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The University of California, San Francisco , is a center of health science research, patient care, and education; located in San Francisco, California, and is widely regarded as one of the world's leading universities in health science.Though one of the 10 campuses of the University of California, it is the only University of California campus dedicated solely to graduate education, and in health and biomedical science. Some of UCSF's treatment centers include kidney transplants and liver transplantation, radiology, neurosurgery, neurology, oncology, ophthalmology, gene therapy, women's health, fetal surgery, pediatrics, and internal medicine. With a work force of 22,800 people and annual economic impact of $2 billion, UCSF is San Francisco's second largest employer.Founded in 1873, the mission of UCSF is to serve as a "public university dedicated to saving lives and improving health." The UCSF Medical Center is consistently ranked among the top 10 hospitals in the United States by U.S. News & World Report, who also ranked UCSF's medical school as one of the top 10 in a number of specialties, including a specialty program in AIDS medical care ranked first in the country. Wikipedia.


Lee S.,University of California at San Francisco
Cancer causes & control : CCC | Year: 2012

To understand transnational tobacco companies' (TTCs) practices in low and middle-income countries which serve to block tobacco-control policies and promote tobacco use. Systematic review of published research on tobacco industry activities to promote tobacco use and oppose tobacco-control policies in low and middle-income countries. TTCs' strategies used in low and middle-income countries followed four main themes-economic activity; marketing/promotion; political activity; and deceptive/manipulative activity. Economic activity, including foreign investment and smuggling, was used to enter new markets. Political activities included lobbying, offering voluntary self-regulatory codes, and mounting corporate social responsibility campaigns. Deceptive activities included manipulation of science and use of third-party allies to oppose smoke-free policies, delay other tobacco-control policies, and maintain support of policymakers and the public for a pro-tobacco industry policy environment. TTCs used tactics for marketing, advertising, and promoting their brands that were tailored to specific market environments. These activities included direct and indirect tactis, targeting particular populations, and introducing new tobacco products designed to limit marketing restrictions and taxes, maintain the social acceptability of tobacco use, and counter tobacco-control efforts. TTCs have used similar strategies in high-income countries as these being described in low and middle-income countries. As required by FCTC Article 5.3, to counter tobacco industry pressures and to implement effective tobacco-control policies, governments and health professionals in low and middle-income countries should fully understand TTCs practices and counter them.


Julius D.,University of California at San Francisco | Nathans J.,Johns Hopkins Hospital
Cold Spring Harbor Perspectives in Biology | Year: 2012

Sensory systems detect small molecules, mechanical perturbations, or radiation via the activation of receptor proteins and downstream signaling cascades in specialized sensory cells. In vertebrates, the two principal categories of sensory receptors are ion channels, which mediate mechanosensation, thermosensation, and acid and salt taste; and G-protein-coupled receptors (GPCRs), which mediate vision, olfaction, and sweet, bitter, and umami tastes. GPCRbased signaling in rods and cones illustrates the fundamental principles of rapid activation and inactivation, signal amplification, and gain control. Channel-based sensory systems illustrate the integration of diverse modulatory signals at the receptor, as seen in the thermosensory/ pain system, and the rapid response kinetics that are possible with direct mechanical gating of a channel. Comparisons of sensory receptor gene sequences reveal numerous examples in which gene duplication and sequence divergence have created novel sensory specificities. This is the evolutionary basis for the observed diversity in temperature- and liganddependent gating among thermosensory channels, spectral tuning among visual pigments, and odorant binding among olfactory receptors. The coding of complex external stimuli by a limited number of sensory receptor types has led to the evolution of modality-specific and species-specific patterns of retention or loss of sensory information, a filtering operation that selectively emphasizes features in the stimulus that enhance survival in a particular ecological niche. The many specialized anatomic structures, such as the eye and ear, that house primary sensory neurons further enhance the detection of relevant stimuli. © 2011 Cold Spring Harbor Laboratory Press.


Wynshaw-Boris A.,University of California at San Francisco
Current Topics in Developmental Biology | Year: 2012

Dishevelled proteins are highly conserved throughout evolution and participate in canonical and noncanonical Wnt pathways. In particular, Dvls participate in the planar cell polarity (PCP) pathway that is important for a variety of developmental processes. There are three Dvl genes in mammals. These three genes are highly conserved and broadly expressed throughout development and in the adult. Studies of mice with disruption of a single Dvl gene have revealed phenotypes that range from defective social behavior to developmental defects that include abnormal heart, skeletal, and cochlear morphogenesis, suggesting that each of the Dvl genes had unique functions. However, analysis of double or triple Dvl knock-outs revealed novel phenotypes or more severe phenotypes displayed by single knock-outs suggesting overlapping or redundant functions of these Dvl genes. Most if not all of the phenotypes displayed by the Dvl mutants appear to be the result of PCP pathway functions, not of the canonical Wnt pathway. This suggests that the PCP pathway is sensitive to reduction of Dvls, but only one Dvl allele of six may be required for Wnt pathway. © 2012 Elsevier Inc.


The response of cone photoreceptors to light is stable and reproducible because of the exceptional regulation of the cascade of enzymatic reactions that link visual pigment (VP) excitation to the gating of cyclic GMP (cGMP)-gated ion channels (cyclic nucleotide-gated [CNG]) in the outer segment plasma membrane. Regulation is achieved in part through negative feedback control of some of these reactions by cytoplasmic free Ca 2+. As part of the control process, Ca 2+ regulates the phosphorylation of excited VP, the activity of guanylate cyclase, and the ligand sensitivity of the CNG ion channels. We measured photocurrents elicited by stimuli in the form of flashes, steps, and flashes superimposed on steps in voltage-clamped single bass cones isolated from striped bass retina. We also developed a computational model that comprises all the known molecular events of cone phototransduction, including all Ca-dependent controls. Constrained by available experimental data in bass cones and cone transduction biochemistry, we achieved an excellent match between experimental photocurrents and those simulated by the model. We used the model to explore the physiological role of CNG ion channel modulation. Control of CNG channel activity by both cGMP and Ca 2+ causes the time course of the light-dependent currents to be faster than if only cGMP controlled their activity. Channel modulation also plays a critical role in the regulation of the light sensitivity and light adaptation of the cone photoresponse. In the absence of ion channel modulation, cone photocurrents would be unstable, oscillating during and at the offset of light stimuli. © 2011 Korenbrot.


Valcour V.G.,University of California at San Francisco
Topics in Antiviral Medicine | Year: 2013

The prevalence of HIV-associated neurocognitive disorder has not changed from the pre- to the potent antiretroviral therapy era, remaining at approximately 50%. In research settings, mild neurocognitive disorder (MND) and so-called asymptomatic neurocognitive impairment (ANI) are now more common than HIV-associated dementia. The diagnosis of ANI is misleading because functional deficits, when tested in a laboratory, and degree of neuropsychologic testing abnormalities are often comparable in patients with ANI and those with symptomatic MND. Age-related comorbidities increase the risk of cognitive impairment in HIV infection. In a cohort of patients aged 60 years or older with excellent antiretroviral therapy adherence, correlates to cognitive impairment were apolipoprotein (Apo) E4 genotype and a novel measure of the effectiveness of antiretroviral drugs in monocytes, the monocyte efficacy (ME) score, with trend associations for diabetes and nadir CD4+ cell count. Management of impairment includes ensuring that patients are on and adhere to antiretroviral therapy and addressing comorbidities. Switching from effective and well-tolerated antiretroviral therapy for patients with mild cognitive impairment is not routinely recommended, but this must still be addressed on a case-by-case basis. © 2013, IAS-USA.


Hoffman J.I.E.,University of California at San Francisco
Cardiovascular Journal of Africa | Year: 2013

Although the incidence of congenital heart disease (CHD) is similar worldwide, the burden of supporting these patients falls more heavily on countries with high fertility rates. In a country with a fertility rate of about eight per woman, the population has to support four times as many children with CHD as in a country with a fertility rate of two. Countries with the highest fertility rates tend to have the lowest incomes per capita, thus accentuating the disparity. Countries with high fertility rates have more children with congenital heart disease per wage earner. Improving local health services and controlling infectious diseases (diarrhoeal illness, rheumatic fever, measles, rotoviral infection) are important but are mere 'band-aids' compared to improving education, empowering women and reducing birth rates.


Jones K.D.,University of California at San Francisco
Archives of Pathology and Laboratory Medicine | Year: 2013

The term lepidic is used prominently in the recently published multidisciplinary classification of adenocarcinoma. The lack of use in common (nonmedical) English has led to some confusion over the proper definition of this term. This historical perspective traces the history of the term lepidic from its origins at McGill University in Montreal, Canada, through its uses in English pathologic descriptions, to its current state in pulmonary pathology.


Helbig I.,University of Kiel | Lowenstein D.H.,University of California at San Francisco
Current Opinion in Neurology | Year: 2013

Purpose of Review: We aim to review the most recent advances in the field of epilepsy genetics with particular focus on the progress in gene discovery in monogenic epilepsies, identification of risk genes in complex genetic epilepsies and recent findings in the field of epilepsy pharmacogenomics. Purpose of Review: During the last 12 months, the use of massive parallel sequencing technologies has allowed for the discovery of several genes for monogenic epilepsies. Most importantly, PRRT2 was identified as the long-sought gene for benign familial infantile seizures. Mutations in KCNT1 were found in two seemingly unrelated monogenic epilepsies including malignant migrating partial seizures of infancy and severe autosomal dominant nocturnal frontal lobe epilepsy. A genome-wide association study in idiopathic generalized epilepsy revealed the first common risk variants for human seizure disorders including variants in VRK2, PNPO and SCN1A. Furthermore, a landmark study provided evidence that screening for the HLA-B1502 variant may prevent carbamazepine CBZ-induced side effects in the Taiwanese population. Also, HLA-A3101 variants were identified as a risk factor for carbamazepine side effects in Europeans. Summary: Novel technologies and an unprecedented level of international collaboration have resulted in identification of novel genes for monogenic and complex genetic epilepsies as well as risk factors for side effects of antiepileptic drugs. This review provides an overview of the most relevant studies in the last year and highlights the future direction of the field. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Owens C.D.,University of California at San Francisco
Journal of Vascular Surgery | Year: 2010

For patients with the most severe manifestations of lower extremity arterial occlusive disease, bypass surgery using autogenous vein has been the most durable reconstruction. However, the incidence of bypass graft stenosis and graft failure remains substantial and wholesale improvements in patency are lacking. One potential explanation is that stenosis arises not only from over exuberant intimal hyperplasia, but also due to insufficient adaptation or remodeling of the vein to the arterial environment. Although in vivo human studies are difficult to conduct, recent advances in imaging technology have made possible a more comprehensive structural examination of vein bypass maturation. This review summarizes recent translational efforts to understand the structural and functional properties of human vein grafts and places it within the context of the rich existing literature of vein graft failure. © 2010 Society for Vascular Surgery.


Grinberg L.T.,University of California at San Francisco | Grinberg L.T.,University of Sao Paulo
Acta Neuropathologica | Year: 2010

Cerebral atherosclerosis (AS), small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) are the most prevalent arterial disorders in the aged brain. Pathogenetically, AS and SVD share similar mechanisms: plasma protein leakage into the vessel wall, accumulation of lipid-containing macrophages, and fibrosis of the vessel wall. CAA, on the other hand, is characterized by the deposition of the amyloid β-protein in the vessel wall. Despite these differences between CAA, AS and SVD, apolipoprotein E (apoE) is involved in all three disorders. Such a pathogenetic link may explain the correlations between AS, SVD, CAA, and Alzheimer's disease in the brains of elderly individuals reported in the literature. In addition, AS, SVD, and CAA can lead to tissue lesions such as hemorrhage and infarction. Moreover, intracerebral SVD leads to plasma protein leakage into the damaged vessel wall and into the perivascular space resulting in a blood-brain barrier (BBB) dysfunction. This SVD-related BBB dysfunction is considered to cause white matter lesions (WMLs) and lacunar infarcts. In this review, we demonstrate the relationship between AS, SVD, and CAA as well as their contribution to the development of vascular tissue lesions and we emphasize an important role for apoE in the pathogenesis of vessel disorders and vascular tissue lesions as well as for BBB dysfunction on WML and lacunar infarct development. © The Author(s) 2010.


Roberts J.P.,University of California at San Francisco
Liver Transplantation | Year: 2012

Key Points 1. The reporting of liver transplant center outcomes is required by the final rule of the Department of Health and Human Services. The reported patient and graft survival outcomes are risk-adjusted for specific donor and recipient factors, and the observed survival is compared to the expected survival. Both the Centers for Medicare and Medicaid Services and the Organ Procurement and Transplantation Network flag programs for corrective action when the observed survival is significantly less than the expected survival. Both agencies can take action up to the closure of a center. In the last 5 years, the Organ Procurement and Transplantation Network has not taken an adverse action that required the closure of a liver transplant center because of outcomes. 2. Center survey data suggest that centers may try to select donors and recipients to minimize poor outcomes. This strategy may not be effective if centers stop accepting donors or recipients according to factors that are included in the risk adjustment model. For example, limiting recipients to those less than 65 years old may improve the observed outcomes, but the expected outcomes will also improve because a recipient 65 years or older is included in the model's risk adjustment. 3. For factors such as cardiovascular risk that are not included in the model, it may be reasonable to exclude patients in an attempt to improve the observed outcomes without affecting the expected outcomes. Other examples of these types of factors are smoking, nutritional status, and donor liver biopsy findings. 4. Currently, there is no exemption for patients undergoing experimental protocols. Down-staging for hepatocellular carcinoma, transplantation for human immunodeficiency virus-positive recipients, and the use of left lobe grafts with inflow modification are relatively recent areas of innovation in liver transplantation. Because innovation is frequently associated with a learning curve and, therefore, poor outcomes, the inclusion of patients in innovative protocols potentially could lead to centers being subjected to an adverse action by the Organ Procurement and Transplantation Network or the Centers for Medicare and Medicaid Services. Active consideration is being given to the exclusion of patients in innovative protocols from center-specific outcomes. © 2012 AASLD.


El-Sayed I.H.,University of California at San Francisco
Current Oncology Reports | Year: 2010

Rapid advances in the ability to produce nanoparticles of uniform size, shape, and composition have started a revolution in the sciences. Nano-sized structures herald innovative technology with a wide range of potential therapeutic and diagnostic applications. More than 1000 nanostructures have been reported, many with potential medical applications, such as metallic-, dielectric-, magnetic-, liposomal-, and carbon-based structures. Of these, noble metallic nanoparticles are generating significant interest because of their multifunctional capacity for novel methods of laboratory-based diagnostics, in vivo clinical diagnostic imaging, and therapeutic treatments. This review focuses on recent advances in the applications of nanotechnology in head and neck cancer, with special emphasis on the particularly promising plasmonic gold nanotechnology. © 2010 The Author(s).


Baron R.B.,University of California at San Francisco
Academic Medicine | Year: 2013

Calls for greater public accountability for graduate medical education (GME) outcomes continue to come from a broad array of stakeholders. Creation of ways to measure accountability requires a clear understanding of the domains of GME outcomes and the creation of specific measures that are reliable and accurate and do not create an undue measurement burden. Three domains of outcomes are necessary: individual trainee competence, the quality and diversity of the training environment, and workforce factors that address workforce size, specialty mix, diversity, and geographic distribution. The Accreditation Council for Graduate Medical Education has begun to develop measures that have the potential to form the basis of the first two domains, and other data sources exist to measure the quality of the training environment. Little progress, however, has been made to accurately describe institution-specific workforce outcomes. The article by Chen and colleagues in this issue makes a major contribution in the measurement of institution-specific outcomes. Their article creates optimism that a system that incentivizes and rewards specific desirable GME outcomes can be designed. This commentary further defines some practical next steps to achieve this desired GME accountability.


Heart rate is an important contributor in the pathophysiology of both coronary artery disease (CAD) and heart failure (HF). Ivabradine is an anti-anginal and anti-ischaemic agent, which selectively and specifically inhibits the If current in the sino-atrial node and provides pure heart rate reduction without altering other cardiac parameters, including conduction, and without directly affecting other haemodynamic parameters. It is approved for the treatment of CAD and HF. This article summarises the pharmacological properties, pharmacokinetics, clinical efficacy and tolerability of ivabradine in the treatment of CAD and HF, and presents evidence demonstrating that the pharmacological and clinical properties and clinical efficacy of ivabradine make it an important therapeutic choice for patients with stable CAD or HF. The positive effect of ivabradine on angina pectoris symptoms and its ability to reduce myocardial ischemia make it an important agent in the management of patients with stable CAD or chronic HF. Further studies are underway to add to the already robust evidence of ivabradine for the prevention of cardiovascular events in patients with CAD but without clinical HF. The SIGNIFY (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) trial includes patients with stable CAD and an LVEF above 40 %, with no clinical sign of HF, and is investigating the long-term effects (over a period of 48 months) of ivabradine in a large study population. So far, this study has included more than 19,000 patients from 51 countries.


Shiloh M.U.,University of California at San Francisco | DiGiuseppe Champion P.A.,University of Notre Dame
Current Opinion in Microbiology | Year: 2010

Mycobacterium tuberculosis is the causative agent of the global tuberculosis epidemic. To combat this successful human pathogen we need a better understanding of the basic biology of mycobacterial pathogenesis. The use of mycobacterial model systems has the potential to greatly facilitate our understanding of how M. tuberculosis causes disease. Recently, studies using mycobacterial models, including M. bovis BCG, M. marinum, and M. smegmatis have significantly contributed to understanding M. tuberculosis. Specifically, there have been advances in genetic manipulation of M. tuberculosis using inducible promoters and recombineering that alleviate technical limitations in working with mycobacteria. Model systems have helped elucidate how secretion systems function at both the molecular level and during virulence. Mycobacterial models have also led to interesting hypotheses about how M. tuberculosis mediates latent infection and host response. While there is utility in using model systems to understand tuberculosis, each of these models represent distinct mycobacterial species with unique environmental adaptations. Directly comparing findings in model mycobacteria to those in M. tuberculosis will illuminate the similarities and differences between these species and increase our understanding of why M. tuberculosis is such a potent human pathogen. © 2009 Elsevier Ltd. All rights reserved.


