the severity of illness can often be ambiguous. It can be hard to distinguish between a severe but stable disease state and one that is dynamic and in a critical decline. Clinicians and family members alike may struggle with the uncertainty of functional outcome prediction. Intermediate biomarkers of brain injury can assist with ongoing clinical management of patients, and in some circumstances can guide prognosis. Used in the right setting, biomarkers in neurocritical care can also aid with decisions to intensify treatment or avoid prolonged and unnecessary therapy. The term biomarker is used in various ways, and here we use it to refer to 3 general types: 1) circulating blood macromolecules, 2) brain imaging, and 3) continuous invasive monitors. Despite its promise, biomarkers have several limitations and should be interpreted in the context of the overall clinical assessment. © 2011 The American Society for Experimental NeuroTherapeutics, Inc.

Forman S.A.,Massachusetts General Hospital
Current Opinion in Anaesthesiology | Year: 2012

PURPOSE OF REVIEW: Formal Monod-Wyman-Changeux allosteric mechanisms have proven valuable in framing research on the mechanism of etomidate action on its major molecular targets, γ-aminobutyric acid type A (GABAA) receptors. However, the mathematical formalism of these mechanisms makes them difficult to comprehend. RECENT FINDINGS: We illustrate how allosteric models represent shifting equilibria between various functional receptor states (closed versus open) and how co-agonism can be readily understood as simply addition of gating energy associated with occupation of distinct agonist sites. We use these models to illustrate how the functional effects of a point mutation, α1M236W, in GABAA receptors can be translated into an allosteric model phenotype. SUMMARY: Allosteric co-agonism provides a robust framework for design and interpretation of structure-function experiments aimed at understanding where and how etomidate affects its GABAA receptor target molecules. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Papakostas G.I.,Massachusetts General Hospital
The Journal of clinical psychiatry | Year: 2015

Cognitive functioning is a symptom of major depressive disorder (MDD) that deserves particular attention by clinicians and researchers. Despite the fact that cognitive dysfunction represents a symptom of MDD as well as a functional outcome measure, cognition has been insufficiently investigated in antidepressant trials. While, until recently, few placebo-controlled trials have measured cognition in MDD, those examples which did have consisted of older adults. Of agents tested thus far in placebo-controlled trials (citalopram, duloxetine, vortioxetine), only the latter has been studied in patients aged 18-65, and only the latter has been shown to be superior to placebo in improving measures of executive functioning and to do so across adult age groups. Both duloxetine and vortioxetine appear to result in greater improvements than placebo in immediate and delayed memory. Clinicians who wish to improve the psychosocial recovery of patients with MDD should be familiar with studies of new options for treatment. © Copyright 2015 Physicians Postgraduate Press, Inc.

Surman C.B.H.,Massachusetts General Hospital | Roth T.,Ford Motor Company
Journal of Clinical Psychiatry | Year: 2011

Background: Sleep disturbances may cause distress among individuals with attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the impact of stimulant pharmacotherapy for ADHD on sleep in adults. Method: These post hoc analyses included sleep data collected with the Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire, from 831 adults with DSM-IVTR-defined ADHD in 2 large, randomized, double-blind, placebo-controlled, forced-dose titration studies of lisdexamfetamine (N = 420; conducted from May 25, 2006, to November 16, 2006) and triple-bead mixed amphetamine salts (MAS) (N = 411; conducted from April 25, 2005, to November 4, 2005). Change from baseline to endpoint in PSQI clinically meaningful change categories (ie, "decrease," "no change," or "increase") was analyzed by treatment group in each study using the χ2 test. The Cochran-Mantel-Haenszel method was used (1) to determine whether there was a statistically significant difference in Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2 (improved) versus > 2 (not improved) relative to a decrease or an increase in PSQI and (2) to analyze shifts from good sleep at baseline (PSQI ≤ 5) to poor sleep at endpoint (PSQI > 5). Results: Impaired sleep (PSQI score > 5) relative to baseline was demonstrated in 8.3% and 9.7% of the treatment and placebo groups, respectively (P = .18), in the MAS study and 7.7% and 8.2%, respectively (P = .03), in the lisdexamfetamine study. Clinically meaningful change in baseline to endpoint PSQI was not statistically significantly different between treatment and placebo groups in either study. A significant difference in CGI-I 1 and 2 relative to an increase or decrease in PSQI was found in both the triple-bead MAS (P < .0001) and the lisdexamfetamine (P = .0008) trials. More subjects with improved CGI-I rating of 1 or 2 had improvement in PSQI than had worsening. Conclusions: Approximately one-third of subjects receiving treatment or placebo had clinically meaningful sleep improvement, emphasizing that change in sleep quality during treatment may not necessarily be related to stimulant therapy. When managing complaints of sleep difficulties in ADHD subjects, clinicians should undertake a broad assessment and consider underlying conditions that may contribute to sleep disruption. Trial Registration: clinicaltrials.gov Identifiers: NCT00334880 and NCT00152022 © Copyright 2011 Physicians Postgraduate Press, Inc.

Scaltriti M.,Massachusetts General Hospital | Scaltriti M.,Harvard University | Dawood S.,Dubai Hospital | Cortes J.,Vall dHebron Institute of Oncology VHIO
Clinical Cancer Research | Year: 2012

Many kinases and hormone receptors, important for cancer cell proliferation and survival, bind to and are dependent on the Hsp90 cycle for their folding and maturation. This provides the rationale for the development of small-molecule ATP competitors that, inhibiting Hsp90 function, lead to degradation of the "client" proteins. After continual efforts to improve the pharmacologic properties and the tolerability of these molecules, several Hsp90 inhibitors have exhibited activity in both preclinical models and in the clinical setting. As is the case with many other targeted agents, patient selection seems to be the major limitation to the success of these compounds. ERBB2-positive patients with breast cancer are exquisitely sensitive to Hsp90 inhibition. This is because ERBB2 is indispensable for growth and survival of this subtype of cancer, and at the same time ERBB2 is a client protein strictly dependent on Hsp90 for its maturation and stability. Extensive preclinical work identifying other ERBB-like client proteins will likely lead to the ability to enhance selection of appropriate patients for enrollment in more rational clinical trials. Hsp90 inhibition has also been reported to synergize with other therapeutic agents. Several ongoing studies testing different combinations of Hsp90 inhibitors with other targeted agents will confirm whether Hsp90 inhibition can potentiate the efficacy of targeted therapy and/or prevent the emergence of drug resistance. ©2012 AACR.

Chitnis T.,Massachusetts General Hospital | Chitnis T.,Brigham and Womens Hospital
Clinical Immunology | Year: 2013

Multiple sclerosis (MS) overwhelmingly presents during the reproductive years, and is more common in females than males. The sexual dimorphism observed in post-pubertal cases is absent in pre-pubertal cases, suggesting that puberty is a key risk period for development of disease, particularly in females. Research has identified several risk factors for MS that occur during the adolescent, or post-pubertal reproductive years, which are associated with clinical presentations later in life. These observations necessitate examination of the biological changes associated with puberty, their interactions with MS risk factors, and potential effects on disease immunopathogenesis. Pediatric and adolescent presentations of MS provide a unique opportunity to study the effects of neuroendocrine changes occurring during puberty and its effect on disease development and disease course. Reviewed is the relationship of MS risk factors and puberty, and differences in disease presentation of pre- and post-pubertal children with MS. Further avenues of research are discussed. © 2013 Elsevier Inc.

Porichis F.,Harvard University | Kaufmann D.E.,Harvard University | Kaufmann D.E.,Massachusetts General Hospital
Current Opinion in HIV and AIDS | Year: 2011

Purpose of review: To understand the role of HIV-specific CD4 T cells in viral control and highlight recent progress in the field. Recent findings: HIV-specific CD4 T cells show higher functional avidity in elite controllers than in patients with progressive infection. There is an attrition of the HIV-specific CD4 T-cell population in the digestive mucosa of antiretroviral therapy (ART)-treated patients that contrasts with robust responses in individuals with spontaneous viral control. Secretion of the cytokine IL-21, by HIV-specific CD4 T cells, is associated with disease control and enhances the capacity of HIV-specific CD8 T cells to suppress viral replication. Studies of the PD-1, IL-10, and Tim-3 pathways provided insight into mechanisms of HIV-specific CD4 T-cell exhaustion and new evidence that manipulation of these networks may restore immune functions. Robust, polyfunctional CD4 T-cell responses can be elicited with novel HIV and simian immunodeficiency virus (SIV) vaccines. Summary: These observations show that HIV-specific CD4 T-cell responses are different in elite controllers and individuals with progressive disease. Evidence suggests that HIV-specific CD4 T cells will be an important component of an effective HIV vaccine and significant efforts need to be made to further our understanding of HIV-specific CD4 T-cell functions in different body compartments. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

It is demonstrated that high spatial frequency filtering of time domain fluorescence signals can allow efficient detection of intrinsic fluorescence lifetimes from turbid media and the rejection of diffuse excitation leakage. The basis of this approach is the separation of diffuse fluorescence signals into diffuse and fluorescent components with distinct spatiotemporal behavior. © 2013 Optical Society of America.

Barbesino G.,Massachusetts General Hospital | Tomer Y.,The New School | Tomer Y.,James ters Va Medical Center
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: TSH receptor antibodies (TRAb) cause Graves' disease (GD) hyperthyroidism. Widely available TRAb measurement methods have been significantly improved recently. However, the role of TRAb measurement in the differential diagnosis of hyperthyroidism, the prediction of remission of GD hyperthyroidism, the prediction of fetal/neonatal thyrotoxicosis, and the clinical assessment of Graves' ophthalmopathy (GO) are controversial. Evidence Acquisition: We reviewed and analyzed the literature reporting primary data on the clinical use of TRAb. We focused our analyses on clinical studies analyzing third-generation TRAb assays. Evidence Synthesis: The performance of TRAb in the differential diagnosis of overt hyperthyroidism is excellent, with sensitivity and specificity in the upper 90%. TRAb can accurately predict short-term relapses of hyperthyroidism after a course of antithyroid drugs but are less effective in predicting long-term relapses or remissions. Pregnancies in women with GD with negative TRAb are highly unlikely to result in fetal hyperthyroidism, whereas high titers of TRAb in pregnancy require careful fetal monitoring. GD patients with GO frequently have high TRAb levels. However, there are insufficient data to use the test to predict the clinical course of GO and response to treatment. Conclusions: Third-generation TRAb assays are suitable in the differential diagnosis of hyperthyroidism. In GD, TRAb should be tested before deciding whether methimazole can be stopped. TRAb should be used in pregnant women with GD to assess the risk of fetal thyrotoxicosis. The use of TRAb in GO requires further studies. Copyright © 2013 by The Endocrine Society.

Vyas J.M.,Massachusetts General Hospital
Virulence | Year: 2012

Influenza A virus (IAV) is a dangerous virus equipped with the potential to evoke widespread pandemic disease. The 2009 H1N1 pandemic highlights the urgency for developing effective therapeutics against IAV infection. Vaccination is a major weapon to combat IAV and efforts to improve current regimes are critically important. Here, we will review the role of dendritic cells (DCs), a pivotal cell type in the initiation of robust IAV immunity. The complexity of DC subset heterogeneity in the respiratory tract and lymph node that drains the IAV infected lung will be discussed, together with the varied and in some cases, conflicting contributions of individual DC populations to presenting IAV associated antigen to T cells.

Wu H.,Massachusetts General Hospital | Wu H.,Harvard University | Zhang Y.,University of North Carolina at Chapel Hill
Cell Cycle | Year: 2011

Inner cell mass (ICM) cells of a blastocyst, the source of embryonic stem (ES) cells, are characterized by their unique ability to give rise to all cell types in adult organisms. The epigenomes of germ cells and developing zygotes undergo extensive reprogramming to acquire such a pluripotent state. A major reprogramming event during early embryonic development is the erasure and subsequent re-establishment of patterns of methylation at the 5-position of cytosine (5mC). The recent demonstration that Ten-eleven translocation family proteins, Tet1-3 have the capacity to convert 5mC to 5-hydroxymethylcytosine (5hmC) raises the possibility that 5hmC may act as an distinct epigenetic state contributing to dynamic changes in DNA methylation and transcriptional regulation during embryonic development. In ES cells, Tet1 is highly expressed and 5hmC is present at relatively high levels compared to most differentiated cells, but the functional significance of Tet1 and 5hmC in these pluripotent cells are not clear. Recently, a flurry of papers that profile the distribution of Tet1 and/or 5hmC across the genome of mouse ES cells provide new insights into the role of Tet proteins and 5hmC in regulating expression of genes related to pluripotency and cellular differentiation. Through integrative analyses of datasets from different groups, we reveal the common Tet1 and 5hmC targets in undifferentiated mouse ES cells, which suggest that Tet1 may play a key role in orchestrating the balance between pluripotent and lineage committed states. © 2011 Landes Bioscience.

Wu H.,University of North Carolina at Chapel Hill | Wu H.,Massachusetts General Hospital | Wu H.,Harvard University | Zhang Y.,University of North Carolina at Chapel Hill
Genes and Development | Year: 2011

Ten-eleven translocation 1-3 (Tet1-3) proteins have recently been discovered inmammalian cells to be members of a family of DNA hydroxylases that possess enzymatic activity toward the methyl mark on the 5-position of cytosine (5-methylcytosine [5mC]), a well-characterized epigenetic modification that has essential roles in regulating gene expression and maintaining cellular identity. Tet proteins can convert 5mC into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) through three consecutive oxidation reactions. These modified bases may represent new epigenetic states in genomic DNA or intermediates in the process of DNA demethylation. Emerging biochemical, genetic, and functional evidence suggests that Tet proteins are crucial for diverse biological processes, including zygotic epigenetic reprogramming, pluripotent stem cell differentiation, hematopoiesis, and development of leukemia. Insights into how Tet proteins contribute to dynamic changes in DNA methylation and gene expression will greatly enhance our understanding of epigenetic regulation of normal development and human diseases. © 2011 by Cold Spring Harbor Laboratory Press.

Neer R.M.,Massachusetts General Hospital
Annals of the New York Academy of Sciences | Year: 2010

The Study of Women's Health Across the Nation (SWAN) is an NIH-funded, multidisciplinary, longitudinal observational study of middle-aged U.S. women of multiple ethnicities in or near Boston, Newark, Pittsburgh, Detroit, Chicago, Oakland, and Los Angeles. SWAN measures multiple variables annually, including spine and hip areal bone mineral density (aBMD), serum and urine indices of bone remodeling, and pituitary, ovarian, and adrenal hormones. This chapter outlines the findings of the SWAN study so far. © 2010 New York Academy of Sciences.

Gardner A.,University of Newcastle | Iverson G.L.,Harvard University | Iverson G.L.,Massachusetts General Hospital | McCrory P.,Florey Institute of Neuroscience and Mental Health
British Journal of Sports Medicine | Year: 2014

Objective: To provide a critical review of chronic traumatic encephalopathy (CTE) by considering the range of clinical presentations, neuropathology and the strength of evidence for CTE as a distinct syndrome. Data sources: Seven electronic databases were searched using a combination of MeSH terms and key words to identify relevant articles. Review methods: Specific inclusion and exclusion criteria were used to select studies for review. Data extracted where present included study population, exposure/outcome measures, clinical data, neurological examination findings, cognitive assessment, investigation results and neuropathology results. Results: The data from 158 published case studies were reviewed. Critical differences between the older descriptions of CTE (the 'classic' syndrome) and the recent descriptions (the 'modern' syndrome) exist in the age of onset, natural history, clinical features, pathological findings and diagnostic criteria, which suggests that modern CTE is a different syndrome. The methodology of the current studies does not allow determination of aetiology or risk factors. Conclusions: The clinicopathological differences between the 'classic' CTE syndrome and the 'modern' syndrome suggest that the new syndrome needs a different nomenclature. Further research is required to clearly define the clinical phenotype of the modern CTE syndrome and establish the underlying aetiology. Future research needs to address these issues through largescale, prospective clinicopathological studies.

Ring D.,Massachusetts General Hospital
Hand Clinics | Year: 2013

Laceration and irrecoverable stretch, crush, or avulsion of a major peripheral nerve in the upper extremity causes substantial impairment in an adult patient. Hand care professionals who treat these patients encounter a wide range of coping strategies leading to varied courses of recovery and strikingly different final outcomes. There is evidence that the cognitive, emotional, and behavioral aspects of recovery (not to mention the circumstantial aspects such as worker compensation and litigation) are as important as the physical aspects. Awareness of the factors that facilitate or hinder these aspects of recovery might improve the quality and effectiveness of our care. © 2013 Elsevier Inc.

Gerits A.,Catholic University of Leuven | Vanduffel W.,Catholic University of Leuven | Vanduffel W.,Massachusetts General Hospital | Vanduffel W.,Harvard University
Trends in Genetics | Year: 2013

To understand the functional role of specific neurons in micro- and macro-brain circuitry, health, and disease, it is critical to control their activity precisely. This ambitious goal was first achieved by optogenetics, allowing researchers to increase or decrease neural activity artificially with high temporal and spatial precision. In contrast to the revolution optogenetics engendered in invertebrate and rodent research, only a few studies have reported optogenetic-induced neuronal and behavioral effects in primates. Such studies are nonetheless critical before optogenetics can be applied in a clinical setting. Here, we review the state-of-the-art tools for performing optogenetics in mammals, emphasizing recent neuronal and behavioral results obtained in nonhuman primates. © 2013 Elsevier Ltd.

Greer D.M.,Yale University | Rosenthal E.S.,Massachusetts General Hospital | Wu O.,Biomedical Imaging Center
Nature Reviews Neurology | Year: 2014

Neurological prognostication after cardiac arrest has always been challenging, and has become even more so since the advent of therapeutic hypothermia (TH) in the early 2000s. Studies in this field are prone to substantial biases - most importantly, the self-fulfilling prophecy of early withdrawal of life-sustaining therapies - and physicians must be aware of these limitations when evaluating individual patients. TH mandates sedation and prolongs drug metabolism, and delayed neuronal recovery is possible after cardiac arrest with or without hypothermia treatment; thus, the clinician must allow an adequate observation period to assess for delayed recovery. Exciting advances have been made in clinical evaluation, electrophysiology, chemical biomarkers and neuroimaging, providing insights into the underlying pathophysiological mechanisms of injury, as well as prognosis. Some clinical features, such as pupillary reactivity, continue to provide robust information about prognosis, and EEG patterns, such as reactivity and continuity, seem promising as prognostic indicators. Evoked potential information is likely to remain a reliable prognostic tool in TH-treated patients, whereas traditional serum biomarkers, such as neuron-specific enolase, may be less reliable. Advanced neuroimaging techniques, particularly those utilizing MRI, hold great promise for the future. Clinicians should continue to use all the available tools to provide accurate prognostic advice to patients after cardiac arrest. © 2014 Macmillan Publishers Limited.

Gillette M.A.,The Broad Institute of MIT and Harvard | Gillette M.A.,Massachusetts General Hospital | Carr S.A.,The Broad Institute of MIT and Harvard
Nature Methods | Year: 2013

Targeted mass spectrometry (MS) is becoming widely used in academia and in pharmaceutical and biotechnology industries for sensitive and quantitative detection of proteins, peptides and post-translational modifications. Here we describe the increasing importance of targeted MS technologies in clinical proteomics and the potential key roles these techniques will have in bridging biomedical discovery and clinical implementation. © 2013 Nature America, Inc. All rights reserved.

Surman O.S.,Massachusetts General Hospital
Transplantation Proceedings | Year: 2013

Transplant Psychiatrist: "Why is it important to take (routine) medications after transplantation?" Transplant candidate: "To protect the liver." Doctor: "How?" Patient: "I don't know." Doctor: "Think about it for a moment." Patient: "To prevent rejection and infection." Doctor: "Which one: rejection or infection?" Patient: "Both." This article reports significant conceptual limitations in patient medical knowledge. In the course of customary comprehensive psychiatric evaluation, patients with end-stage renal and/or hepatic disease were asked about knowledge of benefits and side effects of required post-transplant medication. Liver transplant candidates were asked about their understanding of primary organ function and instructed in reference to components of Model for End-stage Liver Disease status on the deceased donor transplant list. Candidates for renal transplantation were selectively asked about risks regarding medical dietary compliance, including dangers of hyperkalemia. Patients had less than expected understanding of required immunosuppression. Liver transplant candidates, with infrequent exception, described the organ as a filter. Those with medical compliance problems related to end-stage renal disease had limited understanding of the kidney's role in homeostasis and impact of hyperkalemia on neurologic function. Additional teaching centered on narrative and analogy specific to individual life experience and skills. Historical reference to Sir Peter Medawar's Nobel Prize-winning work on skin allograft failure for treatment of World War II burn victims effectively illustrated the primacy of immunosuppression for successful organ transplantation. Patients were receptive to this teaching approach. Many expressed gratitude for improved understanding. Clinical awareness of patient skills and life experience can enrich understanding of transplantation objectives and importance of medical compliance. © 2013 by Elsevier Inc. All rights reserved.

Guintivano J.,Johns Hopkins University | Aryee M.J.,Johns Hopkins University | Aryee M.J.,Massachusetts General Hospital | Aryee M.J.,Harvard University | Kaminsky Z.A.,Johns Hopkins University
Epigenetics | Year: 2013

Brain cellular heterogeneity may bias DNA methylation patterns, influencing findings in psychiatric epigenetic studies. We performed fluorescence activated cell sorting (FACS) of neuronal nuclei and Illumina HM450 DNA methylation profiling in post mortem frontal cortex of 29 major depression subjects and 29 matched controls. We identify genomic features and ontologies enriched for cell type specific epigenetic variation. Using the top cell epigenotype specific (CETS) marks, we generated a publically available R package, "CETS," located at http://psychiatry.igm.jhmi.edu/kaminsky/software.htm that is capable of quantifying neuronal proportions and generating in silico neuronal profiles capable of removing cell type heterogeneity bias from DNA methylation data. We demonstrate a significant overlap in major depression DNA methylation associations between FACS separated and CETS model generated neuronal profiles relative to bulk profiles. CETS derived neuronal proportions correlated significantly with age in the frontal cortex and cerebellum and accounted for epigenetic variation between brain regions. CETS based control of cellular heterogeneity will enable more robust hypothesis testing in the brain. © 2013 Landes Bioscience.

Hasserjian R.P.,Massachusetts General Hospital
International Journal of Laboratory Hematology | Year: 2013

Acute myeloid leukemia is an aggressive myeloid neoplasm characterized by ≥20% myeloblasts in the blood or bone marrow. Current treatment strategies for acute myeloid leukemia are based on both patient-related parameters such as age and performance status as well as the intrinsic characteristics of particular disease subtypes. Subtyping of acute myeloid leukemia requires an integration of information from the patient's clinical history (such as any prior preleukemic myeloid neoplasm or cytotoxic potentially leukemogenic therapy), the leukemia morphology, cytogenetic findings, and the mutation status of particular genes (NPM1, FLT3, and CEBPA). In recent years, a barrage of information has become available regarding gene mutations that occur in acute myeloid leukemia and their influence on prognosis. Future therapies for acute myeloid leukemia will increasingly rely on the genetic signatures of individual leukemias and will adjust therapy to the predicted disease aggressiveness as well as employ therapies targeted against particular deregulated genetic pathways. This article reviews current standards for diagnosing and classifying acute myeloid leukemia according to the 2008 WHO Classification. Data that have subsequently accumulated regarding newly characterized gene mutations are also presented. It is anticipated that future leukemia classifications will employ a combination of karyotypic features and the gene mutation pattern to stratify patients to increasingly tailored treatment plans. © 2013 Blackwell Publishing Ltd.

Chan K.E.,Clinical Research Division | Thadhani R.I.,Massachusetts General Hospital | Maddux F.W.,Clinical Research Division
Journal of the American Society of Nephrology | Year: 2014

Hemodialysis patients often do not attend their scheduled treatment session. We investigated factors associated with missed appointments and whether such nonadherence poses significant harmto patients and increases overall health care utilization in an observational analysis of 44 million hemodialysis treatments for 182,536 patients with ESRD in the United States. We assessed the risk of hospitalization, emergency room visit, or intensive-coronary care unit (ICU-CCU) admission in the 2 days after amissed treatment relative to the risk for patientswho received hemodialysis.Over the 5-year study period, the averagemissed treatment rate was 7.1 days per patient-year. In covariate adjusted logistic regression, the risk of hospitalization (odds ratio [OR], 3.98; 95% confidence interval [95% CI], 3.93 to 4.04), emergency room visit (OR, 2.00; 95% CI, 1.87 to 2.14), or ICU-CCU admission (OR, 3.89; 95%CI, 3.81 to 3.96) increased significantly after a missed treatment. Overall, 0.9 missed treatment days per year associated with suboptimal transportation to dialysis, inclement weather, holidays, psychiatric illness, pain, and gastrointestinal upset. These barriers also associated with excess hospitalization (5.6 more events per patient-year), emergency room visits (1.1 more visits), and ICU-CCU admissions (0.8 more admissions). In conclusion, poor adherence to hemodialysis treatments may be a substantial roadblock to achieving better patient outcomes. Addressing systemic and patient barriers that impede access to hemodialysis care may decrease missed appointments and reduce patient morbidity. © 2014 by the American Society of Nephrology.

Rosenquist J.N.,Massachusetts General Hospital | Rosenquist J.N.,Harvard University | Fowler J.H.,University of California at San Diego | Christakis N.A.,Harvard University
Molecular Psychiatry | Year: 2011

The etiology of depression has long been thought to include social environmental factors. To quantitatively explore the novel possibility of person-to-person spread and network-level determination of depressive symptoms, analyses were performed on a densely interconnected social network of 12 067 people assessed repeatedly over 32 years as part of the Framingham Heart Study. Longitudinal statistical models were used to examine whether depressive symptoms in one person were associated with similar scores in friends, co-workers, siblings, spouses and neighbors. Depressive symptoms were assessed using CES-D scores that were available for subjects in three waves measured between 1983 and 2001. Results showed both low and high CES-D scores (and classification as being depressed) in a given period were strongly correlated with such scores in one's friends and neighbors. This association extended up to three degrees of separation (to one's friends friends friends). Female friends appear to be especially influential in the spread of depression from one person to another. The results are robust to multiple network simulation and estimation methods, suggesting that network phenomena appear relevant to the epidemiology of depression and would benefit from further study. © 2011 Macmillan Publishers Limited.