Hauser S.L.,University of California at San Francisco
Multiple Sclerosis Journal | Year: 2015

Autoimmune B cells play a major role in mediating tissue damage in multiple sclerosis (MS). In MS, B cells are believed to cross the blood-brain barrier and undergo stimulation, antigen-driven affinity maturation and clonal expansion within the supportive CNS environment. These highly restricted populations of clonally expanded B cells and plasma cells can be detected in MS lesions, in cerebrospinal fluid, and also in peripheral blood.In phase II trials in relapsing MS, monoclonal antibodies that target circulating CD20-positive B lymphocytes dramatically reduced disease activity. These beneficial effects occurred within weeks of treatment, indicating that a direct effect on B cells - and likely not on putative autoantibodies - was responsible. The discovery that depletion of B cells has an impact on MS biology enabled a paradigm shift in understanding how the inflammatory phase of MS develops, and will hopefully lead to development of increasingly selective therapies against culprit B cells and related humoral immune system pathways.More broadly, these studies illustrate how lessons learned from the bedside have unique power to inform translational research. They highlight the essential role of clinician scientists, currently endangered, who navigate the rocky and often unpredictable terrain between the worlds of clinical medicine and biomedical research. © The Author(s), 2015.


Kaye H.S.,University of California at San Francisco
Health Affairs | Year: 2012

States are shifting Medicaid spending on long-term services and supports from institutional to home and community-based services, a process known as rebalancing. Using fifteen years of state expenditure data, a statistical model was developed to assess the effect of rebalancing on overall spending for long-term services and supports. The model indicates that spending is affected by the way rebalancing is implemented: Gradual rebalancing, by roughly two percentage points annually, can reduce spending by about 15 percent over ten years. More rapid rebalancing can save money, break even, or increase spending, depending on the pace and program specifics. Cuts to home and community-based services that hinder rebalancing are likely to increase, not decrease, overall spending on long-term services and supports as people who were receiving these services shift into nursing homes. Because many states continue to experience budget crises, policy makers must think carefully before altering spending patterns for long-term services and supports and adopt strategies that particular states have used to successfully reduce overall spending, such as gradually shifting expenditures toward home and community-based waiver programs. © 2012 by Project HOPE The People-to-People Health Foundation, Inc.


Kevany S.,University of California at San Francisco
Global Public Health | Year: 2014

Both the theory and practice of foreign policy and diplomacy, including systems of hard and soft power, are undergoing paradigm shifts, with an increasing number of innovative actors and strategies contributing to international relations outcomes in the 'New World Order'. Concurrently, global health programmes continue to ascend the political spectrum in scale, scope and influence. This concatenation of circumstances has demanded a re-examination of the existing and potential effectiveness of global health programmes in the 'smart power' context, based on adherence to a range of design, implementation and assessment criteria, which may simultaneously optimise their humanitarian, foreign policy and diplomatic effectiveness. A synthesis of contemporary characteristics of 'global health diplomacy' and 'global health as foreign policy', grouped by common themes and generated in the context of related field experiences, are presented in the form of 'Top Ten' criteria lists for optimising both diplomatic and foreign policy effectiveness of global health programmes, and criteria are presented in concert with an examination of implications for programme design and delivery. Key criteria for global health programmes that are sensitised to both diplomatic and foreign policy goals include visibility, sustainability, geostrategic considerations, accountability, effectiveness and alignment with broader policy objectives. Though diplomacy is a component of foreign policy, criteria for 'diplomatically-sensitised' versus 'foreign policy-sensitised' global health programmes were not always consistent, and were occasionally in conflict, with each other. The desirability of making diplomatic and foreign policy criteria explicit, rather than implicit, in the context of global health programme design, delivery and evaluation are reflected in the identified implications for (1) international security, (2) programme evaluation, (3) funding and resource allocation decisions, (4) approval systems and (5) training. On this basis, global health programmes are shown to provide a valuable, yet underutilised, tool for diplomacy and foreign policy purposes, including their role in the pursuit of benign international influence. A corresponding alignment of resources between 'hard' and 'smart' power options is encouraged. © 2014 © 2014 Taylor & Francis.


Wu A.H.,University of California at San Francisco
The American journal of managed care | Year: 2010

To provide evidence supporting the discontinuation of laboratory tests that do not have clinical utility today. We selected 10 representative tests considered antiquated by most experts in the clinical laboratory medicine field: creatine kinase-MB, myoglobin, serum folate and red blood cell folate, amylase, lecithin/sphingomyelin ratio, qualitative serum human chorionic gonadotropin, prostatic acid phosphatase, bleeding time, and erythrocyte sedimentation rate. Published literature was reviewed to provide evidence of the poor performance and/or limited clinical utility of these tests. When available, subscriptions to the Proficiency Testing Program of the College of American Pathologists were tracked from 1993 to 2008 as supporting evidence. Finally, when appropriate, alternative testing was suggested. The data show clearly that there is a national trend toward reduction or elimination of these 10 tests. Together with their clinical colleagues, clinical laboratorians should review their menu of tests and consider removing tests that do not provide clinical benefit. In most cases, alternative tests are already in clinical use.


Elias P.M.,University of California at San Francisco
Seminars in cutaneous medicine and surgery | Year: 2013

The healthy stratum corneum allows optimum permeability of water and provides the first line of defense against pathogenic and environmental assaults. The barrier functions of the stratum corneum are interrelated, coregulated, and interdependent. Research has demonstrated that three lipid species, which usually comprise 10% of the stratum corneum, are crucial to both its structure and its function; these must be present in sufficient quantities and in the correct proportions to provide optimum barrier function. The clinical implications of how the skin barrier works--and is supported and restored--can be seen in the current and emerging understanding of atopic dermatitis management.


Devireddy L.R.,Case Western Reserve University | Hart D.O.,Howard Hughes Medical Institute | Goetz D.H.,University of California at San Francisco | Green M.R.,Howard Hughes Medical Institute
Cell | Year: 2010

Intracellular iron homeostasis is critical for survival and proliferation. Lipocalin 24p3 is an iron-trafficking protein that binds iron through association with a bacterial siderophore, such as enterobactin, or a postulated mammalian siderophore. Here, we show that the iron-binding moiety of the 24p3-associated mammalian siderophore is 2,5-dihydroxybenzoic acid (2,5-DHBA), which is similar to 2,3-DHBA, the iron-binding component of enterobactin. We find that the murine enzyme responsible for 2,5-DHBA synthesis, BDH2, is the homolog of bacterial EntA, which catalyzes 2,3-DHBA production during enterobactin biosynthesis. RNA interference-mediated knockdown of BDH2 results in siderophore depletion. Mammalian cells lacking the siderophore accumulate abnormally high amounts of cytoplasmic iron, resulting in elevated levels of reactive oxygen species, whereas the mitochondria are iron deficient. Siderophore-depleted mammalian cells and zebrafish embryos fail to synthesize heme, an iron-dependent mitochondrial process. Our results reveal features of intracellular iron homeostasis that are conserved from bacteria through humans. © 2010 Elsevier Inc.


Miller R.H.,University of California at San Francisco
Health Affairs | Year: 2012

In June 2010 sixteen organizations representing California patients and consumers adopted nine principles for electronically exchanging health information among and within provider organizations. The principles were formulated with the goal of improving patient and population health care by increasing the availability and use of patient data while protecting patients' privacy. This study assesses to what extent five health care organizations-all in different stages of increasing their capacity for health information exchange-conformed to the principles in early 2011. Although an increasing amount of electronic data has been exchanged among organizations and with patients, progress has been modest, and patients still have little control over their data. For organizations to comply with all nine patient and consumer principles, clear "rules of the road" for information sharing must be defined, and patient education in health information exchange and control over personal data must be increased. © 2012 Project HOPE-The People-to-People Health Foundation, Inc.


Loh M.L.,University of California at San Francisco
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Expansion of myeloid blasts with suppression of normal hematopoiesis is a hallmark of acute myeloid leukemia (AML). In contrast, myeloproliferative neoplasms (MPNs) are clonal disorders characterized by overproliferation of one or more lineages that retain the ability to differentiate. Juvenile myelomonocytic leukemia (JMML) is an aggressive MPN of childhood that is clinically characterized by the overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. Major progress in understanding the pathogenesis of JMML has been achieved by mapping out the genetic lesions that occur in patients. The spectrum of mutations described thus far in JMML occur in genes that encode proteins that signal through the Ras/mitogen-activated protein kinase (MAPK) pathways, thus providing potential new opportunities for both diagnosis and therapy. These genes include NF1, NRAS, KRAS, PTPN11, and, most recently, CBL. While the current standard of care for patients with JMML relies on allogeneic hematopoietic stem-cell transplant, relapse is the most frequent cause of treatment failure. Rarely, spontaneous resolution of this disorder can occur but is unpredictable. This review is focused on the genetic abnormalities that occur in JMML, with particular attention to germ-line predisposition syndromes associated with the disorder. Current approaches to therapy are also discussed.


Holtzman D.J.,University of California at San Francisco
Journal of magnetic resonance imaging : JMRI | Year: 2010

To examine T(1ρ) (T1rho) and T(2) quantitative magnetic resonance imaging (MRI) in evaluating cartilage regeneration following microfracture (MFx) and mosaicplasty (MOS) cartilage resurfacing procedures. Eighteen patients underwent MFx and eight patients underwent MOS to treat symptomatic focal cartilage defects. Quantitative T(1ρ) and T(2) maps were acquired at 3-6 months and 1 year after surgery. The area of resurfacing was identified, and T(1ρ) and T(2) values for the regenerated tissue (RT) and normal cartilage (NC) were acquired. RT/NC ratios were calculated to standardize absolute T(1ρ) and T(2) values. Data were prospective, cross-sectional, and nonrandomized. T(1ρ) and T(2) showed good reanalysis reproducibility for RT and NC. Significant differences between RT and NC were present following MFx at 3-6 months for T(1ρ) and T(2) values as well as following MOS at 3-6 months and 1 year for T(1ρ) values. Following MFx, the T(2) RT/NC ratio was significantly different between 3-6 months and 1 year (P = 0.02), while the T(1ρ) RT/NC ratio approached significance (P = 0.07). Following MOS, the T(1ρ) and T(2) RT/NC ratios were not significantly different between the two timepoints. T(1ρ) and T(2) MRI are complementary and reproducible methods for quantitatively and noninvasively monitoring regeneration of RT following MFx and MOS.


Harrington C.,University of California at San Francisco
International Journal of Health Services | Year: 2011

This study examined the ownership, financing, and management strategies of the 10 largest for-profit nursing home chains in the United States, including the four largest chains purchased by private equity corporations. Descriptive data were collected from Internet searches, company reports, and other sources for the decade 1998-2008. Since 1998, the largest chains have made many changes in their ownership and structure, and some have converted from publicly traded companies to private ownership. This study shows the increasing complexity of corporate nursing home ownership and the lack of public information about ownership and financial status. The chains have used strategies to maximize shareholder and investor value that include increasing Medicare revenues, occupancy rates, and company diversification, establishing multiple layers of corporate ownership, developing real estate investment trusts, and creating limited liability companies. These strategies enhance shareholder and investor profits, reduce corporate taxes, and reduce liability risk. There is a need for greater transparency in ownership and financial reporting and for more government oversight of the largest for-profit chains, including those owned by private equity companies. © 2011, Baywood Publishing Co., Inc.


Conte M.S.,University of California at San Francisco
Journal of Vascular Surgery | Year: 2010

The Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial is the only randomized controlled trial (RCT) to date comparing open surgical bypass with endovascular therapy for severe limb ischemia (SLI). In their initial 2005 publication, the BASIL investigators reported that the main clinical outcomes (overall survival and amputation-free survival) were no different at 2 years after randomization to angioplasty-first or bypass-first revascularization strategies. However, beyond 2 years there appeared to be a benefit for open bypass surgery, providing impetus for an extension study. The final analysis of the long-term outcomes from BASIL is now presented in a set of articles that are reviewed in this commentary. The benefit of initial randomization to open surgery for patients surviving ≥2 years (70% of the BASIL cohort) was confirmed. When outcomes were analyzed by treatment received, patients who had received prosthetic bypass grafts (25% of the surgical arm) fared much more poorly than those treated with a vein bypass. Patients who underwent surgical bypass after an initial failed angioplasty also fared significantly worse than those who were treated initially with bypass surgery. Health-related quality of life measures and costs were not significantly different overall. There are many controversies surrounding the BASIL trial and its interpretation, which are reviewed herein. These include the choice of study population, end points examined, and the nature of procedures performed. The BASIL trial confirms the primacy of open surgical bypass with vein for most patients with SLI and raises questions about the sequelae of failed endovascular interventions. Further multicenter trials are needed to address the large gap in evidence for treatment selection in this patient population. © 2010 Society for Vascular Surgery.


Diaz A.,University of California at San Francisco
Statistical applications in genetics and molecular biology | Year: 2012

Next-generation sequencing is rapidly transforming our ability to profile the transcriptional, genetic, and epigenetic states of a cell. In particular, sequencing DNA from the immunoprecipitation of protein-DNA complexes (ChIP-seq) and methylated DNA (MeDIP-seq) can reveal the locations of protein binding sites and epigenetic modifications. These approaches contain numerous biases which may significantly influence the interpretation of the resulting data. Rigorous computational methods for detecting and removing such biases are still lacking. Also, multi-sample normalization still remains an important open problem. This theoretical paper systematically characterizes the biases and properties of ChIP-seq data by comparing 62 separate publicly available datasets, using rigorous statistical models and signal processing techniques. Statistical methods for separating ChIP-seq signal from background noise, as well as correcting enrichment test statistics for sequence-dependent and sonication biases, are presented. Our method effectively separates reads into signal and background components prior to normalization, improving the signal-to-noise ratio. Moreover, most peak callers currently use a generic null model which suffers from low specificity at the sensitivity level requisite for detecting subtle, but true, ChIP enrichment. The proposed method of determining a cell type-specific null model, which accounts for cell type-specific biases, is shown to be capable of achieving a lower false discovery rate at a given significance threshold than current methods.


Tompa P.,Vrije Universiteit Brussel | Tompa P.,Hungarian Academy of Sciences | Davey N.E.,University of California at San Francisco | Gibson T.J.,Structural and Computational Biology Unit | Babu M.M.,University of Cambridge
Molecular Cell | Year: 2014

A molecular description of functional modules in the cell is the focus of many high-throughput studies in the postgenomic era. A large portion of biomolecular interactions in virtually all cellular processes is mediated by compact interaction modules, referred to as peptide motifs. Such motifs are typically less than ten residues in length, occur within intrinsically disordered regions, and are recognized and/or posttranslationally modified by structured domains of the interacting partner. In this review, we suggest that there might be over a million instances of peptide motifs in the human proteome. While this staggering number suggests that peptide motifs are numerous and the most understudied functional module in the cell, it also holds great opportunities for new discoveries. © 2014 Elsevier Inc.


Watkins E.S.,University of California at San Francisco
American Journal of Public Health | Year: 2012

Marketing decisions, rather than scientific innovations, have guided the development and positioning of contraceptive products in recent years. I review the stalled progress in contraceptive development in the decades following the advent of the Pill in 1960 and then examine the fine-tuning of the market for oral contraceptives in the 1990s and 2000s. Although birth control has been pitched in the United States as an individual solution, rather than a public health strategy, the purpose of oral contraceptives was understood by manufacturers, physicians, and consumers to be the prevention of pregnancy, a basic health care need for women. Since 1990, the content of that message has changed, reflecting a shift in the drug industry's view of the contraception business. Two factors contributed to bring about this change: first, the industry's move away from research and development in birth control and second, the growth of the class of medications known as lifestyle drugs.


Hunt P.W.,University of California at San Francisco
Current HIV/AIDS Reports | Year: 2012

Persistent immune activation and inflammation despite sustained antiretroviral therapy (ART)-mediated viral suppression has emerged as a major challenge of the modern HIV treatment era. While immune activation, inflammatory, and coagulation markers typically decline during suppressive ART, they remain abnormally elevated in many HIV-infected individuals and predict subsequent mortality and non-AIDS morbidities including cardiovascular disease. The goal of this review is to summarize the current state of our knowledge regarding the underlying causes of persistent immune activation during ART-mediated viral suppression as well as the link between persistent immune activation and morbidity and mortality in this setting. Several recent studies have linked surrogate markers of this persistent inflammatory state to clinical outcomes, validating persistent immune activation as a viable therapeutic target. Other recent studies have helped clarify the roles of persistent HIV expression and/or replication, microbial trans-location, and co-infections in driving this persistent inflammatory state, identifying targets for novel interventions. © Springer Science+Business Media, LLC 2012.


Woodruff P.G.,University of California at San Francisco
Proceedings of the American Thoracic Society | Year: 2011

Biomarker development in chronic obstructive pulmonary disease (COPD) is a nascent field, in part because of the complexity underlying COPD pathogenesis. The objective of this review is to provide examples of how biomarkers may be effectively applied in clinical trials of COPD by limiting their use to specific contexts and using them to answer well delineated questions. Types of novel outcomes or "biomarkers" that may be useful in clinical trials in COPD include analyses performed on bronchoscopically obtained samples, sputum, exhaled gases, blood, and urine and "ex vivo" assays performed using biological samples obtained from trial participants. These novel biological outcomes are rarely useful as primary end points in phase III clinical trials in COPD, because they are not typically recognized by the U.S. Food and Drug Administration or other regulatory agencies. More commonly, the applications of these outcomes include "proof-of-concept" decisions, demonstration that the intervention had the intended pharmacologic or biological effect, identification of patient subgroups that benefit most, and safety monitoring. Examples given in this review include outcomes used in a phase IIA study of an inhaled small molecule inhibitor of epidermal growth factor receptor. Large observational studies ofCOPD,including the ECLIPSE,COPDGene,and SPIROMICS studies will further inform our use of biomarkers in COPD clinical trials. To encourage the application of novel biomarkers in clinical trials, the Food and Drug Administration has developed a new process for biomarker "qualification." This process has been designed to be more efficient and to promote consensus building and sharing of preclinical data.