Saylor P.J.,Massachusetts General Hospital
Nature Reviews Clinical Oncology | Year: 2011

Zoledronic acid is a potent bisphosphonate used as the standard therapy for the prevention of skeletal-related events in patients with solid tumors metastatic to bone. Three phase III studies have reported head-to-head comparisons of zoledronic acid with denosumab, an inhibitor of the RANK signaling pathway. © 2011 Macmillan Publishers Limited. All rights reserved.

Zou J.,Microsoft | Zou J.,The Broad Institute of MIT and Harvard | Zou J.,Harvard University | Lippert C.,Microsoft | And 4 more authors.
Nature Methods | Year: 2014

In epigenome-wide association studies, cell-type composition often differs between cases and controls, yielding associations that simply tag cell type rather than reveal fundamental biology. Current solutions require actual or estimated cell-type composition-information not easily obtainable for many samples of interest. We propose a method, FaST-LMM-EWASher, that automatically corrects for cell-type composition without the need for explicit knowledge of it, and then validate our method by comparison with the state-of-the-art approach. © 2014 Nature America, Inc.

Rhee E.P.,Massachusetts General Hospital
Current Opinion in Nephrology and Hypertension | Year: 2015

Purpose of review: This review summarizes recent metabolomics studies of renal disease, outlining some of the limitations of the literature to date. Recent findings: The application of metabolomics in nephrology research has expanded from the initial analyses of uremia to include both cross-sectional and longitudinal studies of earlier stages of kidney disease. Although these studies have nominated several potential markers of incident chronic kidney disease (CKD) and CKD progression, a lack of overlap in metabolite coverage has limited the ability to synthesize results across groups. Furthermore, direct examination of renal metabolite handling has underscored the substantial impact kidney function has on these potential markers (and many other circulating metabolites). In experimental studies, metabolomics has been used to identify a signature of decreased mitochondrial function in diabetic nephropathy and a preference for aerobic glucose metabolism in polycystic kidney disease. In each case, these studies have outlined novel therapeutic opportunities. Finally, as a complement to the longstanding interest in renal metabolite clearance, the microbiome has been increasingly recognized as the source of many plasma metabolites, including some with potential functional relevance to CKD and its complications. Summary: The high-throughput, high-resolution phenotyping enabled by metabolomics technologies has begun to provide insight on renal disease in clinical, physiologic, and experimental contexts. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Jiang T.,Harvard University | Jiang T.,Shanghai University | Zhu A.X.,Massachusetts General Hospital | Sahani D.V.,Harvard University
Journal of Hepatology | Year: 2013

The management of hepatocellular carcinoma (HCC) is evolving because of recently introduced novel therapeutic approaches. There is growing recognition that optimal outcome requires choosing treatment tailored to suit each individual patient, necessitating an early and accurate assessment of tumor response to therapy. The established and adapted image biomarkers based on size for tumor burden measurement continues to be applied to HCC as size measurement can easily be used in any clinical practice. However, in the setting of novel targeted therapies and liver directed treatments, simple tumor anatomical changes can be less informative and usually appear later than biological changes. Therefore the importance of image biomarkers such as tumor viability measurement, functional perfusion and diffusion imaging for response assessment is increasingly being recognized. Although promising, these imaging biomarkers have not gone through all the required steps of standardization and validation. In this review, we discuss various established, evolving and emerging imaging biomarkers and the criteria of response evaluation and their challenges in HCC. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chitnis T.,Harvard University | Chitnis T.,Massachusetts General Hospital
Neurotherapeutics | Year: 2013

Multiple sclerosis (MS) is increasingly recognized in children and adolescents. Improved awareness, access to care, and subspecialty training in pediatric MS has allowed for better access to treatment. Children with MS present with an overwhelmingly relapsing form of the disease and have more frequent relapses than their adult counterparts during the early phases of disease. Cognitive deficits are prominent in pediatric MS, as opposed to locomotor disability. Beta interferons and glatiramer acetate are frequently used off-label drugs. Additional second-line therapies have occasionally been used in treatment failures. No randomized clinical trials have been performed to date in pediatric MS; however, recent legislation necessitates pediatric studies for new agents, which will allow for better defined pharmacokinetic, dosing, and efficacy data to guide the treating neurologist. © 2012 The American Society for Experimental NeuroTherapeutics, Inc.

Pierre V.C.,University of Minnesota | Allen M.J.,Wayne State University | Caravan P.,Massachusetts General Hospital
Journal of Biological Inorganic Chemistry | Year: 2014

Thirty years ago, Schering filed the first patent application for a contrast agent for magnetic resonance imaging (MRI) covering the forefather of the gadolinium contrast agents and still the most widely used gadolinium probe: gadolinium(III) diethylenetriaminepentaacetate (Magnevist). To date, 11 contrast agents have been approved by the US Food and Drug Administration for intravenous use. Coordination chemists have done a great deal to move the field forward. Our understanding of lanthanide chemistry now makes possible the design of complexes with long rotational correlation times, fast or slow water-exchange rates, high thermodynamic stabilities, and kinetic inertness, leading to sensitive and nontoxic contrast agents. Chemists did not stop there. The last few decades has seen the development of novel classes of probes that yield contrast through different mechanisms, such as paramagnetic chemical exchange saturation transfer agents. Thirty years since the first patent, chemists are still leading the way. The development of high-sensitivity contrast agents for high magnetic fields, safe probes for patients with kidney disorders, and multimodal, targeted, and responsive agents demonstrates that the field of contrast agents for MRI still has much to offer. © 2014 SBIC.

Vajro P.,University of Salerno | Paolella G.,University of Salerno | Fasano A.,Massachusetts General Hospital
Journal of Pediatric Gastroenterology and Nutrition | Year: 2013

A specific bacterial gut microbiota profile with increased extraction of energy has recently been associated with obesity, which has been shown to be a transmissible phenotype by microbiota transplantation. At the same time, there is now increasing evidence that gut microbiota plays a role in the development of hepatic steatosis and its progression to nonalcoholic steatohepatitis. This review summarizes well known and unexpected interacting factors leading to obesity and its related hepatic diseases, including intestinal mucosal permeability and its regulation, gut microbiota and translocation of its biological products, and gut-associated lymphoid tissue. These intestinal factors dictate also the balance between tolerance and immune response, which are critical for most of the complications in near and far organs or systems. We review novel mechanisms involving the development of gut permeability and adipose tissue plasticity, for example, the cross-talk between the gut microbiota, lipopolysaccharide, high-fat diet, and the endocannabinoid system tone, which have not been fully explored. Interactions between gut microbiota and other factors (eg, inflammasome deficiency) also are reviewed as emerging but far from being completely elucidated mechanisms influencing the onset of obesity and nonalcoholic fatty liver disease. Copyright © 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Neuringer I.P.,Massachusetts General Hospital
Clinical and Developmental Immunology | Year: 2013

Posttransplant lymphoproliferative disease (PTLD) after lung transplantation occurs due to immunosuppressant therapy which limits antiviral host immunity and permits Epstein-Barr viral (EBV) replication and transformation of B cells. Mechanistically, EBV survives due to latency, escape from cytotoxic T cell responses, and downregulation of host immunity to EBV. Clinical presentation of EBV may occur within the lung allograft early posttransplantation or later onset which is more likely to be disseminated. Improvements in monitoring through EBV viral load have provided a means of earlier detection; yet, sensitivity and specificity of EBV load monitoring after lung transplantation may require further optimization. Once PTLD develops, staging and tissue diagnosis are essential to appropriate histopathological classification, prognosis, and guidance for therapy. The overall paradigm to treat PTLD has evolved over the past several years and depends upon assessment of risk such as EBV-naïve status, clinical presentation, and stage and sites of disease. In general, clinical practice involves reduction in immunosuppression, anti-CD20 biologic therapy, and/or use of plasma cell inhibition, followed by chemotherapy for refractory PTLD. This paper focuses upon the immunobiology of EBV and PTLD, as well as the clinical presentation, diagnosis, prognosis, and emerging treatments for PTLD after lung transplantation. © 2013 Isabel P. Neuringer.

Halassa M.M.,Massachusetts General Hospital | Halassa M.M.,Massachusetts Institute of Technology
Seminars in Cell and Developmental Biology | Year: 2011

Thalamocortical dynamics, the millisecond to second changes in activity of thalamocortical circuits, are central to perception, action and cognition. Generated by local circuitry and sculpted by neuromodulatory systems, these dynamics reflect the expression of vigilance states. In sleep, thalamocortical dynamics are thought to mediate "offline" functions including memory consolidation and synaptic scaling. Here, I discuss thalamocortical sleep dynamics and their modulation by the ascending arousal system and locally released neurochemicals. I focus on modulation of these dynamics by electrically silent astrocytes, highlighting the role of purinergic signaling in this glial form of communication. Astrocytes modulate cortical slow oscillations, sleep behavior, and sleep-dependent cognitive function. The discovery that astrocytes can modulate sleep dynamics and sleep-related behaviors suggests a new way of thinking about the brain, in which integrated circuits of neurons and glia control information processing and behavioral output. © 2011 Elsevier Ltd.

Kuter D.J.,Massachusetts General Hospital
Cancer Treatment and Research | Year: 2011

Thrombocytopenia is a common clinical problem associated with a wide range of medical conditions including immune thrombocytopenia (ITP), chemotherapy-induced thrombocytopenia (CIT), hepatitis C-related thrombocytopenia, and myelodysplastic syndromes (MDS). Until recently, the only treatments for thrombocytopenia were to alleviate the underlying cause or to provide platelet transfusions. With the discovery and recent clinical availability of thrombopoietin (TPO) mimetics, a new treatment option has emerged. Two TPO mimetics are currently clinically available for treating ITP: romiplostim (an injectable peptide TPO mimetic) and eltrombopag (a non-peptide, orally available TPO mimetic). This chapter reviews the development, biology, and clinical trials with romiplostim. With few adverse effects, romiplostim is effective in raising the platelet count in over 80% of ITP patients, allowing them to discontinue other therapies, reduce the need for splenectomy, and improve their quality of life. Long-term theoretical side effects of romiplostim treatment include reticulin formation, thromboembolism, and antibody formation to romiplostim. A practical way of using romiplostim is provided: a higher starting dose of 3 mg/kg is recommended along with efforts to avoid withholding the dose. Future studies will assess the utility of romiplostim in CIT, hepatitis-C related thrombocytopenia, and MDS. © 2011 Springer Science+Business Media, LLC.

Dasatinib is a kinase inhibitor that inhibits BCR-ABL, Src family kinases, c-Kit, and platelet-derived growth factor receptor kinase. It is licensed for the first- and second-line treatment of chronic myeloid leukemia and second-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia on the basis of BCR-ABL inhibition, but the activity of dasatinib against additional molecular targets may enable treatment of other hematologic disorders. Potential targets for dasatinib in chronic lymphocytic leukemia (CLL) include Lyn (a Src family kinase), ABL, and the associated CD40 pathway. Although dasatinib monotherapy has modest clinical activity in CLL, ongoing studies are evaluating combination treatment. In acute myeloid leukemia (AML), FLT3, Lyn, c-Kit, and BCR-ABL are expressed in a subpopulation of patients. To date, clinical responses to dasatinib in patients with unselected AML have been mixed and larger studies are needed, particularly correlating clinical response to molecular markers. Imatinib has been used successfully to treat patients with chronic eosinophilic disorders with the FIP1L1-PDGFRA fusion kinase; limited clinical data indicate that dasatinib could be active in imatinib-resistant disease. Ongoing clinical studies should further define the value of dasatinib in these disorders. © 2011 Informa UK, Ltd.

Dotto G.P.,University of Lausanne | Dotto G.P.,Massachusetts General Hospital
Cancer Research | Year: 2011

Calcineurin is the only known serine-threonine phosphatase under calcium - calmodulin control and key regulator of the immune system. Treatment of patients with calcineurin-inhibitory drugs like cyclosporin A and FK506 to prevent graft rejection dramatically increases the risk of cutaneous squamous cell carcinoma, which is a major cause of death after organ transplants. Recent evidence indicates that suppression of calcineurin signaling, together with its impact on the immune system, exerts direct tumor-promoting effects in keratinocytes, enhancing cancer stem cell potential. The underlying mechanism involves interruption of a double negative regulatory axis, whereby calcineurin and nuclear factors of activated T-cell signaling inhibits expression of ATF3, a negative regulator of p53. The resulting suppression of keratinocyte cancer cell senescence is of likely clinical significance for the many patients under treatment with calcineurin inhibitors and may be of relevance for other cancer types in which altered calcium - calcineurin signaling plays a role. ©2011 AACR.

Raje N.,Massachusetts General Hospital | Raje N.,Harvard University | Roodman G.D.,University of Pittsburgh
Clinical Cancer Research | Year: 2011

Osteolytic bone disease is pathognomonic of multiple myeloma (MM) and affects more than 80% of patients. Bone disease results in skeletal-related events (SRE) such as vertebral compression fractures, which may cause cord compression, hypercalcemia, pathologic fractures that require radiation or surgical fixation, and severe pain. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. Osteolytic disease is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Bisphosphonates are a well-established treatment of myeloma-related skeletal disease and are the current standard of care. However, complications arising from their long-term use have prompted studies of schedule optimization and alternate strategies. Several novel agents are currently under investigation for their positive effect on bone remodeling via OC inhibition. The identification of negative regulators of OB differentiation has prompted the use of anabolic agents. In addition to restoring bone remodeling, these drugs may inhibit tumor growth in vivo. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from bone disease but also capitalizing on the resultant antitumor activity. ©2011 AACR.

Bjork J.M.,U.S. National Institute on Drug Abuse | Gilman J.M.,Massachusetts General Hospital
Neuropharmacology | Year: 2014

Over the last quarter century, researchers have peered into the living human brain to develop and refine mechanistic accounts of alcohol-induced behavior, as well as neurobiological mechanisms for development and maintenance of addiction. These in vivo neuroimaging studies generally show that acute alcohol administration affects brain structures implicated in motivation and behavior control, and that chronic intoxication is correlated with structural and functional abnormalities in these same structures, where some elements of these decrements normalize with extended sobriety. In this review, we will summarize recent findings about acute human brain responses to alcohol using neuroimaging techniques, and how they might explain behavioral effects of alcohol intoxication. We then briefly address how chronic alcohol intoxication (as inferred from cross-sectional differences between various drinking populations and controls) may yield individual brain differences between drinking subjects that may confound interpretation of acute alcohol administration effects. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. © Published by Elsevier Ltd.

Berthiaume F.,Rutgers University | Maguire T.J.,Rutgers University | Yarmush M.L.,Rutgers University | Yarmush M.L.,Massachusetts General Hospital
Annual Review of Chemical and Biomolecular Engineering | Year: 2011

The past three decades have seen the emergence of an endeavor called tissue engineering and regenerative medicine in which scientists, engineers, and physicians apply tools from a variety of fields to construct biological substitutes that can mimic tissues for diagnostic and research purposes and can replace (or help regenerate) diseased and injured tissues. A significant portion of this effort has been translated to actual therapies, especially in the areas of skin replacement and, to a lesser extent, cartilage repair. A good amount of thoughtful work has also yielded prototypes of other tissue substitutes such as nerve conduits, blood vessels, liver, and even heart. Forward movement to clinical product, however, has been slow. Another offshoot of these efforts has been the incorporation of some new exciting technologies (e.g., microfabrication, 3D printing) that may enable future breakthroughs. In this review we highlight the modest beginnings of the field and then describe three application examples that are in various stages of development, ranging from relatively mature (skin) to ongoing proof-of-concept (cartilage) to early stage (liver). We then discuss some of the major issues that limit the development of complex tissues, some of which are fundamentals-based, whereas others stem from the needs of the end users. © Copyright 2011 by Annual Reviews. All rights reserved.

Hill A.S.,Columbia University | Sahay A.,Massachusetts General Hospital | Sahay A.,Harvard Stem Cell Institute | Sahay A.,Harvard University | And 2 more authors.
Neuropsychopharmacology | Year: 2015

Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on hypothalamic-pituitary-adrenal (HPA) axis regulation, either at baseline or following chronic CORT administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects. © 2015 American College of Neuropsychopharmacology.

Dasgupta S.,Harvard University | Erturk-Hasdemir D.,Harvard University | Ochoa-Reparaz J.,Sanford Burnham Institute for Medical Research | Reinecker H.-C.,Massachusetts General Hospital | Kasper D.L.,Harvard University
Cell Host and Microbe | Year: 2014

Polysaccharide A (PSA), the archetypical immunomodulatory molecule of the gut commensal Bacteroides fragilis, induces regulatory T cells to secrete the anti-inflammatory cytokine interleukin-10 (IL-10). The cellular mediators of PSA's immunomodulatory properties are incompletely understood. In a mouse model of colitis, we find that PSA requires both innate and adaptive immune mechanisms to generate protection. Plasmacytoid DCs (PDCs) exposed to PSA do not produce proinflammatory cytokines, but instead they specifically stimulate IL-10 secretion by CD4+ T cells and efficiently mediate PSA-afforded immunoprotection. PSA induces and preferentially ligates Toll-like receptor 2 on PDCs but not on conventional DCs. Compared with other TLR2 ligands, PSA is better at enhancing PDC expression of costimulatory molecules required for protection against colitis. PDCs can thus orchestrate the beneficial immunoregulatory interaction of commensal microbial molecules, such as PSA, through both innate and adaptive immune mechanisms. © 2014 Elsevier Inc.

Ananthakrishnan A.N.,Massachusetts General Hospital
Nature Reviews Gastroenterology and Hepatology | Year: 2015

IBD, comprising Crohn's disease and ulcerative colitis, is a chronic immunologically mediated disease at the intersection of complex interactions between genetics, environment and gut microbiota. Established high-prevalence populations of IBD in North America and Europe experienced the steepest increase in incidence towards the second half of the twentieth century. Furthermore, populations previously considered 'low risk' (such as in Japan and India) are witnessing an increase in incidence. Potentially relevant environmental influences span the spectrum of life from mode of childbirth and early-life exposures (including breastfeeding and antibiotic exposure in infancy) to exposures later on in adulthood (including smoking, major life stressors, diet and lifestyle). Data support an association between smoking and Crohn's disease whereas smoking cessation, but not current smoking, is associated with an increased risk of ulcerative colitis. Dietary fibre (particularly fruits and vegetables), saturated fats, depression and impaired sleep, and low vitamin D levels have all been associated with incident IBD. Interventional studies assessing the effects of modifying these risk factors on natural history and patient outcomes are an important unmet need. In this Review, the changing epidemiology of IBD, mechanisms behind various environmental associations and interventional studies to modify risk factors and disease course are discussed. © 2015 Macmillan Publishers Limited.

Ramos-Casals M.,Sjogren Syndrome Research Group AGAUR | Tzioufas A.G.,National and Kapodistrian University of Athens | Stone J.H.,Massachusetts General Hospital | Siso A.,Primary Care Research Group | Bosch X.,Instituto Clinico Of Medicina Y Dermatologia
JAMA - Journal of the American Medical Association | Year: 2010

Context: A variety of topical and systemic drugs are available to treat primary Sjögren syndrome, although no evidence-based therapeutic guidelines are currently available. Objective: To summarize evidence on primary Sjögren syndrome drug therapy from randomized controlled trials. Data Sources: We searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010. Study Selection: Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source. Results: The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline. Conclusions: In primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab. ©2010 American Medical Association. All rights reserved.

Conner T.S.,University of Otago | Barrett L.F.,Massachusetts General Hospital
Psychosomatic Medicine | Year: 2012

In this article, we review the differences between momentary, retrospective, and trait self-report techniques and discuss the unique role that ambulatory reports of momentary experience play in psychosomatic medicine. After a brief historical review of self-report techniques, we discuss the latest perspective that links ambulatory self-reports to a qualitatively different conscious self-the "experiencing self"-which is functionally and neuroanatomically different from the "remembering" and "believing" selves measured through retrospective and trait questionnaires. The experiencing self functions to navigate current environments and is relatively more tied to the salience network and corporeal information from the body that regulates autonomic processes. As evidence, we review research showing that experiences measured through ambulatory assessment have stronger associations with cardiovascular reactivity, cortisol response, immune system function, and threat/reward biomarkers compared with memories or beliefs. By contrast, memories and beliefs play important roles in decision making and long-term planning, but they are less tied to bodily processes and more tied to default/long-term memory networks, which minimizes their sensitivity for certain research questions. We conclude with specific recommendations for using self-report questionnaires in psychosomatic medicine and suggest that intensive ambulatory assessment of experiences may provide greater sensitivity for connecting psychological with biologic processes. Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

Long A.A.,Massachusetts General Hospital
The American journal of managed care | Year: 2011

Asthma is a significant national burden owing to patient morbidity and mortality, rising healthcare costs, and employee absenteeism. The National Asthma Education and Prevention Program (NAEPP) guidelines were created to improve the diagnosis and treatment of asthma, and stress 4 central components for the management of asthma: (1) measures of assessment and monitoring (obtained by patient history and patient reports; physical examinations and objective tests to confirm, diagnose, and assess severity of asthma initially, and to monitor asthma control subsequently); (2) education for a partnership in asthma care; (3) a focus on control of environmental factors and comorbid conditions that affect asthma; and (4) evidence-based decision making about pharmacologic therapy. The NAEPP guidelines recommend step-up and step-down programs for pharmacologic therapy. There are several barriers to effective asthma control. Treatment adherence in patients with asthma is suboptimal. Moreover, clinicians may not completely adhere to treatment guidelines. Finally, insurance companies may indirectly contribute to poor guideline adherence by failing to adequately recognize the time required to educate patients on asthma and develop a partnership for success, as requested by the guidelines. Successful asthma management requires effort by all parties involved, with the ultimate goal of improved outcomes, including reduced medical complications and costs.

Higgins J.M.,Massachusetts General Hospital | Higgins J.M.,Harvard University | Mahadevan L.,Harvard University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

The systems controlling the number, size, and hemoglobin concentrations of populations of human red blood cells (RBCs), and their dysregulation in anemia, are poorly understood. After release from the bone marrow, RBCs undergo reduction in both volume and total hemoglobin content by an unknown mechanism [Lew VL, et al. (1995) Blood 86:334-341; Waugh RE, et al. (1992) Blood 79:1351-1358]; after ̃120 d, responding to an unknown trigger, they are removed. We used theory from statistical physics and data from the hospital clinical laboratory [d'Onofrio G, et al. (1995) Blood 85:818-823] to develop a master equation model for RBC maturation and clearance. The model accurately identifies patients with anemia and distinguishes thalassemia-trait anemia from irondeficiency anemia. Strikingly, it also identifies many pre-anemic patients several weeks before anemia becomes clinically detectable. More generally we illustrate how clinical laboratory data can be used to develop and to test a dynamic model of human pathophysiology with potential clinical utility.

Oaklander A.L.,Massachusetts General Hospital
Acta Dermato-Venereologica | Year: 2012

Patients with chronic itch are diagnosed and treated by dermatologists. However, itch is a neural sensation and some forms of chronic itch are the presenting symptoms of neurological diseases. Dermatologists need some familiarity with the most common neuropathic itch syndromes to initiate diagnostic testing and to know when to refer to a neurologist. This review summarizes current knowledge, admittedly incomplete, on neuropathic itch caused by diseases of the brain, spinal cord, cranial or spinal nerve-roots, and peripheral nerves. © 2012 The Authors.

Wang S.A.,University of Houston | Hasserjian R.P.,Massachusetts General Hospital
Human Pathology | Year: 2012

Prominent erythroid proliferations (in which erythroid elements comprise ≥50% of total bone marrow cells) can be seen in various hematopoietic stem cell neoplasms. The myeloproliferative neoplasm polycythemia vera exhibits effective, overexuberant erythropoiesis resulting in an increased red blood cell mass; in contrast, most other diseases characterized by erythroid predominance exhibit ineffective hemopoiesis. The latter include acute erythroid leukemia (erythroid-myeloid and pure erythroid leukemia subtypes) as well as some cases of myelodysplastic syndromes, acute myeloid leukemia with myelodysplasia-related changes, and therapy-related myeloid neoplasms. Some nonneoplastic reactive conditions may also manifest a striking bone marrow erythroid predominance. In this article, we review the literature relevant to this group of diseases for a better understanding of their clinicopathologic features and surrounding controversies. We also examine the position of neoplastic erythroid proliferations in the current 2008 World Health Organization Classification of Myeloid Neoplasms and provide recommendations as to how to approach the differential diagnosis of this group of diseases. © 2012 Elsevier Inc. All rights reserved.

Venkatesan A.M.,U.S. National Institutes of Health | Wood B.J.,U.S. National Institutes of Health | Gervais D.A.,Massachusetts General Hospital
Radiology | Year: 2011

Percutaneous ablation in the kidney is now performed as a standard therapeutic nephron-sparing option in patients who are poor candidates for resection. Its increasing use has been largely prompted by the rising incidental detection of renal cell carcinomas with cross-sectional imaging and the need to preserve renal function in patients with comorbid conditions, multiple renal cell carcinomas, and/or heritable renal cancer syndromes. Clinical studies to date indicate that radiofrequency ablation and cryoablation are effective therapies with acceptable short- to intermediateterm outcomes and with a low risk in the appropriate setting, with attention to pre-, peri-, and postprocedural detail. The results following percutaneous radiofrequency ablation and cryoablation in the treatment of renal cell carcinoma are reviewed in this article, including those of several larger scale studies of ablation of T1a tumors. Clinical and technical considerations unique to ablation in the kidney are presented, and potential complications are discussed. © RSNA, 2011.

Stolp J.,University of Oxford | Turka L.A.,Massachusetts General Hospital | Wood K.J.,University of Oxford
Nature Reviews Nephrology | Year: 2014

In transplantation, the contribution of B cells to the rejection or acceptance of the allograft is a topic of major interest. The presence of donor-specific antibodies in transplant recipients is often associated with decreased graft function and rejection, clearly indicating a pathogenetic role of B cells in transplantation. However, data from studies in humans and rodents suggest that under certain conditions, B cells have the capacity to control or regulate the immune response to a transplanted organ. Although a great deal of attention has been focused on B cells in human and murine models of autoimmunity, our understanding of the role of these cells in transplantation is limited at present. Indeed, results in this setting are controversial and seem to depend on the model system used or the clinical situation studied. Here, we review the current understanding of the various phenotypes and roles that have been associated with immune-regulating B cells. We also discuss the mechanisms employed by subsets of these regulatory B cells to control the immune response in transplant recipients and in animal models of transplantation. © 2014 Macmillan Publishers Limited. All rights reserved.