Lustig R.H.,University of California at San Francisco
Advances in Nutrition | Year: 2013

What do the Atkins Diet and the traditional Japanese diet have in common? The Atkins Diet is low in carbohydrate and usually high in fat; the Japanese diet is high in carbohydrate and usually low in fat. Yet both work to promote weight loss. One commonality of both diets is that they both eliminate the monosaccharide fructose. Sucrose (table sugar) and its synthetic sister high fructose corn syrup consist of 2 molecules, glucose and fructose. Glucose is the molecule that when polymerized forms starch, which has a high glycemic index, generates an insulin response, and is not particularly sweet. Fructose is found in fruit, does not generate an insulin response, and is very sweet. Fructose consumption has increased worldwide, paralleling the obesity and chronic metabolic disease pandemic. Sugar (i.e., fructose-containing mixtures) has been vilified by nutritionists for ages as a source of "empty calories," no different from any other empty calorie. However, fructose is unlike glucose. In the hypercaloric glycogen-replete state, intermediary metabolites from fructose metabolism overwhelm hepatic mitochondrial capacity, which promotes de novo lipogenesis and leads to hepatic insulin resistance, which drives chronic metabolic disease. Fructose also promotes reactive oxygen species formation, which leads to cellular dysfunction and aging, and promotes changes in the brain's reward system, which drives excessive consumption. Thus, fructose can exert detrimental health effects beyond its calories and in ways that mimic those of ethanol, its metabolic cousin. Indeed, the only distinction is that because fructose is not metabolized in the central nervous system, it does not exert the acute neuronal depression experienced by those imbibing ethanol. These metabolic and hedonic analogies argue that fructose should be thought of as "alcohol without the buzz ". © 2013 American Society for Nutrition.


Kerlikowske K.,University of California at San Francisco
JAMA Internal Medicine | Year: 2015

Importance Breast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality. OBJECTIVE To update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer. PROCESS The ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. EVIDENCE SYNTHESIS Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screeningmethod for women at average risk. RECOMMENDATIONS The ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation).Women aged 45 to 54 years should be screened annually (qualified recommendation).Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation).Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation).Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation). CONCLUSIONS AND RELEVANCE These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening. © 2015 American Medical Association. All rights reserved.


Owens C.D.,University of California at San Francisco
Journal of Vascular Surgery | Year: 2012

During the past 2 decades, atherosclerosis and its clinical sequelae have increasingly been recognized as an inflammatory disease. Examination of multiple circulating inflammatory biomarkers has shown that they independently predict cardiovascular risk in patients with and without overt cardiovascular disease. Among these, high-sensitivity C-reactive protein has proved to be most robust in adding to global risk prediction models. Statins, a class of drugs that reduce levels of high-sensitivity C-reactive protein and other inflammatory biomarkers, have been the most thoroughly studied anti-inflammatory agents to reduce cardiovascular risk. However, all such trials are necessarily confounded by the ability of statins to markedly reduce cholesterol, a well-known causal risk factor for adverse vascular outcomes. Nevertheless, the provocative results of several key statin trials have provided the scientific basis to test the hypothesis that reducing inflammation will improve cardiovascular outcomes with novel and specific anti-inflammatory agents. These newer drugs promise to reduce inflammatory marker levels without affecting lipids, glucose, or blood pressure. The results of these trials will provide key data to help us understand the relationship between inflammation and vascular risk. © 2012 Society for Vascular Surgery.


Rubenstein J.L.R.,University of California at San Francisco
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2011

The cerebral cortex has a central role in cognitive and emotional processing. As such, understanding the mechanisms that govern its development and function will be central to understanding the bases of severe neuropsychiatric disorders, particularly those that first appear in childhood. In this review, I highlight recent progress in elucidating genetic, molecular and cellular mechanisms that control cortical development. I discuss basic aspects of cortical developmental anatomy, and mechanisms that regulate cortical size and area formation, with an emphasis on the roles of fibroblast growth factor (Fgf) signaling and specific transcription factors. I then examine how specific types of cortical excitatory projection neurons are generated, and how their axons grow along stereotyped pathways to their targets. Next, I address how cortical inhibitory (GABAergic) neurons are generated, and point out the role of these cells in controlling cortical plasticity and critical periods. The paper concludes with an examination of four possible developmental mechanisms that could contribute to some forms of neurodevelopmental disorders, such as autism. © 2010 The Author. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing.


Ferriero D.M.,University of California at San Francisco
Neonatology | Year: 2016

Background: Over the past two decades, imaging techniques have allowed for better visualization of the newborn brain. This has enabled us to detect patterns, understand mechanisms and guide diagnosis and treatment. Objectives: The purpose of this review is to discuss imaging characteristics of acquired perinatal brain injury. Methods: Through literature review and the author's research, this review assesses published data on the distinct imaging patterns that occur in the neonatal period due to acquired brain insults. Results: In the term brain, susceptibility to hypoxia-ischemia, hypoglycemia and hyperbilirubinemia results in unique patterns of injury. Stroke commonly occurs in the newborn period. Infections, especially viral, have distinct patterns of white matter injury. In the preterm brain, white matter injury occurs commonly and is affected by postnatal growth, stress and infection. The cerebellum is uniquely vulnerable during this period, with resultant hemorrhages in almost half of preterm infants. Cerebellar growth is affected by intraventricular hemorrhage, drugs and placental pathology. Periventricular hemorrhagic infarction is the most serious consequence of the spectrum of intraventricular hemorrhage and results in profound disabilities. Conclusions: Taken together, the acquired perinatal brain injuries can have lifelong devastating consequences, so the search for therapies must continue. © 2016 S. Karger AG, Basel.


Creager M.A.,Harvard University | Kaufman J.A.,Oregon Health And Science University | Conte M.S.,University of California at San Francisco
New England Journal of Medicine | Year: 2012

A 57-year-old man presents with an acute onset of left foot pain, numbness, and partial loss of motor function. Four months ago, he underwent endovascular treatment for disabling claudication, which included placement of overlapping polytetrafluoroethylene-coated stents in the left superficial femoral and popliteal arteries. His popliteal and pedal pulses are absent, and the foot is cool and mottled. Angiography reveals complete occlusion of the stent, with thrombosis extending distally into the popliteal and tibial arteries below the knee. How should his case be managed? Copyright © 2012 Massachusetts Medical Society.


Johnston S.C.,University of California at San Francisco
Stroke | Year: 2010

BACKGROUND-: The societal costs and health benefits of tissue plasminogen activator (tPA) for ischemic stroke can be modeled and extended to the US population. Similarly, the societal impact of new thrombolytics with improved efficacy or safety or extending eligibility can also be modeled. METHODS-: We previously modeled the impact of tPA on societal costs and health in the United States. Pertinent publications on utilization, societal cost, and health impact were identified by systematic review, updated to include studies describing the impact of extending the tPA time window. Information on utilization of tPA was integrated with published per-use data on costs and health impact (converted to 2004 dollars) to generate annual projections for the US population. Model inputs were modified to reflect various characteristics of new thrombolytics. RESULTS-: At its current price, tPA saves $6074 and adds 0.75 quality-adjusted life year (QALY) per use. If tPA were priced at $50 000/QALY, a standard benchmark for cost-effectiveness, it would cost $45 800 per dose and would be expected to generate $458 million in revenue annually for its manufacturer. Thrombolytics for stroke that extended the time window or improved efficacy could generate greater revenue if priced at an accepted level of cost-effectiveness. Given current clinical development costs, development of candidate drugs with 2.8% to 5.7% probability of ultimate FDA approval would be justified. CONCLUSIONS-: tPA produces substantial health and economic benefits in the United States. Better thrombolytics for stroke could have substantial impact on society, and potential returns to developers would appear to justify greater investment in new candidates. © 2010 American Heart Association, Inc.


Nkansah N.,University of California at San Francisco
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: The roles of pharmacists in patient care have expanded from the traditional tasks of dispensing medications and providing basic medication counseling to working with other health professionals and the public. Multiple reviews have evaluated the impact of pharmacist-provided patient care on health-related outcomes. Prior reviews have primarily focused on in-patient settings. This systematic review focuses on services provided by outpatient pharmacists in community or ambulatory care settings. This is an update of the Cochrane review published in 2000. OBJECTIVES: To examine the effect of outpatient pharmacists' non-dispensing roles on patient and health professional outcomes. SEARCH STRATEGY: This review has been split into two phases. For Phase I, we searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register (January 1966 through March 2007). For Phase II, we searched MEDLINE/EMBASE (January 1966 through March 2008). The Phase I results are reported in this review; Phase II will be summarized in the next update. SELECTION CRITERIA: Randomized controlled trials comparing 1. Pharmacist services targeted at patients versus services delivered by other health professionals; 2. Pharmacist services targeted at patients versus the delivery of no comparable service; 3. Pharmacist services targeted at health professionals versus services delivered by other health professionals; 4. Pharmacist services targeted at health professionals versus the delivery of no comparable service. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed studies for inclusion, extracted data, and assessed risk of bias of included studies. MAIN RESULTS: Forty-three studies were included; 36 studies were pharmacist interventions targeting patients and seven studies were pharmacist interventions targeting health professionals. For comparison 1, the only included study showed a significant improvement in systolic blood pressure for patients receiving medication management from a pharmacist compared to usual care from a physician. For comparison 2, in the five studies evaluating process of care outcomes, pharmacist services reduced the incidence of therapeutic duplication and decreased the total number of medications prescribed. Twenty-nine of 36 studies reported clinical and humanistic outcomes. Pharmacist interventions resulted in improvement in most clinical outcomes, although these improvements were not always statistically significant. Eight studies reported patient quality of life outcomes; three studies showed improvement in at least three subdomains. For comparison 3, no studies were identified meeting the inclusion criteria. For comparison 4, two of seven studies demonstrated a clear statistically significant improvement in prescribing patterns. AUTHORS' CONCLUSIONS: Only one included study compared pharmacist services with other health professional services, hence we are unable to draw conclusions regarding comparisons 1 and 3. Most included studies supported the role of pharmacists in medication/therapeutic management, patient counseling, and providing health professional education with the goal of improving patient process of care and clinical outcomes, and of educational outreach visits on physician prescribing patterns. There was great heterogeneity in the types of outcomes measured across all studies. Therefore a standardized approach to measure and report clinical, humanistic, and process outcomes for future randomized controlled studies evaluating the impact of outpatient pharmacists is needed. Heterogeneity in study comparison groups, outcomes, and measures makes it challenging to make generalised statements regarding the impact of pharmacists in specific settings, disease states, and patient populations.


Debnath J.,University of California at San Francisco
Journal of Mammary Gland Biology and Neoplasia | Year: 2011

Autophagy is an evolutionarily conserved lysosomal degradation process that is crucial for adaptation to stress as well as in cellular homeostasis. In cancer, our current understanding has uncovered multifaceted roles for autophagy in tumor initiation and progression. Although genetic evidence corroborates a critical role for autophagy as a tumor suppressor mechanism, autophagy can also promote the survival and fitness of advanced tumors subject to stress, which has important implications during breast cancer progression and metastasis. Here, I discuss the mechanisms and the evidence underlying these diverse roles for autophagy in cancer and speculate on specific circumstances in which autophagy can be most effectively targeted for breast cancer treatment. © Springer Science+Business Media, LLC 2011.


Kim C.C.,University of California at San Francisco
Current opinion in immunology | Year: 2013

The Immunological Genome Consortium has generated a public resource (www.immgen.org) that provides a compendium of gene expression profiles of ∼270 leukocyte subsets in the mouse. This effort established carefully standardized operating procedures that resulted in a transcriptional dataset of unprecedented comprehensiveness and quality. The findings have been detailed recently in a series of publications providing molecular insights into the development, heterogeneity, and/or function of these cellular lineages and distinct subpopulations. Here, we review the key findings of these studies, highlighting what has been gained and how the knowledge can be used to accelerate progress toward a comprehensive understanding of the immune system. Copyright © 2013 Elsevier Ltd. All rights reserved.


Kurtz T.W.,University of California at San Francisco
Hypertension | Year: 2010

Over the past few years, it has been asserted that genome-wide association studies would open the door to identifying primary genetic mechanisms underlying a variety of common clinical disorders, including essential hypertension. Great hope was expressed that such research would ultimately lead to improved clinical outcomes by facilitating the discovery of novel targets for therapy and by spawning a new era of personalized medicine in which the results of genetic tests would be useful for guiding customized risk assessment and individual patient management. In this Controversies in Hypertension series, I contend that genome-wide association studies have failed, and will continue to fail, to unlock the genetic basis of essential hypertension and the research dollars being devoted to genome-wide association studies should be shifted to other strategies and technologies that may hold greater chance for advancing our understanding of the genetic factors that influence population variation in blood pressure and risk for hypertension. © 2010 American Heart Association, Inc.


Pogrel M.A.,University of California at San Francisco
Journal of Oral and Maxillofacial Surgery | Year: 2012

The purpose of this article is to summarize the literature that addresses the following question: "Among patients undergoing third molar removal, do patients who are younger, eg, <25 years, when compared with older patients, have a decreased risk for postoperative complications and more rapid recovery?" For the purposes of this study, relevant articles were identified through a search of PubMed, Scopus, and the Cochrane Database, using the Medical Subject Headings search terms "third molars" or "wisdom teeth," "complications" and "age," linked to "recovery," "infections," "periodontal conditions," "temporomandibular joint problems," "nerve involvement," "sinus communication," and "mandibular fracture." Relevant studies have been identified and are reported for the following complications and their relationship to the patient's age: 1) time to recovery; 2) incidence of fractures; 3) rates of infection; 4) periodontal complications; 5) nerve involvement; 6) temporomandibular joint complications; 7) nerve injury; and 8) sinus-related complications. Studies indicate that as one becomes older, third molars (M3s) become more difficult to remove, may take longer to remove, and may result in an increased risk for complications associated with removal. The age of 25 years appears in many studies to be a critical time after which complications increase more rapidly. Conversely, there are no studies indicating a decrease in complications with increasing age. It also appears that recovery from complications is more prolonged and is less predictable and less complete with increasing age. As such, many clinicians recommend removal of M3s in patients as young adults. Advocates of M3 retention need to review carefully with their patients the risks of delaying M3 removal with the same degree of emphasis as the risks associated with operative treatment. © 2012 American Association of Oral and Maxillofacial Surgeons.


Glenn O.A.,University of California at San Francisco
Pediatric Radiology | Year: 2010

Fetal MRI is clinically performed to evaluate the brain in cases where an abnormality is detected by prenatal sonography. These most commonly include ventriculomegaly, abnormalities of the corpus callosum, and abnormalities of the posterior fossa. Fetal MRI is also increasingly performed to evaluate fetuses who have normal brain findings on prenatal sonogram but who are at increased risk for neurodevelopmental abnormalities, such as complicated monochorionic twin pregnancies. This paper will briefly discuss the common clinical conditions imaged by fetal MRI as well as recent advances in fetal MRI research.


Boyce W.T.,University of California at San Francisco
Neuropsychopharmacology | Year: 2016

A swiftly growing volume of literature, comprising both human and animal studies and employing both observational and experimental designs, has documented striking individual differences in neurobiological sensitivities to environmental circumstances within subgroups of study samples. This differential susceptibility to social and physical environments operates bidirectionally, in both adverse and beneficial contexts, and results in a minority subpopulation with remarkably poor or unusually positive trajectories of health and development, contingent upon the character of environmental conditions. Differences in contextual susceptibility appear to emerge in early development, as the interactive and adaptive product of genetic and environmental attributes. This paper surveys what is currently known of the mechanisms or mediators of differential susceptibility, at the levels of temperament and behavior, physiological systems, brain circuitry and neuronal function, and genetic and epigenetic variation. It concludes with the assertion that differential susceptibility is inherently grounded within processes of biological moderation, the complexities of which are at present only partially understood. © 2016 American College of Neuropsychopharmacology. All rights reserved.


Aronson L.,University of California at San Francisco
Medical Teacher | Year: 2011

Background: Review of studies published in medical education journals over the last decade reveals a diversity of pedagogical approaches and educational goals related to teaching reflection. Aim: The following tips outline an approach to the design, implementation, and evaluation of reflection in medical education. Method: The method is based on the available literature and the author's experience. They are organized in the sequence that an educator might use in developing a reflective activity. Results: The 12 tips provide guidance from conceptualization and structure of the reflective exercise to implementation and feedback and assessment. The final tip relates to the development of the faculty member's own reflective ability. Conclusion: With a better understanding of the conceptual frameworks underlying critical reflection and greater advance planning, medical educators will be able to create exercises and longitudinal curricula that not only enable greater learning from the experience being reflected upon but also develop reflective skills for life-long learning. © 2011 Informa UK Ltd All rights reserved.


Harrison-Uy S.J.,University of California at San Francisco
Cold Spring Harbor perspectives in biology | Year: 2012

Components of the Wnt signaling pathway are expressed in a tightly regulated and spatially specific manner during development of the forebrain, and Wnts are key regulators of regional forebrain identity. Wnt signaling from the cortical hem regulates the expansion and cell-type specification of the adjacent neuroepithelium and, in conjunction with Bmp, Fgf, and Shh signaling, controls dorsal-ventral forebrain patterning. Subsequently, Wnt signaling dynamically regulates the behavior of cortical progenitor cells, initially promoting the expansion of radial glia progenitor cells and later inducing neurogenesis by promoting terminal differentiation of intermediate progenitor cells. A role for Wnt signaling in cell-type specification has also been proposed.


Vail T.P.,University of California at San Francisco
Journal of the American Academy of Orthopaedic Surgeons | Year: 2011

Hip resurfacing arthroplasty is an alternative to THA in patients with end-stage articular cartilage degeneration, excellent bone quality, and minimal mechanical changes resulting from bone loss or remodeling. Hip resurfacing is contraindicated in patients with inadequate bone stock of the femoral head, femoral neck, or acetabulum. Additional contraindications include a history of sensitivity to metal and renal insufficiency. Women of childbearing age must be notified of the risks associated with exposure to the constituents of metal alloy. Femoral neck fracture is the most common early complication of hip resurfacing. Outcome is dependent on several factors, including surgeon experience, patient selection, proper preparation of the acetabulum and the femoral head, good cement technique, device performance, and restoration of optimal hip mechanics. Copyright 2011 by the American Academy of Orthopaedic Surgeons.


Schickedanz A.,University of California at San Francisco
The oncologist | Year: 2010

The U.S. spends far more per person than any other country in the world in treating cancer, without demonstrably superior results. Though the pursuit and pace of innovation in oncology are perhaps unmatched and promise great benefit for cancer patients, this explosion of innovation has been accompanied by dramatic increases in cost, often without significant increases in patient survival. These trends have led to a growing interest in addressing value--understood as treatment benefits or quality weighed against economic cost--in cancer care. In February 2009, the Institute of Medicine convened a group of experts with diverse perspectives, including those of clinical oncology, patient advocacy, the insurance industry, pharmaceutical manufacturing, health economics, and bioethics, to identify challenges to value in cancer care, suggest potential solutions, and discuss what value entails in oncology. This article presents many of the ideas that emerged from this symposium, including ways to correct misaligned economic incentives, improve clinical communication, and generate evidence to promote value in cancer care.


Chaumeil M.M.,University of California at San Francisco
Nature communications | Year: 2013

Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-(13)C] α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using (13)C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-(13)C] α-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-(13)C] α-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-(13)C] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.


Alexopoulos G.S.,Cornell College | Arean P.,University of California at San Francisco
Molecular Psychiatry | Year: 2014

A critical task for psychotherapy research is to create treatments that can be used by community clinicians. Streamlining of psychotherapies is a necessary first step for this purpose. We suggest that neurobiological knowledge has reached the point of providing biologically meaningful behavioral targets, thus guiding the development of effective, simplified psychotherapies. This view is supported by the Research Domain Criteria (RDoC) Project, which reflects the field's consensus and recognizes the readiness of neurobiology to guide research in treatment development. 'Engage' is an example of such a streamlined therapy. It targets behavioral domains of late-life depression grounded on RDoC constructs using efficacious behavioral strategies selected for their simplicity. 'Reward exposure' targeting the behavioral expression of positive valence systems' dysfunction is the principal therapeutic vehicle of 'Engage'. Its first three sessions consist of direct 'reward exposure', but the therapists search for barriers in three behavioral domains, that is, 'negativity bias' (negative valence), 'apathy' (arousal) and 'emotional dysregulation' (cognitive control), and add strategies targeting these domains when needed. The end result is a structured, stepped approach using neurobiological constructs as targets and as a guide to personalization. We argue that the 'reduction' process needed in order to arrive to simplified effective therapies can be achieved in three steps: (1) identify RDoC constructs driving the syndrome's psychopathology; (2) create a structured intervention utilizing behavioral and ecosystem modification techniques targeting behaviors related to these constructs; (3) examine whether the efficacy of the new intervention is mediated by change in behaviors related to the targeted RDoC constructs. © 2014 Macmillan Publishers Limited.


Marshall W.F.,University of California at San Francisco
Trends in Cell Biology | Year: 2015

Cells are not just amorphous bags of enzymes, but precise and complex machines. With any machine, it is important that the parts be of the right size, yet our understanding of the mechanisms that control size of cellular structures remains at a rudimentary level in most cases. One problem with studying size control is that many cellular organelles have complex 3D structures that make their size hard to measure. Here we focus on linear structures within cells, for which the problem of size control reduces to the problem of length control. We compare and contrast potential mechanisms for length control to understand how cells solve simple geometry problems. The mechanisms that control organelle size are unknown. Length control of linear structures provides a simplified version of the more general organelle size-control problem.Numerous distinct mechanisms have been proposed for regulating the length of various structures, including molecular rulers, limiting precursor production, balanced assembly/disassembly, and molecular gradients.While molecular rulers play a prominent role in regulating length in prokaryotes, it is less obvious whether rulers are similarly important in eukaryotic cells.Organelle size control, as a problem that spans the molecular and cellular scales of organization, is emerging as a key challenge for quantitative cell biology. © 2015 Elsevier Ltd.


Marshall W.F.,University of California at San Francisco
Cell | Year: 2013

A new study by Terasaki et al. highlights the role of physical forces in biological form by showing that connections between stacked endoplasmic reticulum cisternae have a shape well known in classical differential geometry, the helicoid, and that this shape is a predictable consequence of membrane physics. © 2013 Elsevier Inc.


Dever J.B.,VA San Diego Healthcare System | Sheikh M.Y.,University of California at San Francisco
Alimentary Pharmacology and Therapeutics | Year: 2015

Background Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with cirrhosis and ascites. Aim To review the known and changing bacteriology, risk factors, ascitic fluid interpretation, steps in performing paracentesis, treatment, prophylaxis and evolving perspectives related to SBP. Methods Information was obtained from reviewing medical literature accessible on PubMed Central. The search term 'spontaneous bacterial peritonitis' was cross-referenced with 'bacteria', 'risk factors', 'ascites', 'paracentesis', 'ascitic fluid analysis', 'diagnosis', 'treatment', 'antibiotics', 'prophylaxis', 'liver transplantation' and 'nutrition'. Results Gram-positive cocci (GPC) such as Staphylococcus, Enterococcus as well as multi-resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Health care-associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta-adrenergic antagonist therapies are strongly associated with SBP in at-risk individuals. Conclusions Third-generation, broad-spectrum cephalosporins remain a good initial choice for SBP treatment. Levofloxacin is an acceptable alternative for patients not receiving long-term flouroquinolone prophylaxis or for those with a penicillin allergy. For uncomplicated SBP, early oral switch therapy is reasonable. Alternative antibiotics such as pipercillin-tazobactam should be considered for patients with nosocomial SBP or for patients who fail to improve on traditional antibiotic regimens. Selective albumin supplementation remains an important adjunct in SBP treatment. Withholding acid suppressive medication deserves strong consideration, and discontinuing beta-adrenergic antagonist therapy in patients with end-stage liver disease and resistant ascites is standard care. Liver transplant evaluation should be undertaken for patients who develop SBP barring contraindications. © 2015 John Wiley & Sons Ltd.


Parker J.M.,University of California at San Francisco
Journal of Neurophysiology | Year: 2011

Neurophysiological recording in alert monkeys requires the creation of a permanent aperture in the skull for repeated insertion of microelectrodes. Most laboratories use polymethyl methacrylate to attach a recording chamber over the skull opening. Here, we describe a titanium chamber that fastens to the skull with screws, using no polymethyl methacrylate. The gap between the base of the chamber and the skull is filled with hydroxyapatite, forming a watertight gasket. As the chamber base osseointegates with the skull, the hydroxyapatite is replaced with bone. Rather than having a finite lifetime, the recording chamber becomes more firmly anchored the longer it is in place. It has a small footprint, low profile, and needs little maintenance to control infection. Toilette consists of occasional application of betadine to clean the scalp margin, followed by application of neomycin, polymyxin, and bacitracin ointment. Antibiotic is also placed inside the chamber to suppress bacterial proliferation. Thickening of the dura within the chamber can be prevented by regular application of mitocycin C and/or bevacizumab, an antibody against vascular endothelial growth factor. By conducting an e-mail survey, this protocol for chamber maintenance was compared with procedures used in 37 other vision research laboratories. Refinement of appliances and techniques used for recordings in awake monkeys promises to increase the pace of scientific discovery and to benefit animal welfare. © 2011 the American Physiological Society 1581.


Guydish J.,University of California at San Francisco
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco | Year: 2011

This review explores whether smoking prevalence in addiction treatment samples exceeds that shown in epidemiological data for persons with alcohol or other drug use disorders and whether smoking may have decreased over time in the addiction treatment population as it has done in the general population. English language papers published between 1987 and 2009 were searched electronically. Forty papers reporting smoking prevalence for addiction treatment samples in the United States were identified, and key predictor variables were abstracted. Random logistic models were used to assess relationships between each individual predictor (year, treatment modality, primary drug treated, government status, and public/private funding status) and smoking prevalence. The lowest smoking prevalence aggregated for studies reported in any single year was 65%, well above epidemiological estimates reported among those with alcohol use and drug use disorders. The odds of smoking were higher in methadone maintenance programs (odds ratio [OR] = 2.25, CI = 1.08, 4.68) as compared with outpatient programs. No other variables in the model were significant. Reanalysis omitting recent studies that may represent outliers or confounding with type of treatment showed a small but significant decrease in smoking over time (OR = 0.9891, CI = 0.9888, 0.9893). The very high smoking rates reported in addiction treatment samples warrant significant, organized, and systemic response from addiction treatment systems, from agencies that fund and regulate those systems, and from agencies concerned with tobacco control.


Giudice L.C.,University of California at San Francisco
New England Journal of Medicine | Year: 2010

A healthy 25-year-old woman presents with worsening dysmenorrhea, pain of recent onset in the left lower quadrant, and dyspareunia. She has regular menstrual cycles, and her last menstrual period was 3 weeks before presentation. How should this patient be evaluated and treated? Copyright © 2010 Massachusetts Medical Society.


Daniels N.A.,University of California at San Francisco
Urology | Year: 2010

Objective: To assess whether sex hormone levels are associated with subsequent development of prostate cancer. Methods: A case-cohort study was conducted within the ongoing Osteoporotic Fractures in Men cohort study of community-dwelling men <65 years old recruited at 6 US clinical sites. After a mean follow-up of 4.7 years, all men with incident-confirmed prostate cancer and a random sample of the full cohort (subcohort) were selected for analysis: after excluding men with a history of prostate cancer and those who reported androgen or antiandrogen therapy at baseline, the resulting analytic sample comprised 275 cases and 1652 noncases with complete sex hormone measurements. Serum testosterone, estradiol, estrone, and sex hormonebinding globulin were assayed at baseline (prediagnosis) by gas chromatography combined with mass spectrometry. Associations between incident prostate cancer and each sex hormone were evaluated using Cox proportional hazards regression models adjusted for age, race, study site, body mass index, and person-time. Results: In the subcohort, the mean age was 73 years. Higher serum estrone was strongly related to an increased risk of prostate cancer: compared with men in the lower quartile, the risk of prostate cancer among those in the highest 3 quartiles (>24.9 pg/dL) was nearly 4-fold higher (adjusted heart rate = 3.93, CI: 1.61-9.57). Other sex hormones were not associated with the risk of prostate cancer. Conclusions: In this cohort of older men, higher estrone levels were strongly associated with an increased risk of incident prostate cancer. This association between estrone and prostate cancer risk needs to be clarified by further study. © 2010 Elsevier Inc. All Rights Reserved.


Lazarus S.C.,University of California at San Francisco
New England Journal of Medicine | Year: 2010

A 46-year-old woman who has had two admissions to the intensive care unit (ICU) for asthma during the past year presents with a 4-day history of upper respiratory illness and a 6-hour history of shortness of breath and wheezing. An inhaled corticosteroid has been prescribed, but she takes it only when she has symptoms, which is rarely. She generally uses albuterol twice per day but has increased its use to six to eight times per day for the past 3 days. How should this case be managed in the emergency department? Copyright © 2010 Massachusetts Medical Society.


Plesh O.,University of California at San Francisco
Journal of orofacial pain | Year: 2011

To compare prevalences of self-reported comorbid headache, neck, back, and joint pains in respondents with temporomandibular joint and muscle disorder (TMJMD)-type pain in the 2000-2005 US National Health Interview Survey (NHIS), and to analyze these self-reported pains by gender and age for Non-Hispanic (NH) Whites (Caucasians), Hispanics, and NH Blacks (African Americans). Data from the 2000-2005 NHIS included information on gender, age, race, ethnicity, education, different common types of pain (specifically TMJMD-type, severe headache/migraine, neck, and low back pains), changes in health status, and health care utilization. Estimates and test statistics (ie, Pearson correlations, regressions, and logistic models) were conducted using SAS survey analysis and SUDAAN software that take into account the complex sample design. A total of 189,977 people (52% female and 48% males, 73% NH Whites, 12% Hispanic, 11% NH Blacks, and 4% "Other") were included. A total of 4.6% reported TMJMD-type pain, and only 0.77% overall reported it without any comorbid headache/migraine, neck, or low back pains; also 59% of the TMJMD-type pain (n = 8,964) reported two comorbid pains. Females reported more comorbid pain than males (odds ratio [OR] = 1.41, P < .001); Hispanic and NH Blacks reported more than NH Whites (OR = 1.56, P <.001; OR= 1.38, P <.001, respectively). In addition, 53% of those with TMJMD-type pain had severe headache/migraines, 54% had neck pain, 64% low back pain, and 62% joint pain. Differences in gender and race by age patterns were detected. For females, headache/migraine pain with TMJMD-type pain peaked around age 40 and decreased thereafter regardless of race/ethnicity. Neck pain continued to increase up to about age 60, with a higher prevalence for Hispanic women at younger ages, and more pronounced in males, being the highest in the non-Whites. Low back pain was higher in Black and Hispanic females across the age span, and higher among non-White males after age 60. Joint pain demonstrated similar patterns by race/ethnicity, with higher rates for Black females, and increased with age regardless of gender. TMJMD-type pain was most often associated with other common pains, and seldom existed alone. Two or more comorbid pains were common. Gender, race, and age patterns for pains with TMJMD-type pain resembled the specific underlying comorbid pain.


Hong M.,Iowa State University | DeGrado W.F.,University of California at San Francisco
Protein Science | Year: 2012

The influenza M2 protein forms an acid-activated and drug-sensitive proton channel in the virus envelope that is important for the virus lifecycle. The functional properties and high-resolution structures of this proton channel have been extensively studied to understand the mechanisms of proton conduction and drug inhibition. We review biochemical and electrophysiological studies of M2 and discuss how high-resolution structures have transformed our understanding of this proton channel. Comparison of structures obtained in different membrane-mimetic solvents and under different pH using X-ray crystallography, solution NMR, and solid-state NMR spectroscopy revealed how the M2 structure depends on the environment and showed that the pharmacologically relevant drug-binding site lies in the transmembrane (TM) pore. Competing models of proton conduction have been evaluated using biochemical experiments, high-resolution structural methods, and computational modeling. These results are converging to a model in which a histidine residue in the TM domain mediates proton relay with water, aided by microsecond conformational dynamics of the imidazole ring. These mechanistic insights are guiding the design of new inhibitors that target drug-resistant M2 variants and may be relevant for other proton channels. © 2012 The Protein Society.


Ford J.M.,University of California at San Francisco
Nature protocols | Year: 2010

In this paper, we present a vocal production protocol for studying the neurophysiological action of the corollary discharge, a mechanism that allows animals to ignore sensations resulting from their own actions, and tag them as 'self'. Electroencephalograms are recorded while subjects say 'ah' about 100 times with minimal throat, jaw and tongue movements (Talk condition). This sequence of sounds is recorded and played back during the Listen condition. Event-related potentials are synchronized to the onset of speech sounds during the Talk and Listen conditions. Neural responses from the auditory cortex to the spoken sound as it is being spoken during the Talk condition are compared with neural responses to the same sounds when played back during the Listen condition. The successful action of the corollary discharge is seen when the response of the auditory cortex is suppressed during the Talk compared with the Listen condition. The protocol takes about 5 min to complete.


Ekstrand M.L.,University of California at San Francisco
Journal of the International AIDS Society | Year: 2013

HIV stigma inflicts hardship and suffering on people living with HIV (PLHIV) and interferes with both prevention and treatment efforts. Health professionals are often named by PLHIV as an important source of stigma. This study was designed to examine rates and drivers of stigma and discrimination among doctors, nurses and ward staff in different urban healthcare settings in high HIV prevalence states in India. This cross-sectional study enrolled 305 doctors, 369 nurses and 346 ward staff in both governmental and non-governmental healthcare settings in Mumbai and Bengaluru, India. The approximately one-hour long interviews focused on knowledge related to HIV transmission, personal and professional experiences with PLHIV, instrumental and symbolic stigma, endorsement of coercive policies, and intent to discriminate in professional and personal situations that involve high and low risk of fluid exposure. High levels of stigma were reported by all groups. This included a willingness to prohibit female PLHIV from having children (55 to 80%), endorsement of mandatory testing for female sex workers (94 to 97%) and surgery patients (90 to 99%), and stating that people who acquired HIV through sex or drugs "got what they deserved" (50 to 83%). In addition, 89% of doctors, 88% of nurses and 73% of ward staff stated that they would discriminate against PLHIV in professional situations that involved high likelihood of fluid exposure, and 57% doctors, 40% nurses and 71% ward staff stated that they would do so in low-risk situations as well. Significant and modifiable drivers of stigma and discrimination included having less frequent contact with PLHIV, and a greater number of transmission misconceptions, blame, instrumental and symbolic stigma. Participants in all three groups reported high rates of endorsement of coercive measures and intent to discriminate against PLHIV. Stigma and discrimination were associated with multiple modifiable drivers, which are consistent with previous research, and which need to be targeted in future interventions. Stigma reduction intervention programmes targeting healthcare providers in urban India need to address fear of transmission, improve universal precaution skills, and involve PLHIV at all stages of the intervention to reduce symbolic stigma and ensure that relevant patient interaction skills are taught.