Chen Y.-B.,Massachusetts General Hospital | Cutler C.S.,Dana-Farber Cancer Institute
Bone Marrow Transplantation | Year: 2013

Acute GVHD remains an important complication after allogeneic hematopoietic cell transplantation (HCT). Many efforts have been devoted to identifying potential noninvasive peripheral blood biomarkers to help improve the diagnosis or management of acute GVHD while avoiding invasive tissue biopsies. Early attempts to identify biomarkers focused on inflammatory cytokines, especially IL-2 or TNF-α, however, both of these and others were not specific for GVHD, often being elevated in the setting of generalized inflammation, accompanying other major complications of HCT as well. More recent efforts have focused on additional cytokines and other cell-surface molecules, which function in leukocyte trafficking and activation with the hope that these can also serve as targets for novel therapeutic approaches. Modern proteomic methods have allowed the screening of large numbers of patient samples and yielded several novel candidate biomarkers, including elafin and reg3α, which may not be directly involved in the immunological pathogenesis of GVHD, but may be unique biomarkers for end-organ injury. Combining these new molecules with traditionally identified cytokines to form an acute GVHD biomarker panel has recently shown the ability to predict outcomes in patients who develop acute GVHD. The ultimate goals of identifying a specific biomarker are to refine diagnosis, guide therapy and develop risk-adapted approaches in order to better treat patients and improve outcomes after allogeneic HCT. These approaches include differential treatment for patients who develop acute GVHD with a high-risk biomarker profile as well as pre-emptive therapy in patients after HCT prior to the development of symptoms. With the recent progress summarized below, these goals may soon be realized. © 2013 Macmillan Publishers Limited All rights reserved.

Gill I.S.,University of Southern California | Aron M.,University of Southern California | Gervais D.A.,Massachusetts General Hospital | Jewett M.A.S.,University of Toronto
New England Journal of Medicine | Year: 2010

A 65-year-old man with a history of well-controlled hypertension presents for a follow-up visit after an incidental finding of a small mass in the right kidney on an abdominal computed tomographic (CT) scan. (The scan had been ordered to evaluate pain in the lower quadrant, which resolved.) The mass is 3.2 cm in its largest dimension, anterior, heterogeneous, and solid, and it is in the right renal hilum near the main renal artery, vein, and ureter; the left kidney appears normal. The patient feels well, and his physical examination is unremarkable. His serum creatinine level is 1.2 mg per deciliter (106 μmol per liter). How should this patient be further evaluated and treated? Copyright © 2010 Massachusetts Medical Society.

Spitzer T.R.,Massachusetts General Hospital
Bone Marrow Transplantation | Year: 2015

Engraftment syndrome (ES) after hematopoietic cell transplantation (HCT) is increasingly diagnosed. Common features include fever, pulmonary vascular leak, rash and organ dysfunction. Different diagnostic criteria likely account for the wide (7-90%) range of reported incidences. ES typically occurs within 4 days of granulocyte recovery although a recently described seemingly similar syndrome occurs >1 week before granulocyte recovery after umbilical cord blood cell transplants. Although the clinical manifestations of ES may be identical to those of acute GVHD, ES also has been well described in patients without acute GVHD. The data are conflicting as to whether ES is associated with a higher nonrelapse mortality and worse survival after HCT. The pathophysiology of ES is unclear, but endothelial injury and activated granulocytes in the setting of proinflammatory cytokines may be important. ES typically is self-limited, but, like acute GVHD, responds to corticosteroids. Because ES and acute GVHD may have overlapping features and response to therapy, these disease processes may often not be distinct events. Moreover, features of ES may overlap with those of drug- and radiation-induced toxicities and infection. Further research to better characterize the clinical spectrum and etiology of ES and to determine its relationship to GVHD is needed. © 2015 Macmillan Publishers Limited.

Hobbs G.S.,Massachusetts General Hospital | Rampal R.K.,Sloan Kettering Cancer Center
Current Opinion in Hematology | Year: 2015

PURPOSE OF REVIEW: The myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. Of these, myelofibrosis often has the most aggressive course. There is, however, often significant clinical heterogeneity among patients with myelofibrosis. We seek to summarize recent clinical and biological findings in myelofibrosis as well as review the spectrum of clinically relevant mutation in myelofibrosis and their implications. RECENT FINDINGS: The mutational spectrum in myelofibrosis includes driver mutations in genes such as JAK2, calreticulin, and myeloproliferative leukemia virus oncogene. In addition, recurrent mutations in epigenetic modifiers such as ASXL1 and TET2 have also been described. Importantly, several studies have indicated that specific mutations, as well as the number of mutations, that a patient bears may have important clinical consequences. The presence or absence of certain mutations may help to determine a patient's risk for thrombosis, leukemic transformation, and survival. SUMMARY: Myelofibrosis often has variable outcomes among patients. Prognostic systems based on clinical observations have been developed in an attempt to predict risks of disease progression and transformation. The discovery of recurrent genomic alterations in myelofibrosis, and the observation that many of these alterations may help predict clinical outcomes, has heralded a new era in the biologic understanding and clinical approach to myelofibrosis. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Januzzi Jr. J.L.,Massachusetts General Hospital | Troughton R.,University of Otago
Circulation | Year: 2013

To deny the fact that standard HF care has substantial opportunity for improvement is at the peril of even worse outcomes in our patients affected by the disorder. We have presented a strong rationale for the value of BNP- and NT-proBNP-guided HF management. Experience gained in biomarker-guided HF trials suggests that the approach results in improvement in the quality of care without an excess of adverse events related to more aggressive management. This alone is difficult to ignore given the gaps in care that exist between RCTs and real-world practice. Beyond this fact, studies examining the strategy of biomarker-guided HF care have shown substantial improvement in outcome compared with well-managed control arms, benefits that are confirmed in meta-analysis and pooled data analyses, and justifies the imminent launch of the pivotal RCT that will lead to more widespread adoption of the approach.29 Compared with standard management, biomarker-guided care appears cost effective, may improve patient quality of life, and may promote reverse ventricular remodeling. Although certain subgroups such as the elderly may respond in a less vigorous manner to the approach, this may reflect the effects of age on HF therapy and how the strategy is deployed in elders rather than a weakness of the approach in older patients. A fair-minded assessment of the available data suggests that care supported by BNP/NT-proBNP-guided HF treatment-as an adjunct to standard clinical acumen-is superior to standard care. The limitation of standard care strategies is evident from the suboptimal uptake and application of proven therapies documented in HF registries. Far from being a crutch to support what we should already be doing (namely, optimally evaluating and managing our patients solely with clinical means), the inclusion of NP measurement within the HF management strategy augments the quality of monitoring and treatment. Denial of the benefits of NP monitoring potentially retards advances in the care of a high-risk population of patients that continues to grow in size and importance every day. © 2013 American Heart Association, Inc.

Chen Y.E.,Harvard University | Tsao H.,Massachusetts General Hospital | Tsao H.,Wellman Center for Photomedicine
Journal of the American Academy of Dermatology | Year: 2013

Complex communities of bacteria, fungi, and viruses thrive on our skin. The composition of these communities depends on skin characteristics, such as sebaceous gland concentration, moisture content, and temperature, as well as on host genetics and exogenous environmental factors. Recent metagenomic studies have uncovered a surprising diversity within these ecosystems and have fostered a new view of commensal organisms as playing a much larger role in immune modulation and epithelial health than previously expected. Understanding microbe-host interactions and discovering the factors that drive microbial colonization will help us understand the pathogenesis of skin diseases and develop new promicrobial and antimicrobial therapeutics. © 2012 by the American Academy of Dermatology, Inc.

Forman S.A.,Massachusetts General Hospital
Anesthesiology Clinics | Year: 2010

Over the last several decades, the average age of patients has steadily increased, whereas the use of general anesthesia and deep sedation has grown largely outside the operating room environment. Currently available general anesthetics and delivery models represent limitations in addressing these trends. At the same time, research has tremendously expanded the knowledge of how general anesthetics produce their beneficial effects and also revealed evidence of previously unappreciated general anesthetic toxicities. The goal of this review is to highlight these important developments and describe translational research on new general anesthetics with the potential to improve and reshape clinical care. © 2010 Elsevier Inc.

Khandekar M.J.,Dana-Farber Cancer Institute | Khandekar M.J.,Massachusetts General Hospital | Cohen P.,Dana-Farber Cancer Institute | Cohen P.,Brigham and Womens Hospital | Spiegelman B.M.,Dana-Farber Cancer Institute
Nature Reviews Cancer | Year: 2011

The increasing incidence of obesity and its co-morbid conditions poses a great challenge to global health. In addition to cardiovascular disease and diabetes, epidemiological data demonstrate a link between obesity and multiple types of cancer. The molecular mechanisms underlying how obesity causes an increased risk of cancer are poorly understood. Obesity disrupts the dynamic role of the adipocyte in energy homeostasis, resulting in inflammation and alteration of adipokine (for example, leptin and adiponectin) signalling. Additionally, obesity causes secondary changes that are related to insulin signalling and lipid deregulation that may also foster cancer development. Understanding these molecular links may provide an avenue for preventive and therapeutic strategies to reduce cancer risk and mortality in an increasingly obese population. © 2011 Macmillan Publishers Limited. All rights reserved.

Vassallo M.F.,Allergy and Immunology | Camargo Jr. C.A.,Allergy and Immunology | Camargo Jr. C.A.,Harvard University | Camargo Jr. C.A.,Massachusetts General Hospital
Journal of Allergy and Clinical Immunology | Year: 2010

Epidemiologic data suggest that the incidence of food allergy (FA) is increasing among children, yet a satisfactory model of its pathogenesis remains elusive. FA is the consequence of maladaptive immune responses to common and otherwise innocuous food antigens. Concurrent with the increase in FA is an epidemic of vitamin D deficiency (VDD) caused by several factors, especially decreased sunlight/UVB exposure. There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity. We propose a "multiple- hit" model in which VDD in a developmentally critical period increases susceptibility to colonization with abnormal intestinal microbial flora and gastrointestinal infections, contributing to abnormal intestinal barrier permeability and excess and inappropriate exposure of the immune system to dietary allergens. A compounding effect (and additional "hit") of VDD is the promotion of a pro-sensitization immune imbalance that might compromise immunologic tolerance and contribute to FA. We propose that early correction of VDD might promote mucosal immunity, healthy microbial ecology, and allergen tolerance and thereby blunt the FA epidemic in children. (J Allergy Clin Immunol 2010; 126: 217-22.) © 2010 American Academy of Allergy, Asthma & Immunology.

Tewari K.S.,University of California at Irvine | Sill M.W.,State University of New York at Buffalo | Long III H.J.,Mayo Medical School | Penson R.T.,Massachusetts General Hospital | And 8 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. Copyright © 2014 Massachusetts Medical Society.

Kostis W.J.,Massachusetts General Hospital
Current Atherosclerosis Reports | Year: 2014

There is evidence from epidemiology, pathophysiology, and clinical trials that high LDL cholesterol levels cause atherosclerotic heart disease. Current guidelines recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk. The risk imposed by LDL cholesterol is modulated by the presence of additional risk factors such as age, smoking, and indices of inflammation. Epidemiologic studies as well as rare congenital conditions (e.g., hypobetalipoproteinemia) have shown that very low LDL cholesterol (lower than 70 mg/dL) levels are associated with a very low risk of cardiovascular disease. Analyses of randomized clinical trials have shown a greater benefit in reducing the risk of cardiovascular disease (without an increase in adverse events) among those with very low achieved LDL (below 40 mg/dL). In one study of patients with achieved LDL cholesterol below 30 mg/dL, there was no increase in the usual adverse events compared to patients with LDL cholesterol levels above 30 mg/dL. High-intensity statin therapy is associated with a higher rate of transaminase elevations, but no hepatic failure, a very small risk of myopathy, and an increased risk of developing diabetes. However, the small increase in the risk of developing diabetes is much smaller than the marked lowering of cardiovascular risk. The duration of statin therapy may be important in studies of primary prevention and early, probably low-dose statin therapy, may achieve primordial prevention of atherosclerotic disease. © Springer Science+Business Media 2014.

Sepulcre J.,Harvard University | Sepulcre J.,Massachusetts General Hospital
Neuroscientist | Year: 2014

The processing of brain information relies on the organization of neuronal networks and circuits that in the end must provide the substrate for human cognition. However, the presence of highly complex and multirelay neuronal interactions has limited our ability to disentangle the assemblies of brain systems. The present review article focuses on the latest developments to understand the architecture of functional streams of the human brain at the large-scale level. Particularly, this article presents a comprehensive framework and recent findings about how the highly modular sensory cortex, such as the visual, somatosensory, auditory, as well as motor cortex areas, connects to more parallel-organized cortical hubs in the brain's functional connectome. © The Author(s) 2014.

Kostic A.D.,The Broad Institute of MIT and Harvard | Xavier R.J.,The Broad Institute of MIT and Harvard | Xavier R.J.,Massachusetts General Hospital | Gevers D.,The Broad Institute of MIT and Harvard
Gastroenterology | Year: 2014

Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general. © 2014 by the AGA Institute.