Plesh O.,University of California at San Francisco
Journal of orofacial pain | Year: 2011

To compare prevalences of self-reported temporomandibular joint and muscle disorders (TMJMD)-type pain, headaches, and neck and back pains in the 2000 to 2005 US National Health Interview Survey (NHIS) by gender and age for non-Hispanic Whites (Whites), Hispanics, and non-Hispanic Blacks (Blacks). Data from the 2000 to 2005 NHIS included information on gender, age, race, ethnicity, and different common types of pain specifically: TMJMD-type pain, severe headaches/migraine, neck, and low back pains. A total of 189,992 people were included: 52% female and 48% male, 73% White, 12% Hispanic, 11% Black, and 4% "Other." The overall prevalence of TMJMD-type pain was 4.6%; severe headaches/migraine was 15.4%; neck, 14.9%; and low back, 28.0%. Survey logistic regression models estimating race-specific, age-adjusted curves revealed race by age pain differences. For TMJMD-type pain, White females presented the highest prevalence at younger ages, decreasing after age 40. Prevalences for Hispanic and Black females, although lower at younger ages, increased up to age 60 and remained higher than Whites. Males showed less racial/ethnic and age variation. Severe headaches/migraines presented an age pattern similar to TMJMD-type pain for White females and little overall variation for males, but without racial differences. Neck pain showed some similarities to TMJMD-type pain: higher in Whites at younger ages, lower at older ages, with Hispanics having the highest rates after their 60's. For low back pain, the rates peaked around the sixth decade for all racial/ethnic groups. The patterns of TMJMD-type pain varied greatly within and across racial/ethnic groups by gender and across the adult lifespan. Similarities and differences for the other pains were noted.


Li L.-C.,University of California at San Francisco
Epigenetics | Year: 2014

Chromatin states, quite different from changes in DNA sequence, can impact fundamental cellular processes such as determination of cell identity and development of disease. However, how chromatin states are established and regulated remain to be fully elucidated. In several lower eukaryotes, the small RNA machinery comprised of small RNA and its partners, the Argonaute proteins, is known to play important roles in the establishment of heterochromatin and silencing of repetitive sequences. In mammalian cells, however, the nuclear function of the small RNA machinery is largely unknown. Emerging evidence suggests that components of the small RNA pathway interact with chromatin to regulate nuclear events, including gene transcription and alternative splicing. In addition, these endogenous mechanisms are being exploited to target specific genomic loci for manipulation of gene expression and splicing events. In this review, I summarize current understanding of chromatin remodeling by small RNAs in mammalian cells and highlight recent efforts to map genome-wide interactions between RNAi-related factors and chromatin. © 2014 Landes Bioscience.


Greninger A.L.,University of California at San Francisco
Progress in Molecular Biology and Translational Science | Year: 2015

Picornaviruses are positive-stranded RNA viruses of significant disease burden and ubiquitous global reach. Microscopic examination of picornavirus-infected cells has long revealed a drastic reordering of intracellular membranes. Through a confluence of candidate-based approaches and genomic and proteomic screens, the past decade has seen great leaps in understanding how picornaviruses usurp intracellular membranes for their own replication. The growing cast of assembled characters allows for a rich plot in the upcoming years. With their widespread genomic divergence, the number of potential mechanisms for RNA virus vesicogenesis for driving membrane formation and lipid synthesis required for viral replication is broad, but the overall story arch remains surprisingly recognizable. This chapter reviews the major discoveries associating picornavirus pathogenic interactions with the secretory system and highlights important questions and opportunities for future study. © 2015 Elsevier Inc. All rights reserved.


Napoles A.M.,University of California at San Francisco
Preventing chronic disease | Year: 2013

Populations composed of racial/ethnic minorities, disabled persons, and people with low socioeconomic status have worse health than their counterparts. Implementing evidence-based behavioral interventions (EBIs) to prevent and manage chronic disease and disability in community settings could help ameliorate disparities. Although numerous models of implementation processes are available, they are broad in scope, few offer specific methodological guidance, and few address the special issues in reaching vulnerable populations. Drawing from 2 existing models, we describe 7 methodological phases in the process of translating and implementing EBIs in communities to reach these vulnerable groups: establish infrastructure for translation partnership, identify multiple inputs (information gathering), review and distill information (synthesis), adapt and integrate program components (translation), build general and specific capacity (support system), implement intervention (delivery system), and develop appropriate designs and measures (evaluation). For each phase, we describe specific methodological steps and resources and provide examples from research on racial/ethnic minorities, disabled persons, and those with low socioeconomic status. Our methods focus on how to incorporate adaptations so that programs fit new community contexts, meet the needs of individuals in health-disparity populations, capitalize on scientific evidence, and use and build community assets and resources. A key tenet of our approach is to integrate EBIs with community best practices to the extent possible while building local capacity. We discuss tradeoffs between maintaining fidelity to the EBIs while maximizing fit to the new context. These methods could advance our ability to implement potentially effective interventions to reduce health disparities.


Loh M.L.,University of California at San Francisco | Mullighan C.G.,St Jude Childrens Research Hospital
Clinical Cancer Research | Year: 2012

Hematologic malignancies of childhood comprise the most common childhood cancers. These neoplasms derive from the pathologic clonal expansion of an abnormal cancer-initiating cell and span a diverse spectrum of phenotypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). Expansion of immature lymphoid or myeloid blasts with suppression of normal hematopoiesis is the hallmark of ALL and AML, whereasMPNis associated with proliferation of 1 or more lineages that retain the ability to differentiate, and MDS is characterized by abnormal hematopoiesis and cytopenias. The outcomes for children with the most common childhood cancer, B-progenitor ALL (B-ALL), in general, is quite favorable, in contrast to children affected by myeloid malignancies. The advent of highly sensitive genomic technologies reveals the remarkable genetic complexity of multiple subsets of high-risk B-progenitor ALL, in contrast to a somewhat simpler model of myeloid neoplasms, although a number of recently discovered alterations displayed by both types of malignancies may lead to common therapeutic approaches. This review outlines recent advances in our understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlapMPN/MDSfound exclusively in children, and we also discuss novel therapeutic approaches that are currently being tested in clinical trials. Recent insights into the clonal heterogeneity of leukemic samples and the implications for diagnostic and therapeutic approaches are also discussed. ©2012 AACR.


Huang Y.J.,University of Michigan | Boushey H.A.,University of California at San Francisco
Journal of Allergy and Clinical Immunology | Year: 2015

The application of recently developed sensitive, specific, culture-independent tools for identification of microbes is transforming concepts of microbial ecology, including concepts of the relationships between the vast complex populations of microbes associated with ourselves and with states of health and disease. Although most work initially focused on the community of microbes (microbiome) in the gastrointestinal tract and its relationship to gastrointestinal disease, interest has expanded to include study of the relationships of the airway microbiome to asthma and its phenotypes and to the relationships between the gastrointestinal microbiome, development of immune function, and predisposition to allergic sensitization and asthma. Here we provide our perspective on the findings of studies of differences in the airway microbiome between asthmatic patients and healthy subjects and of studies of relationships between environmental microbiota, gut microbiota, immune function, and asthma development. In addition, we provide our perspective on how these findings suggest the broad outline of a rationale for approaches involving directed manipulation of the gut and airway microbiome for the treatment and prevention of allergic asthma. © 2014 American Academy of Allergy, Asthma & Immunology.


Bikle D.D.,University of California at San Francisco
Trends in Endocrinology and Metabolism | Year: 2010

Vitamin D is not just for preventing rickets and osteomalacia. Recent findings in animal experiments, epidemiologic studies and clinical trials indicate that adequate vitamin D levels are important for cancer prevention, controlling hormone levels and regulating the immune response. Although 25 hydroxyvitamin D (25OHD) levels >10 ng/ml can prevent rickets and osteomalacia, these levels are not sufficient to provide these more recently discovered clinical benefits. Rather, levels of 25OHD >30 ng/ml are generally recommended. Determining optimal levels of 25OHD and the amount of vitamin D supplementation required to achieve those levels for the numerous actions of vitamin D will only be established with additional trials. In this review, these newer applications are summarized and therapeutic considerations are provided. © 2010.


Schwartz A.V.,University of California at San Francisco
Frontiers in Endocrinology | Year: 2015

With growing interest in the connection between fat and bone, there has been increased investigation of the relationship with marrow fat in particular. Clinical research has been facilitated by the development of non-invasive methods to measure bone marrow fat content and composition. Studies in different populations using different measurement techniques have established that higher marrow fat is associated with lower bone density and prevalent vertebral fracture. The degree of unsaturation in marrow fat may also affect bone health. Although other fat depots tend to be strongly correlated, marrow fat has a distinct pattern, suggesting separate mechanisms of control. Longitudinal studies are limited, but are crucial to understand the direct and indirect roles of marrow fat as an influence on skeletal health. With greater appreciation of the links between bone and energy metabolism, there has been growing interest in understanding the relationship between marrow fat and bone. It is well established that levels of marrow fat are higher in older adults with osteoporosis, defined by either low bone density or vertebral fracture. However, the reasons for and implications of this association are not clear. This review focuses on clinical studies of marrow fat and its relationship to bone. © 2015 Schwartz.


Cheng Y.W.,University of California at San Francisco
Obstetrics and Gynecology | Year: 2010

Objective: To estimate whether length of the first stage of labor is associated with adverse maternal and neonatal outcomes. Methods: This is a retrospective cohort study of nulliparous women with term, singleton gestations delivered in one academic center between 1990 and 2008. The length of the first stage was stratified into three subgroups: less than the 5th percentile, 5th to 95th percentile, and greater than the 95th percentile. Maternal and neonatal outcomes were compared using the χ test. Multivariable logistic regression models were used to control for confounders. Results: Of the 10,661 nulliparous women meeting study criteria, the median (50th percentile) length of the first stage was 10.5 hours. Compared with women with a first stage between 2.8 and 30 hours (5th to 95th percentile thresholds), the risk of cesarean delivery was higher (6.1% compared with 13.5%; adjusted odds ratio [OR], 2.28, 95% confidence interval [CI], 1.92-2.72) in women with a first stage longer than 30 hours (greater than the 95th percentile). These women also had higher odds of chorioamnionitis (12.5% compared with 23.5%; adjusted OR, 1.58; 95% CI, 1.25-1.98) and neonatal admission to the neonatal intensive care unit (4.7% compared with 9.8%; adjusted OR, 1.53; 95% CI, 1.18-1.97) but no other associated adverse neonatal outcomes. Conclusion: Women with a prolonged first stage of labor have higher odds of cesarean delivery and chorioamnionitis, but their neonates are not at risk of increased morbidity. © 2010 by The American College of Obstetricians and Gynecologists.


Cammas L.,University of California at San Francisco
Investigative ophthalmology & visual science | Year: 2012

The lens is a powerful model system to study integrin-mediated cell-matrix interaction in an in vivo context, as it is surrounded by a true basement membrane, the lens capsule. To characterize better the function of integrin-linked kinase (ILK), we examined the phenotypic consequences of its deletion in the developing mouse lens. ILK was deleted from the embryonic lens either at the time of placode invagination using the Le-Cre line or after initial lens formation using the Nestin-Cre line. Early deletion of ILK leads to defects in extracellular matrix deposition that result in lens capsule rupture at the lens vesicle stage (E13.5). If ILK was deleted at a later time-point after initial establishment of the lens capsule, rupture was prevented. Instead, ILK deletion resulted in secondary fiber migration defects and, most notably, in cell death of the anterior epithelium (E18.5-P0). Remarkably, dying cells did not stain positively for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or activated-caspase 3, suggesting that they were dying from a non-apoptotic mechanism. Moreover, cross to a Bax(fl/fl)/Bak-/- mouse line that is resistant to most forms of apoptosis failed to promote cell survival in the ILK-deleted lens epithelium. Electron microscopy revealed the presence of numerous membranous vacuoles containing degrading cellular material. CONCLUSIONS. Our study reveals a role for ILK in extracellular matrix organization, fiber migration, and cell survival. Furthermore, to our knowledge we show for the first time that ILK disruption results in non-apoptotic cell death in vivo.


Murnane J.P.,University of California at San Francisco
Cancer Research | Year: 2010

Cancer cells commonly have a high rate of telomere loss, even when expressing telomerase, contributing to chromosome instability and tumor cell progression. This review addresses the hypothesis that this high rate of telomere loss results from a combination of four factors. The first factor is an increase in the frequency of double-strand breaks (dsb) at fragile sites in cancer cells due to replication stress. The second factor is that telomeres are fragile sites. The third factor is that subtelomeric regions are highly sensitive to dsbs, so that dsbs near telomeres have an increased probability of resulting in chromosome instability. The fourth factor is that cancer cells may be deficient in chromosome healing, the de novo addition of telomeres to the sites of dsbs, a mechanism that prevents chromosome instability resulting from dsbs near telomeres. Understanding these factors and how they influence telomere loss will provide important insights into the mechanisms of chromosome instability and the development of novel approaches for anti-cancer therapy. ©2010 AACR.


Alavi M.V.,University of California at San Francisco | Fuhrmann N.,Institute For Medizinische Genetik Und Molekulare Medizin
Molecular Neurodegeneration | Year: 2013

Mitochondrial quality control is fundamental to all neurodegenerative diseases, including the most prominent ones, Alzheimer's Disease and Parkinsonism. It is accomplished by mitochondrial network dynamics - continuous fission and fusion of mitochondria. Mitochondrial fission is facilitated by DRP1, while MFN1 and MFN2 on the mitochondrial outer membrane and OPA1 on the mitochondrial inner membrane are essential for mitochondrial fusion. Mitochondrial network dynamics are regulated in highly sophisticated ways by various different posttranslational modifications, such as phosphorylation, ubiquitination, and proteolytic processing of their key-proteins. By this, mitochondria process a wide range of different intracellular and extracellular parameters in order to adapt mitochondrial function to actual energetic and metabolic demands of the host cell, attenuate mitochondrial damage, recycle dysfunctional mitochondria via the mitochondrial autophagy pathway, or arrange for the recycling of the complete host cell by apoptosis. Most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases. Mutations in one of these genes are associated with a neurodegenerative disease that originally was described to affect retinal ganglion cells only. Since more and more evidence shows that other cell types are affected as well, we would like to discuss the pathology of dominant optic atrophy, which is caused by heterozygous sequence variants in OPA1, in the light of the current view on OPA1 protein function in mitochondrial quality control, in particular on its function in mitochondrial fusion and cytochrome C release. We think OPA1 is a good example to understand the molecular basis for mitochondrial network dynamics. © 2013 Alavi and Fuhrmann; licensee BioMed Central Ltd.


Kemere C.,University of California at San Francisco
PloS one | Year: 2013

Hippocampal information processing is often described as two-state, with a place cell state during movement and a reactivation state during stillness. Relatively little is known about how the network transitions between these different patterns of activity during exploration. Here we show that hippocampal network changes quickly and continuously as animals explore and become familiar with initially novel places. We measured the relationship between moment-by-moment changes in behavior and information flow through hippocampal output area CA1 in rats. We examined local field potential (LFP) patterns, evoked potentials and ensemble spiking and found evidence suggestive of a smooth transition from strong CA3 drive of CA1 activity at low speeds to entorhinal cortical drive of CA1 activity at higher speeds. These changes occurred with changes in behavior on a timescale of less than a second, suggesting a continuous modulation of information processing in the hippocampal circuit as a function of behavioral state.


Seeley W.W.,University of California at San Francisco
Brain structure & function | Year: 2010

The human anterior insula is anatomically and functionally heterogeneous, containing key nodes within distributed speech-language and viscero-autonomic/social-emotional networks. The frontotemporal dementias selectively target these large-scale systems, leading to at least three distinct clinical syndromes. Examining these disorders, researchers have begun to dissect functions which rely on specific insular nodes and networks. In the behavioral variant of frontotemporal dementia, early-stage frontoinsular degeneration begets progressive "Salience Network" breakdown that leaves patients unable to model the emotional impact of their own actions or inactions. Ongoing studies seek to clarify local microcircuit- and cellular-level factors that confer selective frontoinsular vulnerability. The search for frontotemporal dementia treatments will depend on a rich understanding of insular biology and could help clarify specialized human language, social, and emotional functions.


Yeh I.,University of California at San Francisco
Journal of the National Cancer Institute | Year: 2013

BRAF(V600E) mutations are frequent in melanomas originating from intermittently sun-exposed skin and also in common acquired melanocytic nevi, suggesting that BRAF mutation is an early event in melanocytic neoplasia. All neoplastic melanocytes within such a nevus would be expected to carry the BRAF mutation, and thus we evaluated the frequency of cells with BRAF(V600E) mutations within acquired nevi by droplet digital polymerase chain reaction. In BRAF-mutant nevi the number of BRAF mutant alleles equaled the number of wild-type (WT) alleles in the neoplastic cell population, consistent with a fully clonal heterozygous BRAF mutation. The allelic ratio of BRAF(V600E) to BRAF(WT) in the eight VE1-positive nevi, adjusted for degree of stromal contamination, ranged from 0.84 to 1.12 with an average ratio of 1.01. This was confirmed by immunohistochemistry with an antibody specific for BRAF(V600E), which uniformly labeled the neoplastic cells without any evidence of heterogeneity. We found BRAF(V600E) mutations in the melanocytic nevi to be fully clonal, strongly suggesting that BRAF-activating mutations typically are early initiating events in melanocytic neoplasia.


Fischbach M.A.,University of California at San Francisco | Sonnenburg J.L.,Stanford University
Cell Host and Microbe | Year: 2011

In bacterial communities, "tight economic times" are the norm. Of the many challenges bacteria face in making a living, perhaps none are more important than generating energy, maintaining redox balance, and acquiring carbon and nitrogen to synthesize primary metabolites. The ability of bacteria to meet these challenges depends heavily on the rest of their community. Indeed, the most fundamental way in which bacteria communicate is by importing the substrates for metabolism and exporting metabolic end products. As an illustration of this principle, we will travel down a carbohydrate catabolic pathway common to many species of Bacteroides, highlighting the interspecies interactions established (often inevitably) at its key steps. We also discuss the metabolic considerations in maintaining the stability of host-associated microbial communities. © 2011 Elsevier Inc.


Ott M.,University of California at San Francisco | Geyer M.,Max Planck Institute of Molecular Physiology | Zhou Q.,University of California at Berkeley
Cell Host and Microbe | Year: 2011

Thirteen years ago, human cyclin T1 was identified as part of the positive transcription elongation factor b (P-TEFb) and the long-sought host cofactor for the HIV-1 transactivator Tat. Recent years have brought new insights into the intricate regulation of P-TEFb function and its relationship with Tat, revealing novel mechanisms for controlling HIV transcription and fueling new efforts to overcome the barrier of transcriptional latency in eradicating HIV. Moreover, the improved understanding of HIV and Tat forms a basis for studying transcription elongation control in general. Here, we review advances in HIV transcription research with a focus on the growing family of cellular P-TEFb complexes, structural insights into the interactions between Tat, P-TEFb, and TAR RNA, and the multifaceted regulation of these interactions by posttranscriptional modifications of Tat. © 2011 Elsevier Inc.


Marshall W.F.,University of California at San Francisco
Current Biology | Year: 2011

Centrosome size is controlled by a limiting component mechanism in which a fixed quantity of precursor protein is divided up among however many centrosomes are present. This simple scheme explains size control and scaling of centrosomes relative to cell volume. © 2011 Elsevier Ltd All rights reserved.


Geschwind D.H.,Semel Institute | State M.W.,University of California at San Francisco
The Lancet Neurology | Year: 2015

Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment. © 2015 Elsevier Ltd.


CYP3A4, an integral endoplasmic reticulum (ER)-anchored protein, is the major human liver cytochrome P450 enzyme responsible for the disposition of over 50% of clinically relevant drugs. Alterations of its protein turnover can influence drug metabolism, drug-drug interactions, and the bioavailability of chemotherapeutic drugs. Such CYP3A4 turnover occurs via a classical ER-associated degradation (ERAD) process involving ubiquitination by both UBC7/gp78 and UbcH5a/CHIP E2-E3 complexes for 26 S proteasomal targeting. These E3 ligases act sequentially and cooperatively in CYP3A4 ERAD because RNA interference knockdown of each in cultured hepatocytes results in the stabilization of a functionally active enzyme. We have documented that UBC7/gp78-mediated CYP3A4 ubiquitination requires protein phosphorylation by protein kinase (PK) A and PKC and identified three residues (Ser-478, Thr-264, and Ser-420) whose phosphorylation is required for intracellular CYP3A4 ERAD. We document herein that of these, Ser-478 plays a pivotal role in UBC7/gp78-mediated CYP3A4 ubiquitination, which is accelerated and enhanced on its mutation to the phosphomimetic Asp residue but attenuated on its Ala mutation. Intriguingly, CYP3A5, a polymorphically expressed human liver CYP3A4 isoform (containing Asp-478) is ubiquitinated but not degraded to a greater extent than CYP3A4 in HepG2 cells. This suggests that although Ser-478 phosphorylation is essential for UBC7/gp78-mediated CYP3A4 ubiquitination, it is not sufficient for its ERAD. Additionally, we now report that CYP3A4 protein phosphorylation by PKA and/or PKC at sites other than Ser-478, Thr-264, and Ser-420 also enhances UbcH5a/CHIP-mediated ubiquitination. Through proteomic analyses, we identify (i) 12 additional phosphorylation sites that may be involved in CHIP-CYP3A4 interactions and (ii) 8 previously unidentified CYP3A4 ubiquitination sites within spatially associated clusters of Asp/Glu and phosphorylatable Ser/Thr residues that may serve to engage each E2-E3 complex. Collectively, our findings underscore the interplay between protein phosphorylation and ubiquitination in ERAD and, to our knowledge, provide the very first example of gp78 substrate recognition via protein phosphorylation.


Kenyon C.,University of California at San Francisco
Annals of the New York Academy of Sciences | Year: 2010

In the nematode Caenorhabditis elegans and the fruit fly Drosophila, loss of the germline stem cells activates lifespan-extending FOXO-family transcription factors in somatic tissues and extends lifespan, suggesting the existence of an evolutionarily conserved pathway that links reproductive state and aging. Consistent with this idea, reproductive tissues have been shown to influence the lifespans of mice and humans as well. In C. elegans, loss of the germ cells activates a pathway that triggers nuclear localization of the FOXO transcription factor DAF-16 in endodermal tissue. DAF-16 then acts in the endoderm to activate downstream lifespan-extending genes. DAF-16 is also required for inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling to extend lifespan. However, the mechanisms by which inhibition of insulin/IGF-1 signaling and germline loss activate DAF-16/FOXO are distinct. As loss of the germ cells further doubles the already-long lifespan of insulin/IGF-1 pathway mutants, a better understanding of this reproductive longevity pathway could potentially suggest powerful ways to increase healthy lifespan in humans. © 2010 New York Academy of Sciences.


Egeblad M.,Cold Spring Harbor Laboratory | Nakasone E.S.,Cold Spring Harbor Laboratory | Werb Z.,University of California at San Francisco
Developmental Cell | Year: 2010

Solid tumors are not simply clones of cancer cells. Instead, they are abnormal organs composed of multiple cell types and extracellular matrix. Some aspects of tumor development resemble processes seen in developing organs, whereas others are more akin to tissue remodeling. Some microenvironments, particularly those associated with tissue injury, are favorable for progression of mutant cells, whereas others restrict it. Cancer cells can also instruct surrounding tissues to undergo changes that promote malignancy. Understanding the complex ways in which cancer cells interact with their surroundings, both locally in the tumor organ and systemically in the body as a whole, has implications for effective cancer prevention and therapy. © 2010 Elsevier Inc.


Arron S.T.,University of California at San Francisco
Seminars in cutaneous medicine and surgery | Year: 2014

Targeted therapies for cutaneous squamous cell carcinoma (cSCC) remain limited. Extensive genetic heterogeneity complicates a robust molecular characterization of the evolution of cSCC. Nonetheless, potential targeted therapies for this cancer are under investigation, including the inhibition of epidermal growth factor receptor (EGFR), which may yield promising results. In addition, the emergence of immune checkpoint blockade therapy and vaccine-based methods may provide novel treatment strategies for cSCC that are tailored to the individual patient. Ultimately, a combination of such methods may yield a multi-pronged targeted approach to personalize the treatment of cSCC.


Shusterman D.,University of California at San Francisco
Current allergy and asthma reports | Year: 2014

The upper airway (extending from the nares to larynx) fulfills essential physiologic functions, including sensation, air conditioning, filtration, and communication. As the portal of entry for the respiratory tract, the upper airway's sentinel function is performed by the olfactory and trigeminal nerves. Sensory (eye, nose and throat) irritation figures prominently in symptom reporting in so-called "problem buildings," as well as in industrial exposures to irritant gases, vapors, and smokes. Both irritants and allergens can alter function in the upper airway, leading to loss of air conditioning and filtering due to airflow obstruction and hypersecretion. Increasing evidence points to a "unified airway" model of pathogenesis (in which rhinitis may precede the development of asthma). The spectrum of occupational irritant- and allergen-related upper airway health effects-including sensory irritation, olfactory dysfunction, rhinitis, sinusitis, nasal septal perforation, and sinonasal cancer-is reviewed in this article.


Yang J.,University of Queensland | Zaitlen N.A.,University of California at San Francisco | Goddard M.E.,University of Melbourne | Visscher P.M.,University of Queensland | And 2 more authors.
Nature Genetics | Year: 2014

Mixed linear models are emerging as a method of choice for conducting genetic association studies in humans and other organisms. The advantages of the mixed-linear-model association (MLMA) method include the prevention of false positive associations due to population or relatedness structure and an increase in power obtained through the application of a correction that is specific to this structure. An underappreciated point is that MLMA can also increase power in studies without sample structure by implicitly conditioning on associated loci other than the candidate locus. Numerous variations on the standard MLMA approach have recently been published, with a focus on reducing computational cost. These advances provide researchers applying MLMA methods with many options to choose from, but we caution that MLMA methods are still subject to potential pitfalls. Here we describe and quantify the advantages and pitfalls of MLMA methods as a function of study design and provide recommendations for the application of these methods in practical settings. © 2014 Nature America, Inc.


Mouw J.K.,University of California at San Francisco
Nature Reviews Molecular Cell Biology | Year: 2014

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Beemiller P.,University of California at San Francisco
Cold Spring Harbor perspectives in biology | Year: 2010

Although the actin cytoskeleton and T-cell receptor (TCR) signaling complexes are seemingly distinct molecular structures, they are tightly integrated in T cells. The signaling pathways initiated by TCRs binding to peptide MHC complexes are extensively influenced by the actin cytoskeletal activities of the motile phase before TCR signaling, the signalosome scaffolding function of the cytoskeleton, and the translocation of signaling clusters that precedes the termination of signaling at these complexes. As these three successive phases constitute essentially all the steps consequent to immune synapse formation, it has become clear that the substantial physical forces and signaling interactions generated by the actin cytoskeleton dominate the signaling life cycle of TCR signalosomes. We discuss the contributions of the actin cytoskeleton to TCR signaling phases and model some remaining questions about how specific cytoskeletal factors regulate TCR signaling outcomes.


Stephen Kaye H.,University of California at San Francisco
Health Affairs | Year: 2013

The aging of the baby-boom generation, as well as predicted growth in the number of people with disabilities, is expected to increase the demand for long-term services and supports dramatically. This study analyzed data from the Survey of Income and Program Participation from 1984 to 2010 to discern trends among noninstitutionalized working-age adults and the elderly who had some level of disability or need for help with activities of daily living. Some impairments among the elderly, such as in mobility and mental health, decreased. Meanwhile, some impairments among working-age adults, such as in cognitive ability, increased substantially. Of particular importance, the overall prevalence of disability for both age groups has largely stabilized since 2000. Among working-age adults, that stabilization is good news because it eases concern, fueled by prior research, that this population was becoming increasingly disabled and costly to public benefit programs such as Social Security Disability Insurance. However, the flattening of disability trends among the elderly is not good news, since it suggests that the number of elderly people with disabilities will continue to increase in direct proportion to the growing size of the elderly population. Among other implications, the need for both paid workers and unpaid caregivers to assist elderly people, especially those ages seventy-five and older, will continue to increase sharply. © 2013 Project HOPE-The People-to-People Health Foundation, Inc.


Korennykh A.,Princeton University | Walter P.,Howard Hughes Medical Institute | Walter P.,University of California at San Francisco
Annual Review of Cell and Developmental Biology | Year: 2012

The unfolded protein response (UPR) is a network of intracellular signaling pathways that maintain the protein-folding capacity of the endoplasmic reticulum (ER) in eukaryotic cells. Dedicated molecular sensors embedded in the ER membrane detect incompletely folded or unfolded proteins in the ER lumen and activate a transcriptional program that increases the abundance of the ER according to need. In metazoans the UPR additionally regulates translation and thus relieves unfolded protein load by globally reducing protein synthesis. If homeostasis in the ER cannot be reestablished, the metazoan UPR switches from the prosurvival to the apoptotic mode. The UPR involves a complex, coordinated action of many genes that is controlled by one ER-embedded sensor, Ire1, in yeasts, and three sensors, Ire1, PERK, and ATF6, in higher eukaryotes, including human. We discuss the emerging molecular understanding of the UPR and focus on the structural biology of Ire1 and PERK, the two recently crystallized UPR sensors. Copyright © 2012 by Annual Reviews. All rights reserved.


Luce J.M.,University of California at San Francisco | Luce J.M.,San Francisco General Hospital
Chest | Year: 2015

A 13-year-old patient named Jahi McMath was determined to be dead by neurologic criteria following cardiopulmonary arrest and resuscitation at a hospital in Oakland, California. Her family did not agree that she was dead and refused to allow her ventilator to be removed. The family's attorney stated in the media that families, rather than physicians, should decide whether patients are dead and argued in the courts that the families' constitutional rights of religion and privacy would be violated otherwise. Ultimately, a judge agreed that the patient was dead in keeping with California law, but the constitutional issue was undecided. The patient was then transferred to a hospital in New Jersey, a state whose laws allow families to require on religious grounds that death be determined by cardiopulmonary criteria. Although cases such as this are uncommon, they demonstrate public confusion about the concept of neurologic death and the rejection of this concept by some families. The confusion may be caused in part by a lack of uniformity in state laws regarding the legal basis of death, as reflected in the differences between New Jersey and California statutes. Families who reject the determination of death by neurologic criteria on religious grounds should be given reasonable accommodation in all states, but society should not pay for costly treatments for patients who meet these criteria unless the state requires it, as only New Jersey does. Laws that give physicians the right to determine death by neurologic criteria in other states probably can survive a constitutional challenge. Physicians and hospitals faced with similar cases in the future should follow state laws and work through the courts if necessary. © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.


Westhoff G.,University of California at San Francisco
The Cochrane database of systematic reviews | Year: 2013

Active management of the third stage of labour has been shown to reduce the risk of postpartum haemorrhage (PPH) greater than 1000 mL. One aspect of the active management protocol is the administration of prophylactic uterotonics, however, the type of uterotonic, dose, and and discharge from the labour ward (RR 0.18; 95% CI 0.06 to 0.53; three trials, 1091 women; T2 = 0.41, I2 = 41%) and vomiting between delivery of the baby and discharge from the labour ward (RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women; T2 = 0.45, I2 = 30%). Prophylactic oxytocin + ergometrine versus ergot alkaloids: There was no benefit seen in the combination of oxytocin and ergometrine versus ergometrine alone in preventing PPH greater than 500 mL (RR 0.90; 95% CI 0.34 to 2.41; five trials, 2891 women; T2 = 0.89, I2 = 80%). The use of oxytocin and ergometrine was associated with increased mean blood loss (MD 61.0 mL; 95% CI 6.00 to 116.00 mL; fixed-effect analysis; one trial, 34 women; heterogeneity not applicable).In all three comparisons, there was no difference in mean length of the third stage or need for manual removal of the placenta between treatment arms. Prophylactic oxytocin at any dose decreases both PPH greater than 500 mL and the need for therapeutic uterotonics compared to placebo alone. Taking into account the subgroup analyses from both primary outcomes, to achieve maximal benefit providers may opt to implement a practice of giving prophylactic oxytocin as part of the active management of the third stage of labour at a dose of 10 IU given as an IV bolus. If IV delivery is not possible, IM delivery may be used as this route of delivery did show a benefit to prevent PPH greater than 500 mL and there was a trend to decrease the need for therapeutic uterotonics, albeit not statistically significant.Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL; however, in subgroup analysis this benefit did not persist when only randomised trials with low risk of methodologic bias were analysed. Based on this, there is limited high-quality evidence supporting a benefit of prophylactic oxytocin over ergot alkaloids. However, the use of prophylactic oxytocin was associated with fewer side effects, specifically nausea and vomiting, making oxytocin the more desirable option for routine use to prevent PPH.There is no evidence of benefit when adding oxytocin to ergometrine compared to ergot alkaloids alone, and there may even be increased harm as one study showed evidence that using the combination was associated with increased mean blood loss compared to ergot alkaloids alone.Importantly, there is no evidence to suggest that prophylactic oxytocin increases the risk of retained placenta when compared to placebo or ergot alkaloids.More placebo-controlled, randomised, and double-blinded trials are needed to improve the quality of data used to evaluate the effective dose, timing, and route of administration of prophylactic oxytocin to prevent PPH. In addition, more trials are needed especially, but not only, in low- and middle-income countries to evaluate these interventions in the birth centres that shoulder the majority of the burden of PPH in order to improve maternal morbidity and mortality worldwide.


Smith C.C.,University of California at San Francisco
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

The 21st century ushered in the dawn of a new era of targeted therapeutics and a dramatic shift in the management of chronic-phase chronic myeloid leukemia (CP-CML) patients. Groundbreaking scientific and translational studies have led to the rapid development and approval of several effective BCR-ABL tyrosine kinase inhibitors (TKIs). In the United States, there are currently 3 approved BCR-ABL TKIs for newly diagnosed CP-CML patients. It is anticipated that clinical outcomes will continue to improve as more TKIs that address unmet medical needs are approved. However, to achieve this goal, it is critical to carefully monitor and optimally manage patients. To this end, the latest seminal clinical trial results of approved and investigational BCR-ABL TKIs and some of the salient unique features of each of these agents are summarized herein.


Sbitany H.,University of California at San Francisco
Plastic and Reconstructive Surgery | Year: 2014

Background: Postoperative complications after total skin-sparing mastectomy and expander-implant reconstruction can negatively impact outcomes, particularly in the setting of postmastectomy radiation therapy. The authors studied whether rates of ischemic complications after postmastectomy radiation therapy are impacted by the total skin-sparing mastectomy incision. Methods: The authors queried a prospectively collected database of patients undergoing total skin-sparing mastectomy and immediate two-stage expanderimplant reconstruction. Their hypothesis was that, in the setting of radiation therapy, patients with inframammary incisions would be more likely to develop ischemic complications than those without incisions on the dependent portion of the breast. We divided our patient cohort into two groups, those with inframammary incisions and those with other incisions, and then analyzed the proportion that received radiation therapy. Results: Of 756 cases included in the analysis, 91 (12 percent) received postmastectomy radiation therapy, 62 (68.1 percent) with inframammary incisions and 29 (31.9 percent) with other incisions. Mean follow-up was 3.1 years. Rates of mastectomy skin flap necrosis (3.2 percent versus 6.9 percent, p = 0.4) following radiation therapy were not significantly higher in the inframammary group. However, breakdown of the total skin-sparing mastectomy incision was twice as likely in the inframammary group (21 percent versus 10.3 percent, p = 0.2) and was more likely to lead to subsequent implant removal when incisional breakdown occurred (77 percent versus 0 percent, p = 0.03). Conclusions: Total skin-sparing mastectomy incision type may impact rates of incisional breakdown and implant loss following postmastectomy radiation therapy, with higher rates seen with inframammary incisions. Multiple factors, including breast size, breast ptosis, and likelihood of radiation therapy, should be considered in determining optimal incision. Copyright © 2014 by the American Society of Plastic Surgeon.


Cheng C.M.,University of California at San Francisco
Clinical Pharmacology and Therapeutics | Year: 2011

In its 2006 report Preventing Medication Errors, the Institute of Medicine (IOM) estimated that more than 1.5 million preventable adverse drug events (ADEs) occur annually in the United States. Many organizations, including the IOM, the Institute for Safe Medication Practices, the US Food and Drug Administration, and the Leap Frog Group for Patient Safety have advocated the implementation of technologies to reduce ADEs, particularly in the hospital setting. Many technologies have emerged in recent years to reduce ADEs at various points in the medication use process; however, interfacing some of these key technologies with existing hospital systems poses significant challenges. © 2011 American Society for Clinical Pharmacology and Therapeutics.