Fink M.P.,University of California at Los Angeles | Shaw Warren H.,Massachusetts General Hospital
Nature Reviews Drug Discovery | Year: 2014

Sepsis, a common and potentially fatal systemic illness, is triggered by microbial infection and often leads to impaired function of the lungs, kidneys or other vital organs. Since the early 1980s, a large number of therapeutic agents for the treatment of sepsis have been evaluated in randomized controlled clinical trials. With few exceptions, the results from these trials have been disappointing, and no specific therapeutic agent is currently approved for the treatment of sepsis. To improve upon this dismal record, investigators will need to identify more suitable therapeutic targets, improve their approaches for selecting candidate compounds for clinical development and adopt better designs for clinical trials.

Levine M.,University of Southern California | Goldstein J.N.,Massachusetts General Hospital
Current Neurology and Neuroscience Reports | Year: 2014

Historically, oral anticoagulation involved the administration of vitamin K antagonists, such as warfarin. However, because of the need for frequent monitoring and the desire for safer anticoagulants, several novel oral anticoagulants have been developed. These newer agents include the factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban), along with the direct thrombin inhibitors (eg, dabigatran). This manuscript provides a brief overview of their uses and mechanisms of action, along with a review of currently available evidence for reversal strategies when life-threatening bleeding occurs. © 2014 Springer Science+Business Media.

Gomeni R.,Pharmacometrica | Fava M.,Massachusetts General Hospital
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration | Year: 2014

Our objective was to develop: 1) a longitudinal model to describe amyotrophic lateral sclerosis (ALS) disease progression using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R); and 2) a probabilistic model to estimate the presence of clusters of trajectories in ALS progression over 12 months of treatment. Three hundred and thirty-eight patients treated with placebo from the PRO-ACT database were included in the analyses. A non-linear Weibull model best described the ALS disease progression, and a stepwise logistic regression approach was used to select the variables predicting a slow or fast disease progression. Results identified two clusters of trajectories: 1) slow disease progressors (46% of patients with a change from baseline of 13%); 2) fast disease progressors (54% of patients with a change from baseline of 49%). ROC curve analysis estimated the optimal cut-off for classifying patients as slow or fast disease progressors given ALSFRS-R measurements at 2-4 weeks. Results showed that the degree of ALS disease progression quantified by the ALSFRS-R symptomatic change on placebo is highly heterogeneous. In conclusion, this finding indicates the potential interest of disease progression models for implementing a population enrichment strategy to control the level of heterogeneity in the patients included in new trials. © 2014 Informa Healthcare.

Burton D.R.,Scripps Research Institute | Burton D.R.,Massachusetts General Hospital | Mascola J.R.,National Institute of Allergy and Infectious Diseases
Nature Immunology | Year: 2015

Antibody responses to the HIV-1 envelope glycoproteins can be classified into three groups. Binding but non-neutralizing responses are directed to epitopes that are expressed on isolated envelope glycoproteins but not on the native envelope trimer found on the surface of virions and responsible for mediating the entry of virus into target cells. Strain-specific responses and broadly neutralizing responses, in contrast, target epitopes that are expressed on the native trimer, as revealed by recently resolved structures. The past few years have seen the isolation of many broadly neutralizing antibodies of remarkable potency that have shown prophylactic and therapeutic activities in animal models. These antibodies are helping to guide rational vaccine design and therapeutic strategies for HIV-1.

Januzzi Jr. J.L.,Massachusetts General Hospital
Journal of Investigative Medicine | Year: 2013

Following the initial discovery of a natriuretic and diuretic peptide factor present in atrial myocardial tissue homogenates, subsequent elucidation of the natriuretic peptide (NP) family has led to substantial advances in the understanding of the autocrine, paracrine, and endocrine regulation of the cardiovascular system. Furthermore, with the development of assays for the measurement of the NPs, these important biomarkers have gone from being regarded as biological mediators of the cardiovascular system to now represent important clinical tools for the diagnostic and prognostic evaluation of patients with heart failure and may have potential as a therapeutic target in this setting as well. An historical perspective on the NPs from bench to bedside translation will be discussed. Copyright © 2013 by The American Federation for Medical Research.

Loureiro J.,Instituto Portugues Of Oncologia | Oliva E.,Massachusetts General Hospital
Archives of Pathology and Laboratory Medicine | Year: 2014

• Context.-Premalignant and malignant glandular lesions of the cervix are known to often cause diagnostic problems with a variety of benign (more common) as well as other malignant mimics, the latter setting often being represented by secondary involvement by endometrioid endometrial carcinoma especially in small samplings. Objectives.-To highlight key histologic features and immunohistochemical markers that may be helpful in the distinction of in situ endocervical carcinoma from benign glandular proliferations, and those that separate different subtypes of invasive endocervical carcinoma, as well as invasive carcinoma from other carcinomas secondarily involving the cervix and nonneoplastic proliferations of the cervix. Conclusions.-Clinical and morphologic features as well as immunohistochemistry results should be used in conjunction in the differential diagnosis of glandular proliferations of the cervix, as correct interpretation has major clinical consequences for the patient in most instances (especially benign versus malignant). Immunohistochemical markers should be used as part of a panel of antibodies, as exceptions may occur to the usual pattern of staining, and if used singly, they may mislead the pathologist to establish a wrong diagnosis.

Arnstein P.,Massachusetts General Hospital
Pain management nursing : official journal of the American Society of Pain Management Nurses | Year: 2010

The rapidly expanding number of aged Americans and the increasing prevalence of persistent pain in older adults create an urgent need to unravel the complexities of chronic pain management in this population. This requires health professionals to understand both normal and pathologic changes that occur within the aging body and mind, as well as how those factors affect responses to pain and pain-relieving treatments. The medical management of pharmacologic treatment for pain in older adults is often suboptimal, ranging from failing to use analgesics for patients with considerable pain to exposing older adults to potentially life-threatening toxicities, overdoses, or drug interactions. Models for safe and effective approaches to treating pain in older adults exist, but treatments must still be tailored for each individual's needs. A growing array of targeted therapies are available for managing pain, yet two or three trials of different agents within the same drug class are often needed to optimize treatment because of the considerable variability in responses to the effects of particular medications. Older adults tend to be more vulnerable to side effects and drug interactions than their younger counterparts, owing to differences in drug distribution, metabolism, and elimination. This review delineates these vulnerabilities and informs clinicians of the strategies needed to promote safe and effective use of medications to treat pain in older adults. The goal of this paper was to review specific considerations for balancing efficacy and safety in the pharmacologic treatment of persistent pain in older adults. Copyright 2010 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Katayama R.,Cancer Chemotherapy Center | Lovly C.M.,Vanderbilt University | Shaw A.T.,Massachusetts General Hospital | Shaw A.T.,Harvard University
Clinical Cancer Research | Year: 2015

The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)-ALK in anaplastic large-cell lymphoma (ALCL). Genomic alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKI), including crizotinib, ceritinib, and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALKrearranged NSCLC. © 2015 AACR.

Marneros A.,Massachusetts General Hospital | Marneros A.,Harvard University
Cell Reports | Year: 2013

The NLRP3 inflammasome is activated in age-related macular degeneration (AMD), but it remains unknown whether its activation contributes to AMD pathologies. VEGF-A is increased in neovascular ("wet") AMD, but it is not known whether it plays a role in inflammasome activation, whether an increase of VEGF-A by itself is sufficient to cause neovascular AMD and whether it can contribute to nonexudative ("dry") AMD that often co-occurs with the neovascular form. Here, it is shown that an increase in VEGF-A results in NLRP3 inflammasome activation and is sufficient to cause both forms of AMD pathologies. Targeting NLRP3 or the inflammasome effector cytokine IL-1β inhibits but does not prevent VEGF-A-induced AMD pathologies, whereas targeting IL-18 promotes AMD. Thus, increased VEGF-A provides a unifying pathomechanism for both forms of AMD; combining therapeutic inhibition of both VEGF-A and IL-1β or the NLRP3 inflammasome is therefore likely to suppress both forms of AMD

Blower M.D.,Massachusetts General Hospital | Blower M.D.,Harvard University
International Review of Cell and Molecular Biology | Year: 2013

Localization of mRNAs to specific destinations within a cell or an embryo is important for local control of protein synthesis. mRNA localization is well known to function in very large and polarized cells such as neurons, and to facilitate embryonic patterning during early development. However, recent genome-wide studies have revealed that mRNA localization is more widely utilized than previously thought to control gene expression. Not only can transcripts be localized asymmetrically within the cytoplasm, they are often also localized to symmetrically distributed organelles. Recent genetic, cytological, and biochemical studies have begun to provide molecular insight into how cells select RNAs for transport, move them to specific destinations, and control their translation. This chapter will summarize recent insights into the mechanisms and function of RNA localization with a specific emphasis on molecular insights into each step in the mRNA localization process. © 2013 Elsevier Inc.

Gewirtz H.,Massachusetts General Hospital
Journal of Nuclear Cardiology | Year: 2012

Considerable awareness has been raised of late of the need to reduce radiation exposure and control costs of x-ray and radionuclide imaging procedures. PET/CT cameras are now widely available and in conjunction with appropriate radionuclides and commercially available software make quantitative measurement of absolute MBF feasible for routine clinical practice. Quantitative measurement of absolute MBF under condition of coronary vasodilation permits independent assessment of the functional status of each of the three major coronary perfusion zones and so obviates the need for rest MBF determination in the great majority of cases. Coronary microvascular function also may be assessed in this same way. Thus, the stress-only protocol with quantitative PET measurement of MBF provides essential information required for clinical decision making related to need for catheterization and intervention for patients with known or suspected ischemic heart disease. Moreover, the single PET determination of maximal MBF in contrast to the usual rest/stress procedure addresses both safety and cost concerns. The present review focuses on: (1) quantitative PET measurements of myocardial blood flow for physiological assessment of the coronary circulation and (2) the value and potential limitations of performing stress only imaging in the clinical context. Copyright © 2011 American Society of Nuclear Cardiology.

Gomperts S.N.,Massachusetts General Hospital
CONTINUUM Lifelong Learning in Neurology | Year: 2016

Purpose of Review: This article provides an overview of the clinical features, neuropathologic findings, diagnostic criteria, and management of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), together known as the Lewy body dementias. Recent Findings: DLB and PDD are common, clinically similar syndromes that share characteristic neuropathologic changes, including deposition of α-synuclein in Lewy bodies and neurites and loss of tegmental dopamine cell populations and basal forebrain cholinergic populations, often with a variable degree of coexisting Alzheimer pathology. The clinical constellations of DLB and PDD include progressive cognitive impairment associated with parkinsonism, visual hallucinations, and fluctuations of attention and wakefulness. Current clinical diagnostic criteria emphasize these features and also weigh evidence for dopamine cell loss measured with single-photon emission computed tomography (SPECT) imaging and for rapid eye movement (REM) sleep behavior disorder, a risk factor for the synucleinopathies. The timing of dementia relative to parkinsonism is the major clinical distinction between DLB and PDD, with dementia arising in the setting of well-established idiopathic Parkinson disease (after at least 1 year of motor symptoms) denoting PDD, while earlier cognitive impairment relative to parkinsonism denotes DLB. The distinction between these syndromes continues to be an active research question. Treatment for these illnesses remains symptomatic and relies on both pharmacologic and nonpharmacologic strategies. Summary: DLB and PDD are important and common dementia syndromes that overlap in their clinical features, neuropathology, and management. They are believed to exist on a spectrum of Lewy body disease, and some controversy persists in their differentiation. Given the need to optimize cognition, extrapyramidal function, and psychiatric health, management can be complex and should be systematic. © 2016 by the American Academy of Neurology.

Vela R.M.,Massachusetts General Hospital
Psychiatric Clinics of North America | Year: 2014

Child abuse is the most extreme form of stress in childhood and adolescence, and has severe effects on the child's development. Limbic nuclei and circuitry development are especially vulnerable to child abuse and neglect during the first year of life. Development at the neuronal level can be severely disturbed by trauma during early infancy, resulting in maladaptive synaptic formation, impeding experience-expectant brain development. Development of basic emotions may favor the development of negative instead of positive emotions. The new concept of psychoanatomical formulation is introduced. A case vignette is presented and analyzed, based on the disturbed neuroanatomy underlying symptom expression. © 2014 Elsevier Inc.

Fong Z.V.,Massachusetts General Hospital | Winter J.M.,Thomas Jefferson University
Cancer Journal (United States) | Year: 2012

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. There has been minimal progress with regard to cancer-specific outcomes in recent decades. Although effective therapies will undoubtedly change the natural history of the disease, effective biomarkers are a promising tool that will likely have a positive impact and will undoubtedly have an important role in the management of patients with pancreatic ductal adenocarcinoma (PDA) in the future. At present, serum CA-19-9 (carbohydrate antigen 19-9) is the only Food and Drug Administration-approved biomarker for PDA, and it has utility as a prognostic marker and as a marker of disease recurrence. There has been a recent explosion in the pancreatic cancer biomarker field with more than 2000 biomarker studies implicating thousands of informative genes as candidate biomarkers. In this review, we summarize the literature on CA-19-9 in PDA and highlight the most promising investigational biomarkers. Distinctions are made between diagnostic biomarkers (detection of disease), prognostic biomarkers (provide information on prognosis and recurrence pattern), and predictive biomarkers (predict treatment response). Copyright © 2012 by Lippincott Williams &Wilkins.