Verkman A.S.,University of California at San Francisco
Cold Spring Harbor Perspectives in Medicine | Year: 2013

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/ or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Carvalheira J.B.,University of California at San Francisco
Blood | Year: 2013

The rise of obesity and its attendant pathological sequelae, including type 2 diabetes and coronary artery disease, constitute an ongoing public health catastrophe in both the developed and, more recently, the developing world. Although the underlying pathophysiology is complex, chronic low-grade inflammation has emerged as a central driver of both primary metabolic dysfunction and subsequent tissue failure. Importantly, this inflammation has been shown to arise as a consequence of both the disruption of homeostatic tissue resident leukocytes and the recruitment of antagonistic effector cells from the circulation. In this review, we discuss the roles of visceral adipose tissue's salient leukocyte lineages in the transition to obesity and highlight key points at which this emerging immune axis may be manipulated for therapeutic effect.


Raghu G.,University of Washington | Anstrom K.J.,Duke Clinical Research Institute | King Jr. T.E.,University of California at San Francisco | Lasky J.A.,Tulane University | Martinez F.J.,University of Michigan
New England Journal of Medicine | Year: 2012

BACKGROUND: A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown. METHODS: In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups - receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo - in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period. RESULTS: When approximately 50% of data had been collected (with 77 patients in the combination- therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P = 0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here. CONCLUSIONS: Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.) Copyright © 2012 Massachusetts Medical Society.


Reiter J.F.,University of California at San Francisco | Blacque O.E.,University College Dublin | Leroux M.R.,Simon Fraser University
EMBO Reports | Year: 2012

Both the basal body and the microtubule-based axoneme it nucleates have evolutionarily conserved subdomains crucial for cilium biogenesis, function and maintenance. Here, we focus on two conspicuous but underappreciated regions of these structures that make membrane connections. One is the basal body distal end, which includes transition fibres of largely undefined composition that link to the base of the ciliary membrane. Transition fibres seem to serve as docking sites for intraflagellar transport particles, which move proteins within the ciliary compartment and are required for cilium biogenesis and sustained function. The other is the proximal-most region of the axoneme, termed the transition zone, which is characterized by Y-shaped linkers that span from the axoneme to the ciliary necklace on the membrane surface. The transition zone comprises a growing number of ciliopathy proteins that function as modular components of a ciliary gate. This gate, which forms early during ciliogenesis, might function in part by regulating intraflagellar transport. Together with a recently described septin ring diffusion barrier at the ciliary base, the transition fibres and transition zone deserve attention for their varied roles in forming functional ciliary compartments. © 2012 European Molecular Biology Organization.


Yerger V.B.,University of California at San Francisco
Tobacco control | Year: 2011

To determine what the tobacco industry knew about the potential effects of menthol on smoking topography-how a person smokes a cigarette. A snowball strategy was used to systematically search the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu) between 1 June 2010 and 9 August 2010. We qualitatively analysed a final collection of 252 documents related to menthol and smoking topography. The tobacco industry knew that menthol has cooling, anaesthetic and analgesic properties that moderate the harshness and irritation of tobacco. Owing to its physiological effects, menthol contributes to the sensory qualities of the smoke and affects smoking topography and cigarette preference. Our review of industry studies suggests that the amount of menthol in a cigarette is associated with how the cigarette is smoked and how satisfying it is to the smoker. If menthol in cigarettes was banned, as the US Food and Drug Administration (FDA) is currently considering, new/experimental smokers might choose not to smoke rather than experience the harshness of tobacco smoke and the irritating qualities of nicotine. Similarly, established menthol smokers might choose to quit if faced with an unpleasant smoking alternative.


Liu X.,University of Pennsylvania | Jin D.-Y.,University of Hong Kong | McManus M.T.,University of California at San Francisco | Mourelatos Z.,University of Pennsylvania
Molecular Cell | Year: 2012

Assembly of microRNA ribonucleoproteins (miRNPs) or RNA-induced silencing complexes (RISCs) is essential for the function of miRNAs and initiates from processing of precursor miRNAs (pre-miRNAs) by Dicer or by Ago2. Here, we report an in vitro miRNP/RISC assembly assay programmed by pre-miRNAs from mammalian cell lysates. Combining in vivo studies in Dicer Knockout cells reconstituted with wild-type or catalytically inactive Dicer, we find that the miRNA loading complex (miRLC) is the primary machinery linking pre-miRNA processing to miRNA loading. We show that a miRNA precursor deposit complex (miPDC) plays a crucial role in Dicer-independent miRNA biogenesis and promotes miRNP assembly of certain Dicer-dependent miRNAs. Furthermore, we find that 5'-uridine, 3'-mid base pairing, and 5'-mid mismatches within pre-miRNAs promote their assembly into miPDC. Our studies provide a comprehensive view of miRNP/RISC assembly pathways in mammals, and our assay provides a versatile platform for further mechanistic dissection of such pathways in mammals. © 2012 Elsevier Inc.


Ho T.C.,University of California at San Francisco
Channels (Austin, Tex.) | Year: 2012

We recorded the activity of single mechanosensitive (MS) ion channels from membrane patches on single muscle fibers isolated from mice. We investigated the actions of various TRP (transient receptor potential) channel blockers on MS channel activity. 2-aminoethoxydiphenyl borate (2-APB) neither inhibited nor facilitated single channel activity at submillimolar concentrations. The absence of an effect of 2-APB indicates MS channels are not composed purely of TRPC or TRPV1, 2 or 3 proteins. Exposing patches to 1-oleolyl-2-acetyl-sn-glycerol (OAG), a potent activator of TRPC channels, also had no effect on MS channel activity. In addition, flufenamic acid and spermidine had no effect on the activity of single MS channels. By contrast, SKF-96365 and ruthenium red blocked single-channel currents at micromolar concentrations. SKF-96365 produced a rapid block of the open channel current. The blocking rate depended linearly on blocker concentration, while the unblocking rate was independent of concentration, consistent with a simple model of open channel block. A fit to the concentration-dependence of block gave k(on) = 13 x 10 ( 6) M (-1) s (-1) and k(off) = 1609 sec (-1) with K(D) = ~124 μM. Block by ruthenium red was complex, involving both reduction of the amplitude of the single-channel current and increased occupancy of subconductance levels. The reduction in current amplitude with increasing concentration of ruthenium red gave a K(D) = ~49 μM. The high sensitivity of MS channels to block by ruthenium red suggests MS channels in skeletal muscle contain TRPV subunits. Recordings from skeletal muscle isolated from TRPV4 knockout mice failed to show MS channel activity, consistent with a contribution of TRPV4. In addition, exposure to hypo-osmotic solutions increases opening of MS channels in muscle. Our results provide evidence TRPV4 contributes to MS channels in skeletal muscle.


Murnane J.P.,University of California at San Francisco
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2012

The ends of chromosomes are composed of a short repeat sequence and associated proteins that together form a cap, called a telomere, that keeps the ends from appearing as double-strand breaks (DSBs) and prevents chromosome fusion. The loss of telomeric repeat sequences or deficiencies in telomeric proteins can result in chromosome fusion and lead to chromosome instability. The similarity between chromosome rearrangements resulting from telomere loss and those found in cancer cells implicates telomere loss as an important mechanism for the chromosome instability contributing to human cancer. Telomere loss in cancer cells can occur through gradual shortening due to insufficient telomerase, the protein that maintains telomeres. However, cancer cells often have a high rate of spontaneous telomere loss despite the expression of telomerase, which has been proposed to result from a combination of oncogene-mediated replication stress and a deficiency in DSB repair in telomeric regions. Chromosome fusion in mammalian cells primarily involves nonhomologous end joining (NHEJ), which is the major form of DSB repair. Chromosome fusion initiates chromosome instability involving breakage-fusion-bridge (B/F/B) cycles, in which dicentric chromosomes form bridges and break as the cell attempts to divide, repeating the process in subsequent cell cycles. Fusion between sister chromatids results in large inverted repeats on the end of the chromosome, which amplify further following additional B/F/B cycles. B/F/B cycles continue until the chromosome acquires a new telomere, most often by translocation of the end of another chromosome. The instability is not confined to a chromosome that loses its telomere, because the instability is transferred to the chromosome donating a translocation. Moreover, the amplified regions are unstable and form extrachromosomal DNA that can reintegrate at new locations. Knowledge concerning the factors promoting telomere loss and its consequences is therefore important for understanding chromosome instability in human cancer. © 2011 Elsevier B.V.


Murray J.F.,University of California at San Francisco
American Journal of Respiratory and Critical Care Medicine | Year: 2012

U.S. taxpayers and scientists throughout the world are profiting enormously from the Human Genome Project and will continue to profit in the foreseeable future. Sensational technical advances, which show no signs of slowing, are constantly depressing the price of genomic profiling, and it looks like the NIH's goal of $1000 per analysis might be met before its projected appearance in 2014. Initial efforts to translate the immense cache of fundamental genomic information into improvements in the practice of medicine were both natural and obligatory according to the precedents of science. Though the accomplishments of the more than a decade of all-out research have been disappointing, they were accompanied by an indisputable message: getting from where we are today to where preconceived visions are leading us is going to be immensely more complicated, more time consuming, and more costly than imagined at the outset. My chief complaint is directed at the efforts to co-opt the term "personalized medicine," which doctors have been consistently practicing for centuries. While contemplating this criticism, the powers-that-be should also reappraise where the benefits of hoped-for clinical applications of genomic analysis stand in competition with the need for continued funding in support of traditional basic science and clinical research, which have so greatly enriched the current practice of personalized medicine. Copyright © 2012 by the American Thoracic Society.


Previous studies indicate multiple influences on the overall health of HIV-infected persons; however, few assess and rank longitudinal changes in social and structural barriers that are disproportionately found in impoverished populations. We empirically ranked factors that longitudinally impact the overall health status of HIV-infected homeless and unstably housed men. Between 2002 and 2008, a cohort of 288 HIV+ homeless and unstably housed men was recruited and followed over time. The population was 60% non-Caucasian and the median age was 41 years; 67% of study participants reported recent drug use and 20% reported recent homelessness. At baseline, the median CD4 cell count was 349 cells/μl and 18% of eligible persons (CD4<350) took antiretroviral therapy (ART). Marginal structural models were used to estimate the population-level effects of behavioral, social, and structural factors on overall physical and mental health status (measured by the SF-36), and targeted variable importance (tVIM) was used to empirically rank factors by their influence. After adjusting for confounding, and in order of their influence, the three factors with the strongest negative effects on physical health were unmet subsistence needs, Caucasian race, and no reported source of instrumental support. The three factors with the strongest negative effects on mental health were unmet subsistence needs, not having a close friend/confidant, and drug use. ART adherence >90% ranked 5th for its positive influence on mental health, and viral load ranked 4th for its negative influence on physical health. The inability to meet food, hygiene, and housing needs was the most powerful predictor of poor physical and mental health among homeless and unstably housed HIV-infected men in an urban setting. Impoverished persons will not fully benefit from progress in HIV medicine until these barriers are overcome, a situation that is likely to continue fueling the US HIV epidemic.


Pazarentzos E.,University of California at San Francisco
Oncogene | Year: 2015

Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs widely in human cancers. Although somatic mutations in the PI3K pathway genes PIK3CA and PTEN are known to drive PI3K pathway activation and cancer growth, the significance of somatic mutations in other PI3K pathway genes is less clear. Here, we establish the signaling and oncogenic properties of a recurrent somatic mutation in the PI3K p110β isoform that resides within its kinase domain (PIK3CβD1067V). We initially observed PIK3CβD1067V by exome sequencing analysis of an EGFR-mutant non-small cell lung cancer (NSCLC) tumor biopsy from a patient with acquired erlotinib resistance. On the basis of this finding, we hypothesized that PIK3CβD1067V might function as a novel tumor-promoting genetic alteration, and potentially an oncogene, in certain cancers. Consistent with this hypothesis, analysis of additional tumor exome data sets revealed the presence of PIK3CβD1067V at low frequency in other patient tumor samples (including renal cell carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, melanoma, thyroid carcinoma and endometrial carcinoma). Functional studies revealed that PIK3CβD1067V promoted PI3K pathway signaling, enhanced cell growth in vitro, and was sufficient for tumor formation in vivo. Pharmacologic inhibition of PIK3Cβ with TGX-221 (isoform-selective p110β inhibitor) specifically suppressed growth in patient-derived renal-cell carcinoma cells with endogenous PIK3CβD1067V and in NIH-3T3 and human EGFR-mutant lung adenocarcinoma cells engineered to express this mutant PI3K. In the EGFR-mutant lung adenocarcinoma cells, expression of PIK3CβD1067V also promoted erlotinib resistance. Our data establish a novel oncogenic form of PI3K, revealing the signaling and oncogenic properties of PIK3CβD1067V and its potential therapeutic relevance in cancer. Our findings provide new insight into the genetic mechanisms underlying PI3K pathway activation in human tumors and indicate that PIK3CβD1067V is a rational therapeutic target in certain cancers.Oncogene advance online publication, 18 May 2015; doi:10.1038/onc.2015.173. © 2015 Macmillan Publishers Limited


Stewart L.,University of California at San Francisco
Surgical Clinics of North America | Year: 2014

Because it offers several advantages over open cholecystectomy, laparoscopic cholecystectomy has largely replaced open cholecystectomy for the management of symptomatic gallstone disease. The only potential disadvantage is a higher incidence of major bile duct injury. Although prevention of these biliary injuries is ideal, when they do occur, early identification and appropriate treatment are critical to improving the outcomes of patients suffering a major bile duct injury. This report delineates the key factors in classification (and its relationship to mechanism and management), identification (intraoperative and postoperative), and management principles of these bile duct injuries. © 2014.


Ryan C.J.,University of California at San Francisco
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

In the phase III study COU-AA-301, abiraterone acetate (AA) plus prednisone (P) prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel administration. In this article, we investigate the relationship between baseline serum androgen (SA) levels and OS. COU-AA-301 is a randomized, double-blind study of AA (1,000 mg every day) plus P (5 mg by mouth twice daily; n = 797) versus P alone (n = 398). Randomization was stratified by Eastern Cooperative Oncology Group performance status (0 to 1 v 2), pain (Brief Pain Inventory-Short Form over past 24 hours: 4 to 10, present; v 0 to 3, absent), prior chemotherapy (1 v 2), and progression (prostate-specific antigen v radiographic). Association of baseline SA (testosterone, androstenedione, dehydroepiandrosterone sulfate), was measured by ultrasensitive liquid-liquid extraction or protein precipitation and two-dimensional liquid chromatography coupled to mass spectrometry, with OS determined by bivariate and multivariable Cox models. OS was examined with SA as greater than median and less than or equal to the median. Median survival increased with each quartile increase in testosterone level regardless of treatment arm. SA levels at baseline strongly associated with survival (P < .0001) in bivariate and multivariable analyses. Longer survival was observed for patients with SA above median compared with below median in both the AA and P arms (eg, testosterone, AA; hazard ratio, 0.64; 95% CI, 0.53 to 0.77; P < .0001). Treatment with AA led to longer survival versus P alone in the above- or below-median group for all androgens. SA, measured with a novel ultrasensitive assay in COU-AA-301, is prognostic for OS and may be useful for risk stratification in mCRPC clinical trials.


Maru D.,University of Houston | Venook A.P.,University of California at San Francisco | Ellis L.M.,The Surgical Center
Clinical Cancer Research | Year: 2013

Therapy targeting VEGF has become the standard of care in several solid malignancies. Early investigations attempting to identify predictive markers for the efficacy of therapy failed to identify any predictive markers that could help oncologists decide who should - and, more importantly, who should not - receive VEGF-targeted therapies. However, interest has been renewed in predictive biomarkers for VEGF-targeted therapies, especially in light of the fact that the U.S. Food and Drug Administration withdrew approval for use of bevacizumab, an antibody to VEGF, in patients with metastatic breast cancer. In a recent publication in the Journal of Clinical Oncology, investigators identified circulating VEGF and tumor neuropilin-1 expression as potential predictive biomarkers for bevacizumab. From this perspective, we provide a critical evaluation of the use of these markers and the need for validation in prospective clinical trials. ©2013 AACR.


Miller W.L.,University of California at San Francisco
Molecular and Cellular Endocrinology | Year: 2013

The adrenal is a small gland that escaped anatomic notice until the 16th century, and whose essential role in physiology was not established until the mid 19th century. Early studies were confounded by failure to distinguish the effects of the cortex from those of the medulla, but advances in steroid chemistry permitted the isolation, characterization and synthesis of many steroids by the mid 20th century. Knowledge of steroid structures, radiolabeled steroid conversions, and the identification of accumulated urinary steroids in diseases of steroidogenesis permitted a generally correct description of the steroidogenic pathways, but one confounded by the failure to distinguish species-specific differences. The advent of cloning technologies and molecular genetics rapidly corrected and clarified the understanding of steroidogenic processes. Our laboratory in San Francisco was one of several contributing to this effort, focusing on human steroidogenic enzymes, the genetic disorders in their biosynthesis and the transcriptional and post-translational mechanisms regulating enzyme activity. © 2012 Walter L. Miller.


Madhani H.D.,University of California at San Francisco
Cell | Year: 2013

Eukarytotic gene expression is frustrated by a series of steps that are generally not observed in prokaryotes and are therefore not essential for the basic chemistry of transcription and translation. Their evolution may have been driven by the need to defend against parasitic nucleic acids. © 2013 Elsevier Inc.