Ahmari S.E.,University of Pittsburgh | Dougherty D.D.,Massachusetts General Hospital
Depression and Anxiety | Year: 2015

Obsessive-compulsive disorder (OCD) is a chronic, severe mental illness with up to 2-3% prevalence worldwide. In fact, OCD has been classified as one of the world's 10 leading causes of illness-related disability according to the World Health Organization, largely because of the chronic nature of disabling symptoms.[1] Despite the severity and high prevalence of this chronic and disabling disorder, there is still relatively limited understanding of its pathophysiology. However, this is now rapidly changing due to development of powerful technologies that can be used to dissect the neural circuits underlying pathologic behaviors. In this article, we describe recent technical advances that have allowed neuroscientists to start identifying the circuits underlying complex repetitive behaviors using animal model systems. In addition, we review current surgical and stimulation-based treatments for OCD that target circuit dysfunction. Finally, we discuss how findings from animal models may be applied in the clinical arena to help inform and refine targeted brain stimulation-based treatment approaches. © 2015 Wiley Periodicals, Inc.

Kovacs R.,Indiana University | Baggish A.L.,Massachusetts General Hospital
Trends in Cardiovascular Medicine | Year: 2016

Millions of athletes train for and participate in competitive athletics each year. Many of these athletes will present to a cardiovascular specialist with signs or symptoms that might indicate heart disease and these athletes/patients will ask for advice on their ability to continue to train and compete safely. By virtue of their training, athletes' hearts may undergo significant structural and electrical change, presenting a special challenge for the cardiovascular specialist. It is important to understand normal adaptive changes in order to separate normal physiology from pathology. © 2016 Elsevier Inc.

Flaherty K.T.,Massachusetts General Hospital
Cancer Journal | Year: 2011

Selective BRAF inhibitors have recently emerged as a new standard treatment for patients with metastatic melanoma harboring activating BRAF mutations. Inhibition of the MAP kinase pathway and initial evidence of antitumor effects are very reliably observed. However, many patients experience short-lived responses, whereas others are durable. An overall survival benefit has been established for them, BRAF in it, the agents that have advanced furthest in clinical development. Nonetheless, attention has immediately turned to understanding de novo and acquired resistance and effort to develop rational combination therapy that will further improve patient outcomes. Opportunities for combining BRAF inhibitors with other signal transduction inhibitors as well as targeted therapies with distinct mechanisms of action are discussed. Copyright © 2011 by Lippincott Williams & Wilkins.

Carroll D.L.,Massachusetts General Hospital
Dimensions of Critical Care Nursing | Year: 2014

Background: In a growing number of requests, family members are asking for proximity to their family member during resuscitation and invasive procedures. Objectives: The objective of this study was to measure the impact of intensive care unit environments on nurse perception of family presence during resuscitation and invasive procedures. Research Methods: The study used a descriptive survey design with nurses from 9 intensive care units using the Family Presence Self-confidence Scale for resuscitation/invasive procedures that measures nurses' perception of self-confidence and Family Presence Risk-Benefit Scale for resuscitation and invasive procedures that measures nurses' perception of risks/benefits related to managing resuscitation and invasive procedures with family present. Results: There were 207 nurses who responded: 14 male and 184 female nurses (9 missing data), with mean age of 41 ± 11 years, with a mean of 15 years in critical care practice. The environments were defined as surgical (n = 68), medical (n = 43), pediatric/neonatal (n = 34), and mixed adult medical/surgical (n = 36) intensive care units. There were significant differences in self-confidence, with medical and pediatric intensive care unit nurses rating more self-confidence for family presence during resuscitation (F = 7.73, P < .000) and invasive procedures (F = 6.41, P < .000). There were significant differences in risks/benefits with medical and pediatric intensive care unit nurses rating lower risk and higher benefit for resuscitation (F = 7.73, < G .000). Discussion: Perceptions of family presence were significantly higher for pediatric and medical intensive care unit nurses. Further education and support may be needed in the surgical and mixed intensive care units. Evidence-based practice guidelines that are family centered can define the procedures and resources for family presence, to ultimately promote professional practice. Copyright © 2013 Wolters Kluwer Health.

Allen R.P.,Johns Hopkins University | Chen C.,Pfizer | Garcia-Borreguero D.,Sleep Research Institute | Polo O.,University of Tampere | And 4 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Dopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative. METHODS: In this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. Patients were randomly assigned to receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo followed by 40 weeks of randomly assigned active treatment. The primary analyses involved a comparison of pregabalin and placebo over a period of 12 weeks with use of the International RLS (IRLS) Study Group Rating Scale (on which the score ranges from 0 to 40, with a higher score indicating more severe symptoms), the Clinical Global Impression of Improvement scale (which was used to assess the proportion of patients with symptoms that were "very much improved" or "much improved"), and a comparison of rates of augmentation with pregabalin and pramipexole over a period of 40 or 52 weeks of treatment. RESULTS: A total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P = 0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P = 0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole. CONCLUSIONS: Pregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole. Copyright © 2014 Massachusetts Medical Society.

Kopans D.B.,Harvard University | Kopans D.B.,Massachusetts General Hospital
Breast Cancer Research and Treatment | Year: 2015

Panels are presently reviewing breast cancer screening guidelines. It is critical that they understand which publications are scientifically valid, and which analyses are methodologically flawed and not valid. The scientific evidence clearly supports annual mammography screening beginning at the age of 40. The analyses that suggest that screening leads to overdiagnosis of invasive breast cancers are flawed and incorrect. There is little if any overdiagnosis of these cancers. The vast majority of breast cancers occur in women who are not at elevated risk so that excluding them from screening and only screening high risk women will deny the benefits of early detection to most women who develop breast cancer. Guidelines panels should not make decisions that exclude women from screening. Women should be provided with accurate information so that they can make informed decisions and have unimpeded access to screening if that is their preference. © 2015, Springer Science+Business Media New York.

Bastepe M.,Massachusetts General Hospital
Endocrine Development | Year: 2013

End-organ resistance to the actions of parathyroid hormone (PTH) is defined as pseudohypoparathyroidism (PHP). Described originally by Fuller Albright and his colleagues in early 1940s, this rare genetic disease is subclassified into two types according to the nephrogenous response to the administration of biologically active PTH. In type I, the PTH-induced urinary excretion of both phosphate and cyclic AMP (cAMP) is blunted. In type II, only the PTH-induced urinary excretion of phosphate is blunted, while the cAMP response is unimpaired. Different subtypes of PHP type I have been described based on the existence of additional clinical features, such as resistance to other hormones and Albright's hereditary osteodystrophy, and underlying molecular defects. Genetic mutations responsible for the different subtypes of PHP type I involve the GNAS complex locus, an imprinted gene encoding the α-subunit of the stimulatory G protein (Gsα) and several other transcripts that are expressed in a parent-of-origin specific manner. Mutations in Gsα-coding GNAS exons cause PHP-Ia and, in some cases, PHP-Ic, while mutations that disrupt the imprinting of GNAS lead to PHP-Ib. PHP type II is less well characterized with respect to its molecular cause. Recently, however, mutations in PRKAR1A, a regulatory subunit of the cAMP-dependent protein kinase, have been identified in several cases of PTH and other hormone resistance and skeletal dysplasia that are considered to be affected by PHP type II due to unimpaired urinary excretion of cAMP following PTH administration. Copyright © 2013 S. Karger AG, Basel.

Munn L.L.,Massachusetts General Hospital
Seminars in Cell and Developmental Biology | Year: 2015

The lymphatic system is responsible for controlling tissue fluid pressure by facilitating flow of lymph (i.e. the plasma and cells that enter the lymphatic system). Because lymph contains cells of the immune system, its transport is not only important for fluid homeostasis, but also immune function. Lymph drainage can occur via passive flow or active pumping, and much research has identified the key biochemical and mechanical factors that affect output. Although many studies and reviews have addressed how tissue properties and fluid mechanics (i.e. pressure gradients) affect lymph transport [1-3] there is less known about lymphatic mechanobiology. As opposed to passive mechanical properties, mechanobiology describes the active coupling of mechanical signals and biochemical pathways. Lymphatic vasomotion is the result of a fascinating system affected by mechanical forces exerted by the flowing lymph, including pressure-induced vessel stretch and flow-induced shear stresses. These forces can trigger or modulate biochemical pathways important for controlling the lymphatic contractions. Here, I review the current understanding of lymphatic vessel function, focusing on vessel mechanobiology, and summarize the prospects for a comprehensive understanding that integrates the mechanical and biomechanical control mechanisms in the lymphatic system. © 2015 Elsevier Ltd.

Venkataramani A.S.,Massachusetts General Hospital
Journal of Health Economics | Year: 2012

This study examines the impact of early life malaria exposure on cognition in sample of Mexican adults, using the nationwide introduction of malaria eradication efforts to identify causal impacts. The core findings are that birth year exposure to malaria eradication was associated with increases in Raven Progressive Matrices test scores and consumption expenditures, but not schooling. Additionally, cohorts born after eradication both entered and exited school earlier than their pre-eradication counterparts. These effects were only seen for men and explanations for this are assessed. Collectively, these findings suggest that improvements in infant health help explain secular increases in cognitive test scores, that better cognition may link early life health to adulthood earnings, and that human capital investments through childhood and young adulthood respond sensitively to market returns to early life endowment shocks. © 2012 Elsevier B.V.

McDonald-Hyman C.,University of Minnesota | Turka L.A.,Harvard University | Turka L.A.,Massachusetts General Hospital | Blazar B.R.,University of Minnesota
Science Translational Medicine | Year: 2015

Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome. © 2015, AAAS. All rights reserved.

Satterthwaite T.D.,University of Pennsylvania | Baker J.T.,McLean Hospital | Baker J.T.,Massachusetts General Hospital
Current Opinion in Neurobiology | Year: 2015

Psychosis is increasingly being understood as a neurodevelopmental 'dysconnection' syndrome, in which neural connectivity - at both microscopic and macroscopic levels of brain organization - becomes disrupted during late adolescence and early adulthood. Tools to quantify normative brain development and identify individuals at risk are urgently needed to tailor appropriate strategies for prevention and intervention, and could substantially improve clinical outcomes. Resting-state functional connectivity magnetic resonance imaging (rsfc-MRI) provides a rich, functional description of the brain's macroscopic connectivity structure. Over the past several years, rsfc-MRI has evolved to be a powerful tool for studying both normal brain development and abnormalities associated with psychosis. Several recent advances highlight intriguing and potentially significant parallels between these two lines of research. For instance, rsfc-MRI work suggests that psychosis is accompanied by loss of segregation between large-scale brain association networks, a pattern that is normal in early life but typically matures into more segregated systems by young adulthood. Coupled with data sharing across large-scale neuroimaging studies, longitudinal assessments using rsfc-MRI in patients and those at risk will be essential for improving our biological understanding of psychosis and will help inform diagnosis, prognosis, and clinical decision-making. © 2014 Elsevier Ltd.

Videnovic A.,Massachusetts General Hospital | Lazar A.S.,University of Cambridge | Barker R.A.,University of Cambridge | Overeem S.,Radboud University Nijmegen
Nature Reviews Neurology | Year: 2014

Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep-wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep-wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep-wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases. © 2014 Macmillan Publishers Limited. All rights reserved.

Fishman J.A.,Massachusetts General Hospital
American Journal of Transplantation | Year: 2013

Application of advanced molecular techniques and novel animal models has provided new insights into basic mechanisms underlying clinical transplantation. Investigations in diverse areas, including graft rejection and tolerance, autoimmunity and infectious diseases, have revealed increasing complexity of the mechanisms controlling immune function, notably at the interface of the innate and adaptive immune systems and within secondary lymphoid organs. New roles have been identified for NK and dendritic cells, B-lymphocytes and for Th17 and regulatory T cells, notably in novel animal models of costimulatory blockade and tolerance. Confirmation of these observations will be needed in normal animals and in humans undergoing organ and cell transplantation. The impact of the microbiome, of vaccines, and of antimicrobial therapies on immune memory and reconstitution after lymphocyte depletion is beginning to be defined. This article summarizes emerging insights from the American Transplant Congress 2012. Basic studies of the physiology of transplantation have revealed increased complexity of the mechanisms controlling immune function, notably at the interface of the innate and adaptive immune systems. See companion article by Humar (page 281) for a summary of clinical articles. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Freer P.E.,Massachusetts General Hospital
Radiographics | Year: 2015

Mammographic breast density is rapidly becoming a hot topic in both the medical literature and the lay press. In the United States, recent legislative changes in 19 states now require radiologists to notify patients regarding breast density as well as the possible need for supplemental screening. Federal legislation regarding breast density notification has been introduced, and its passage is likely on the horizon. An understanding of the context, scientific evidence, and controversies surrounding the topic of breast density as a risk factor for breast cancer is critical for radiologists. The current state of evidence is presented regarding supplemental screening for women with dense breasts, including the use of digital breast tomosynthesis, whole-breast ultrasonography, and gadolinium-enhanced magnetic resonance imaging. A review of current practice guidelines and additional sources of information will improve radiologists’ understanding of the relevant subject of breast density and enable them to respond appropriately to questions from patients, clinicians, and the media. © RSNA, 2015.

Patterson B.,St Georges Vascular Institute | Holt P.,St Georges Vascular Institute | Nienaber C.,University of Rostock | Cambria R.,Massachusetts General Hospital | And 2 more authors.
Circulation | Year: 2013

Background-Endovascular repair of the thoracic aorta has become an increasingly utilized therapy. Although the short-term mortality advantage over open surgery is well documented, late mortality and the impact of presenting pathology on long-term outcomes remain poorly reported. Methods and Results-A database was built from 5 prospective studies and a single institutional series. Rates of perioperative adverse events were calculated, as were midterm death and reintervention rates. Multivariate analysis was performed with the use of logistic regression modeling. Kaplan-Meier survival curves were drawn for midterm outcomes. The database contained 1010 patients: 670 patients with thoracic aortic aneurysm, 195 with chronic type B aortic dissection, and 114 with acute type B aortic dissection. Lower elective mortality was observed in patients with chronic dissections (3%) compared with patients with aneurysms (5%). Multivariate analysis identified age, mode of admission, American Society of Anesthesiologists grade, and pathology as independent predictors of 30-day death (P < 0.05). In the midterm, the all-cause mortality rate was 8, 4.9, and 3.2 deaths per 100 patient-years for thoracic aortic aneurysm, acute type B aortic dissection, and chronic type B aortic dissection, respectively. The rates of aortic-related death were 0.6, 1.2, and 0.4 deaths per 100 patient-years for thoracic aortic aneurysm, acute type B aortic dissection, and chronic type B aortic dissection, respectively. Conclusions-This study indicated that the midterm outcomes of endovascular repair of the thoracic aorta are defined by presenting pathology, associated comorbidities, and mode of admission. Nonaortic mortality is high in the midterm for patients with thoracic aortic aneurysm, and managing modifiable risk factors appears vital. Endovascular repair of the thoracic aorta results in excellent midterm protection from aortic-related mortality, regardless of presenting pathology. © 2013 American Heart Association, Inc.

Castelino F.V.,Massachusetts General Hospital
Current Opinion in Rheumatology | Year: 2012

Purpose of Review: Lipid mediators including the lysophospholipids, sphingolipids and eicosanoids have long been implicated in inflammation, cancer and numerous other diseases. Over the last decade, new research suggests a role for these mediators in fibrosis. Recent Findings: Recent developments in the study of fibrotic mediators have centered on lysophospholipids and eicosanoids. New research is evaluating metabolic-profiling strategies to quantitatively measure lipid mediators in human plasma. Lysophosphatidic acid receptor antagonists are currently under development with early phase trials scheduled for idiopathic pulmonary fibrosis and scleroderma dermal fibrosis. Eicosanoids have long been implicated in maintaining tissue homeostasis, and the balance of profibrotic and antifibrotic effects has drawn attention in recent years. Targeting the prostanoids, specifically PGE2 and PGI2, as well as the leukotrienes is now being considered for antifibrotic therapies. Summary: Lipid mediators have significant roles in many disease processes. Significant research now suggests a critical role for these mediators in the pathogenesis of fibrosis. Targeting these mediators is a promising area of drug discovery. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Porichis F.,Harvard University | Kaufmann D.E.,Harvard University | Kaufmann D.E.,Massachusetts General Hospital
Current HIV/AIDS Reports | Year: 2012

Major advances in Antiretroviral Therapy (ART) have resulted in a dramatic decline in HIV-related deaths. However, no current treatment regimen leads to viral eradication or restoration of HIV-specific immune responses capable of durable viral control after cessation of ART. Thus, there is a need for novel interventions that could complement ART in order to eliminate virus or reach a state of "functional cure." It has been shown in murine models and humans that the negative co-signaling molecule programmed-death 1 (PD-1) plays an active and reversible role in mediating T-cell exhaustion in chronic infections. This review summarizes recent advances in our understanding of the PD-1 pathway in HIV infection, and the lessons learned from studies in the SIV model and cancer. We discuss the potential of immunotherapeutic interventions targeting PD-1 in order to augment immune responses or facilitate viral eradication. We also present the challenges to therapies targeting immunoregulatory networks. © 2012 Springer Science+Business Media, LLC.

Kotton C.N.,Massachusetts General Hospital
Nature Reviews Nephrology | Year: 2014

Many transplant recipients are not protected against vaccine-preventable illnesses, primarily because vaccination is still an underutilized tool both before and after transplantation. This missed opportunity for protection can result in substantial morbidity, graft loss and mortality. Immunization strategies should be formulated early in the course of renal disease to maximize the likelihood of vaccine-induced immunity, particularly as booster or secondary antibody responses are less affected by immune compromise than are primary or de novo antibody responses in naive vaccine recipients. However, live vaccines should be avoided in immunocompromised hosts. Although some concern has been raised regarding increased HLA sensitization after vaccination, no clinical data to suggest harm currently exists; overall, non-live vaccines seem to be immunogenic, protective and safe. In organ transplant recipients, some vaccines are indicated based on specific risk factors and certain vaccines, such as hepatitis B, can protect against donor-derived infection. Vaccines given to close contacts of renal transplant recipients can provide an additional layer of protection against infectious diseases. In this article, optimal vaccination of adult transplant recipients, including safety, efficacy, indication and timing, is reviewed. © 2014 Macmillan Publishers Limited. All rights reserved.

Hoggatt J.,Massachusetts General Hospital | Pelus L.M.,Indiana University
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Granulocyte colony-stimulating factor (G-CSF; filgrastim) and its pegylated form (pegfilgrastim) are widely used to treat neutropenia associated with myelosuppressive chemotherapy and bone marrow transplantation, AIDS-associated or drug-induced neutropenia, and neutropenic diseases. G-CSF facilitates restoration of neutrophil counts, decreases incidence of infection/febrile neutropenia and reduces resource utilization. G-CSF is also widely used to mobilize peripheral blood stem cells for hematopoietic transplant. Areas covered: We review the therapeutic use, cost effectiveness and disease impact of G-CSF for neutropenia, development of G-CSF biosimilars and current next-generation discovery efforts. Expert opinion: G-CSF has impacted the treatment and survival of patients with congenital neutropenias. For chemotherapy-associated neutropenia, cost effectiveness and impact on survival are still unclear. G-CSFs are expensive and require systemic administration. Market entry of new biosimilars, some with enhanced half-life profiles, will probably reduce cost and increase cost effectiveness. There is no evidence that marketed or late development biosimilars display effectiveness superior to current G-CSFs. Second-generation compounds that mimic the activity of G-CSF at its receptor, induce endogenous ligand(s) or offer adjunct activity have been reported and represent attractive G-CSF alternatives, but are in preclinical stages. A significant therapeutic advance will require reduced depth and duration of neutropenia compared to current G-CSFs. © 2014 Informa UK, Ltd.

Lui R.,Massachusetts General Hospital
Clinical Obstetrics and Gynecology | Year: 2013

Testing for human papilloma virus (HPV) has been shown to be more sensitive than cervical cytology in detecting both high-grade and low-grade dysplasia. When screening for cervical cancer, unfortunately, the HPV test lacks specificity and has limited its usefulness as a primary screening modality for cervical cancer. In this chapter, we will review HPV and its role in cervical cancer, the utilization of HPV testing in current practice, and the possible future utilization of HPV and its role in screening.

Salama A.K.S.,Duke University | Flaherty K.T.,Massachusetts General Hospital
Clinical Cancer Research | Year: 2013

Selective BRAF inhibitors have now been established as a standard of care option for patients diagnosed with metastatic melanoma whose tumors carry a BRAF mutation. Their successful development represents a milestone in the treatment of this disease, and has the potential to impact therapy for other malignancies as well. The use of these agents, however, has introduced a number of critical questions about the optimal use and selection of patients for BRAF inhibitor therapy. This review discusses the current status of BRAF inhibitor clinical development, the clinicopathologic features of BRAF-mutated melanoma, as well as strategies for overcoming resistance. © 2013 American Association for Cancer Research.

Bruijn L.,ALS Association | Cudkowicz M.,Massachusetts General Hospital
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration | Year: 2014

In May 2013, The ALS Association and The Northeast ALS Consortium (NEALS) convened a meeting of stakeholders for a round-table discussion of ways to improve therapy development in ALS. The following overview summarizes issues raised and potential new directions discussed at the meeting. We recommend that future phase II clinical trials in ALS proceed when the proposed treatment is directed at targets that are likely to be involved in ALS pathogenesis in a defined subgroup of patients, and be accompanied by one or more biomarkers to track both clinical progression and pharmacodynamic engagement of the target. Innovations in trial structure and design, and greater involvement of patient advocates, may also improve trials. © 2014 Informa Healthcare.

Halpern E.F.,Massachusetts General Hospital
Radiology | Year: 2014

Inverse probability weighting is a propensity score-based technique that can be used to compensate for imbalance in study groups. It is an alternative to regression-based adjustment of the outcomes. It has advantages over matching of cases on the basis of propensity scores when there are more than two groups to compare, when finding matches results in insufficient sample sizes, or when the data are censored. However, it can create artificial imbalance unless it is applied carefully. In this article, an introduction to inverse probability weighting is provided by using the Yang et al study published in this issue of Radiology as an example. © 2014 RSNA.

Orkin S.H.,Howard Hughes Medical Institute | Orkin S.H.,Dana-Farber Cancer Institute | Orkin S.H.,Harvard Stem Cell Institute | Hochedlinger K.,Howard Hughes Medical Institute | And 3 more authors.
Cell | Year: 2011

The pluripotent state of embryonic stem cells (ESCs) provides a unique perspective on regulatory programs that govern self-renewal and differentiation and somatic cell reprogramming. Here, we review the highly connected protein and transcriptional networks that maintain pluripotency and how they are intertwined with factors that affect chromatin structure and function. The complex interrelationships between pluripotency and chromatin factors are illustrated by X chromosome inactivation, regulatory control by noncoding RNAs, and environmental influences on cell states. Manipulation of cell state through the process of transdifferentiation suggests that environmental cues may direct transcriptional programs as cells enter a transiently "plastic" state during reprogramming. © 2011 Elsevier Inc. All Rights Reserved.

Geyer J.T.,New York Medical College | Deshpande V.,Massachusetts General Hospital
Current Opinion in Rheumatology | Year: 2011

Purpose of review: An enlarged salivary gland or lacrimal gland raises a wide differential diagnosis that includes both benign inflammatory conditions and malignant disorders. This review aims to address the numerous controversies that have arisen regarding inflammatory diseases of the salivary gland over the past two centuries and more specifically address the relevance of IgG4 in this setting. Recent findings: A significant percentage of cases previously classified as Mikulicz disease, Küttner tumor, and orbital pseudotumor (idiopathic orbital inflammation) show elevated numbers of IgG4-positive plasma cells, and some of these cases also show elevated levels of serum IgG4. These data support the evolving concept of IgG4-associated sialadenitis/dacroadenitis. The disease presents with enlargement of one of more salivary gland(s) and/or lacrimal gland(s). Histologically this disease is characterized by a dense polyclonal lymphoplasmacytic infiltrate, and is frequently associated with germinal centers, fibrosis and obliterative phlebitis. IgG4-bearing plasma cells are virtually always present, as is an elevated ratio of IgG4 to IgG containing plasma cells. Summary: IgG4-related sialadenitis belongs to the IgG4-related systemic disease spectrum and shows a swift response to immunosuppression. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Jacoby G.A.,Lahey Clinic | Hooper D.C.,Massachusetts General Hospital
Antimicrobial Agents and Chemotherapy | Year: 2013

qnr genes were discovered on plasmids by their ability to reduce quinolone susceptibility, but homologs can be found in the genomes of at least 92 Gram-negative, Gram-positive, and strictly anaerobic bacterial species. The related pentapeptide repeat protein-encoding mfpA gene is present in the genome of at least 19 species of Mycobacterium and 10 other Actinobacteria species. The native function of these genes is not yet known. Copyright © 2013, American Society for Microbiology. All Rights Reserved.

Kuter D.J.,Harvard University | Kuter D.J.,Massachusetts General Hospital
International Journal of Hematology | Year: 2013

Thrombopoietin (TPO) is the major physiological regulator of platelet production. TPO binds the TPO receptor, activates JAK and STAT pathways, thus stimulating megakaryocyte growth and platelet production. There is no "sensor" of the platelet count; rather TPO is produced in the liver at a constant rate and cleared by TPO receptors on platelets. TPO levels are inversely proportional to the rate of platelet production. Early recombinant TPO molecules were potent stimulators of platelet production and increased platelets in patients with immune thrombocytopenia, chemotherapy-induced thrombocytopenia, myelodysplastic syndromes and platelet apheresis donors. Neutralizing antibodies formed against one recombinant protein and ended their development. A second generation of TPO receptor agonists, romiplostim and eltrombopag, has been developed. Romiplostim is an IgG heavy chain into which four TPO agonist peptides have been inserted. Eltrombopag is an oral small molecule. These activate the TPO receptor by different mechanisms to increase megakaryocyte growth and platelet production. After administration of either to healthy volunteers, there is a delay of 5 days before the platelet count rises and subsequently reaches a peak after 12-14 days. Both have been highly effective in treating ITP and hepatitis C thrombocytopenia. Studies in a wide variety of other thrombocytopenic conditions are underway. © 2013 The Japanese Society of Hematology.

Ballen K.K.,Massachusetts General Hospital
Blood | Year: 2014

In this issue of Blood, Lindemans et al report on the impact of thymoglobulin (antithymocyte globulin [ATG]) during the preparative regimen for pediatric unrelated umbilical cord blood transplantation (UCBT). Survival and chronic graft-versus-host disease (GVHD) were similar whether or not patients received ATG. The patients who did not receive ATG had a lower rate of