Blackburn E.H.,University of California at San Francisco
Cold Spring Harbor perspectives in biology | Year: 2011

Telomerase is a eukaryotic ribonucleoprotein (RNP) whose specialized reverse transcriptase action performs de novo synthesis of one strand of telomeric DNA. The resulting telomerase-mediated elongation of telomeres, which are the protective end-caps for eukaryotic chromosomes, counterbalances the inevitable attrition from incomplete DNA replication and nuclease action. The telomerase strategy to maintain telomeres is deeply conserved among eukaryotes, yet the RNA component of telomerase, which carries the built-in template for telomeric DNA repeat synthesis, has evolutionarily diverse size and sequence. Telomerase shows a distribution of labor between RNA and protein in aspects of the polymerization reaction. This article first describes the underlying conservation of a core set of structural features of telomerase RNAs important for the fundamental polymerase activity of telomerase. These include a pseudoknot-plus-template domain and at least one other RNA structural motif separate from the template-containing domain. The principles driving the diversity of telomerase RNAs are then explored. Much of the diversification of telomerase RNAs has come from apparent gain-of-function elaborations, through inferred evolutionary acquisitions of various RNA motifs used for telomerase RNP biogenesis, cellular trafficking of enzyme components, and regulation of telomerase action at telomeres. Telomerase offers broadly applicable insights into the interplay of protein and RNA functions in the context of an RNP enzyme.


Preservation of the nipple-areolar complex with total skin-sparing mastectomy is becoming a popular mastectomy technique. As experience increases, the patient inclusion criteria for total skin sparing mastectomy expand. The authors assessed outcomes of total skin-sparing mastectomy and immediate prosthetic reconstruction in women with a prior history of augmentation mammaplasty. Between 2005 and 2012, all women with a history of augmentation mammaplasty and implants in place, undergoing total skin-sparing mastectomy and immediate prosthetic reconstruction, were prospectively tracked. Patient demographics, expander coverage type, adjuvant treatment, and incidence of complications were analyzed. Outcomes in these patients were compared with those of patients undergoing the same operation, without prior augmentation history. Thirty-four women with prior augmentation underwent total skin-sparing mastectomy and immediate tissue expander placement on 51 breasts. Comparison to the nonaugmentation group showed similar rates of superficial nipple necrosis (0 percent, p=0.324), complete nipple necrosis (0 percent, p=0.324), and skin flap necrosis (4 percent, p=1.0). The prior augmentation group did have a higher rate of implant loss (10 percent, p=0.515), with all but one of these occurring in irradiated patients. Total skin-sparing mastectomy and immediate prosthetic reconstruction is a safe technique in women with a history of augmentation mammaplasty. The preferred reconstructive technique is immediate submuscular tissue expander placement. In the setting of no radiation history, this operation carries a safety profile similar to that of patients without a history of prior augmentation, and can be offered safely. Risk, II.


Woolley S.C.,McGill University | Kao M.H.,University of California at San Francisco
Neuroscience | Year: 2015

Many motor behaviors, from walking to speaking, are acquired through experience, in particular, through trial-and-error learning. The acquisition and maintenance of such motor behaviors in a wide range of species, including humans, appear to depend on cortical-basal ganglia circuits. In this review, we discuss recent studies in songbirds that have been pivotal in informing our current understanding of motor learning and cortical-basal ganglia function. Songbirds are important ethological model systems for the study of motor learning because young songbirds naturally develop and refine their songs through trial-and-error learning. In addition, reinforcement mechanisms are hypothesized to be important for the maintenance and plasticity of structured adult song. Computational and experimental studies highlight the importance of vocal motor variability as the substrate upon which reinforcement mechanisms could operate to shape developing song and to maintain adult song. Recent studies in songbirds indicate that this vocal motor variability is actively generated and modulated by a highly specialized cortical-basal ganglia circuit evolved for a single behavior, song. We argue that these and other recent findings illustrate how the tight association between a specialized neural circuit and a natural behavior make songbirds a unique and powerful model in which to investigate the neural substrates of motor learning and plasticity. © 2014 IBRO.


Shusterman D.,University of California at San Francisco
Proceedings of the American Thoracic Society | Year: 2011

The nose and upper airway play a sentinel role in the respiratory tract, alertinganindividual tothequalitiesof theinspiredatmosphere. Theupper airway alsoclears contaminants fromtheinspiredairstream and physically conditions inspired air before its entry into the lower respiratory tract. Given these anatomical and functional considerations, the nose may be the initial - or even prime - target of air pollutants. This article reviews the functional anatomy of the upper airway in humans, its vulnerabilities to various classes of air contaminants, and the relationship between chemical irritation and allergic inflammation in the upper airway.


An international working group has modified the Atlanta classification for acute pancreatitis to update the terminology and provide simple functional clinical and morphologic classifications. The modifications (a) address the clinical course and severity of disease, (b) divide acute pancreatitis into interstitial edematous pancreatitis and necrotizing pancreatitis, (c) distinguish an early phase (1st week) and a late phase (after the 1st week), and (d) emphasize systemic inflammatory response syndrome and multisystem organ failure. In the 1st week, only clinical parameters are important for treatment planning. After the 1st week, morphologic criteria defined on the basis of computed tomographic findings are combined with clinical parameters to help determine care. This revised classification introduces new terminology for pancreatic fluid collections. Depending on presence or absence of necrosis, acute collections in the first 4 weeks are called acute necrotic collections or acute peripancreatic fluid collections. Once an enhancing capsule develops, persistent acute peripancreatic fluid collections are referred to as pseudocysts; and acute necrotic collections, as walled-off necroses. All can be sterile or infected. Terms such as pancreatic abscess and intrapancreatic pseudocyst have been abandoned. The goal is for radiologists, gastroenterologists, surgeons, and pathologists to use the revised classifications to standardize imaging terminology to facilitate treatment planning and enable precise comparison of results among different departments and institutions. © RSNA, 2012.


Vincenti F.,University of California at San Francisco
Kidney International | Year: 2012

The goal of research in transplant therapeutics is to achieve safe and effective immunosuppression strategies that allow durable engraftment free of toxicities. The calcineurin inhibitors (CNIs) regimens, because of their inherent toxicities (including nephrotoxicity), have been unable to meet these promises. Over the past decade acute cellular rejection decreased dramatically with a concomitant robust increase in 1-year graft survival; however, long-term graft outcome showed only modest improvement. This is due in part to the toxicities of the immunosuppressive drugs. The quest for a toxicity-free-CNI- free regimen has been both intense and frustrating. A turning point in CNIs-free therapy may have occurred with the recent approval of belatacept, which represents a new paradigm in immunosuppression: biological therapy for chronic immunosuppression devoid of the usual toxicities associated with the CNIs. Belatacept, a fusion receptor protein, blocks costimulation signals necessary for the activation of T cells. Although costimulation blockade has not been shown to induce tolerance, it can provide safe and effective immunosuppression without renal or cardiovascular toxicities. The approval of belatacept in both the United States and Europe for use in renal transplantation will finally push CNI-free regimens into prime time. Novel biologics such as ASKP1240 (a human anti-CD40 monoclonal antibody) and one small molecule, tofacitinib, may advance further the use of CNI-free regimens in organ transplantation. © 2012 International Society of Nephrology.


Sepulveda J.,University of California at San Francisco
Health Affairs | Year: 2012

There is growing optimism in the global health community that the HIV epidemic can be halted. After decades of relying primarily on behavior change to prevent HIV transmission, a second generation of prevention efforts based on medical or biological interventions such as male circumcision and preexposure prophylaxis-the use of antiretroviral drugs to protect uninfected, at-risk individuals-has shown promising results. This article calls for a third generation of HIV prevention efforts that would integrate behavioral, biological, and structural interventions focused on the social, political, and environmental underpinnings of the epidemic, making use of local epidemiological evidence to target affected populations. In this third wave, global programs should deliver HIV prevention services together with cost-effective interventions for reproductive health and for tuberculosis, malaria, and other diseases. Additionally, new efforts are needed to address gaps in HIV prevention research, evaluation, and implementation. Increased and sustained funding, along with evidence-based allocation of funds, will be necessary to accelerate the decline in new HIV infections. © 2012 Project HOPE-The People-to-People Health Foundation, Inc.


McCormick F.,University of California at San Francisco
Current Opinion in Genetics and Development | Year: 2011

Mutant onco-proteins play a direct, causal role in cancer and are therefore considered attractive drug targets. Clinical experience has supported this view, with some exceptions.However, clinical benefit has often been restricted by rapid emergence of drug-resistant clones through several distinct mechanisms. This problem can, in principle, be addressed through cocktails containing several drugs. However, the number of tumors whose survival is dependent on a single, druggable mutant onco-protein is currently unknown. The majority of tumors may be driven either by single drivers that are un-druggable, or by combinations of drivers. In both cases, new approaches will be necessary. Development of systemic RNA interference may be a solution to these problems. © 2010 Elsevier Ltd.


Levitt J.E.,Stanford University | Matthay M.A.,University of California at San Francisco
Critical Care | Year: 2012

Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation. © 2012 BioMed Central Ltd.


Ramo D.E.,University of California at San Francisco
Addiction science & clinical practice | Year: 2012

There is elevated prevalence of marijuana use among young adults who use tobacco, but little is known about the extent of co-use generated from surveys conducted online. The purpose of the present study was to examine past-month marijuana use and the co-use of marijuana and tobacco in a convenience sample of young adult smokers with national US coverage. Young adults age 18 to 25 who had smoked at least one cigarette in the past 30 days were recruited online between 4/1/09 and 12/31/10 to participate in an online survey on tobacco use. We examined past 30 day marijuana use, frequency of marijuana use, and proportion of days co-using tobacco and marijuana by demographic characteristics and daily smoking status. Of 3512 eligible and valid survey responses, 1808 (51.5%) smokers completed the survey. More than half (53%, n = 960) of the sample reported past-month marijuana use and reported a median use of 18 out of the past 30 days (interquartile range [IR] = 4, 30). Co-use of tobacco and marijuana occurred on nearly half (median = 45.5%; IR = 13.1, 90.3) of the days on which either substance was used and was more frequent among Caucasians, respondents living in the Northeast or in rural areas, in nonstudents versus students, and in daily versus nondaily smokers. Residence in a state with legalized medical marijuana was unrelated to co-use or even the prevalence of marijuana use in this sample. Age and household income also were unrelated to co-use of tobacco and marijuana. These results indicate a higher prevalence of marijuana use and co-use of tobacco in young adult smokers than is reported in nationally representative surveys. Cessation treatments for young adult smokers should consider broadening intervention targets to include marijuana.


Blanc P.D.,University of California at San Francisco
Journal of Asthma | Year: 2012

Background and aims. This review summarizes the scientific literature relevant to occupational risk factors for chronic obstructive pulmonary disease (COPD). Material and methods. This review emphasizes recent work in the field, while placing this in the context of two previous systematic reviews of the subject. Results. Both the earlier summaries of the literature estimated that the population attributable risk percent (PAR%) of COPD linked to occupational exposures is approximately 15%. More recent studies also strongly support the association between workplace exposures and COPD. Among never smokers, the PAR% for work-related factors may approach 40%. Emerging data also indicate that occupational exposures, at a minimum, are additive to smoking-associated risk of COPD. Conclusions. The PAR% for work-related COPD is at least 15%. Scientific significance. The consistency, strength, and plausibility of these data support a causal relationship between occupational exposures and COPD. © 2012 Informa Healthcare USA, Inc.


Anderson S.J.,University of California at San Francisco
Tobacco control | Year: 2011

To examine tobacco industry marketing of menthol cigarettes and to determine what the tobacco industry knew about consumer perceptions of menthol. A snowball sampling design was used to systematically search the Legacy Tobacco Documents Library (LTDL) (http://legacy.library.ucsf.edu) between 28 February and 27 April 2010. Of the approximately 11 million documents available in the LTDL, the iterative searches returned tens of thousands of results from the major US tobacco companies and affiliated organisations. A collection of 953 documents from the 1930s to the first decade of the 21st century relevant to 1 or more of the research questions were qualitatively analysed, as follows: (1) are/were menthol cigarettes marketed with health reassurance messages? (2) What other messages come from menthol cigarette advertising? (3) How do smokers view menthol cigarettes? (4) Were menthol cigarettes marketed to specific populations? Menthol cigarettes were marketed as, and are perceived by consumers to be, healthier than non-menthol cigarettes. Menthol cigarettes are also marketed to specific social and demographic groups, including African-Americans, young people and women, and are perceived by consumers to signal social group belonging. The tobacco industry knew consumers perceived menthol as healthier than non-menthol cigarettes, and this was the intent behind marketing. Marketing emphasising menthol attracts consumers who may not otherwise progress to regular smoking, including young, inexperienced users and those who find 'regular' cigarettes undesirable. Such marketing may also appeal to health-concerned smokers who might otherwise quit.


Starr P.A.,University of California at San Francisco
Movement disorders : official journal of the Movement Disorder Society | Year: 2011

This article reviews the available literature related to the surgical technique for implantation of deep brain stimulation (DBS) hardware for the treatment of dystonia. Topics covered include stereotactic targeting, selection of specific hardware components, site of placement of the cable connectors and pulse generators, and postoperative documentation of electrode location. Techniques in stereotactic neurosurgery are rapidly evolving, and there is no Class I evidence to unequivocally validate any specific technique described. Nevertheless, the guidelines provided may assist surgical teams in tailoring a rational approach to DBS implantation in dystonia. Copyright © 2011 Movement Disorder Society.


Stamper R.L.,University of California at San Francisco
Optometry and Vision Science | Year: 2011

Doctors have not always associated elevated intraocular pressure with the vision loss from glaucoma. Although several individuals appear to have noted firmness of the eye in this condition as far back as the 10th century, elevated intraocular pressure was not routinely assessed until the latter part of the 19th century. von Graefe developed the first instrument for measuring intraocular pressure in 1865. The first reasonably accurate instrument was the Maklakoff applanation tonometer of the late 19th century; it was in widespread use throughout Eastern Europe until relatively recently. Schiötz developed an indentation tonometer that was widely used throughout the world during the first two thirds of the 20th century. Goldmann's applanation tonometer of 1950 began the era of truly accurate intraocular pressure measurement. It is still the most widely used tonometer in the world. Other devices such as the McKay-Marg tonometer (or its offspring the Tono-Pen), the pneumatonometer, and airpuff applanation tonometers are gaining adherents. The dynamic contour tonometer is the first totally new concept in tonometry in over 100 years. It is probably the most accurate of all the tonometers and is relatively independent of corneal biomechanical properties unlike its predecessors. Transpalpebral tonometers are attractive as they do not require topical anesthesia; however, they add the biomechanical properties of the eyelid to the list of potential errors and have not proven very accurate. The future should, hopefully, bring tonometers that can give diurnal or even longer indications of intraocular pressure variation. Although intraocular pressure elevation (or its absence) no longer can be counted on for diagnostic purposes, the role of intraocular pressure in the management of glaucomatous optic neuropathy remains critical. Copyright © 2011 American Academy of Optometry.


Rosenthal P.J.,University of California at San Francisco
Molecular Microbiology | Year: 2013

Summary: Controlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymorphisms on parasite fitness have been characterized in vitro and in animal models. Additional insights have come from analyses of samples from clinical studies, both evaluating parasites under different selective pressures and determining the clinical consequences of infection with different parasites. With some exceptions, resistance-mediating polymorphisms lead to malaria parasites that, compared with wild type, grow less well in culture and in animals, and are replaced by wild type when drug pressure diminishes in the clinical setting. In some cases, the fitness costs of resistance may be offset by compensatory mutations that increase virulence or changes that enhance malaria transmission. However, not enough is known about effects of resistance mediators on parasite fitness. A better appreciation of the costs of fitness-mediating mutations will facilitate the development of optimal guidelines for the treatment and prevention of malaria. © 2013 John Wiley & Sons Ltd.


Seeley E.J.,University of California at San Francisco
Advances in Chronic Kidney Disease | Year: 2013

Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults and can result from several predisposing factors, such as sepsis and trauma, which also predispose patients to acute kidney injury (AKI). Animal models of AKI and ARDS suggest that AKI increases inflammatory cytokines in the circulation such that IL-6 may be a direct mediator of AKI induced lung injury. When ARDS and AKI overlap, intensive care unit length of stay, resource utilization, and mortality increase dramatically. New evidence suggests that the prevalence and clinical implications of even mild AKI in patients with ARDS is likely underestimated. The cornerstone of therapy for ARDS continues to be low tidal volume ventilation, and more recent trials illustrate that diuretic administration to shock-free ARDS patients may help them avoid the deleterious effects of volume overload. This review focuses on new developments in the care of ARDS patients with a specific focus on interactions between the lungs and kidneys in patients with overlapping ARDS and AKI. © 2013 National Kidney Foundation, Inc.


Anglemyer A.,University of California at San Francisco
Cochrane database of systematic reviews (Online) | Year: 2011

Antiretroviral drugs have been shown to reduce risk of mother-to-child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Observational data, ecological studies and models suggest that sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART). To determine if ART use in an HIV-infected member of an HIV-discordant couple is associated with lower risk of HIV transmission to the uninfected partner compared to untreated discordant couples. We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language. Randomised controlled trials, cohort studies and case-control studies of HIV-discordant couples in which the HIV-infected member of the couple was being treated or not treated with ART DATA COLLECTION AND ANALYSIS: Abstracts of all trials identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 1814 references and examined 23 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form. Seven observational studies and no randomised controlled trials were included in the review. These seven studies identified 436 episodes of HIV transmisison, 71 among treated couples and 365 among untreated couples. The summary rate ratio for all seven studies was 0.34 [95% CI 0.13, 0.92], with substantial heterogeneity (I(2)=73%). After excluding two studies with inadequate person-time data, we found a summary rate ratio of 0.16 [95% CI 0.07, 0.35] with no noted heterogeneity (I(2)=0%). We also performed subgroup analyses to see if the effect of ART on prevention of HIV differed by the index partner's CD4 cell count. Among couples in which the infected partner had >350 CD4 cells/μL, we estimated a rate ratio of 0.02 [95% CI 0.00, 2.87]. In this subgroup, there were 61 transmissions in untreated couples and none in treated couples. ART appears to be a potent intervention for prevention of HIV in discordant couples. However, the most important question from a clinical standpoint is whether being in a serodiscordant sexual relationship and having >350 CD4 cells/μL should be an indication for ART. In our analysis, there were broad confidence intervals in this subgroup, overlapping the null hypothesis of no effect. There is currently one large randomised controlled trial in the field, whose results are scheduled to be ready in 2015. Significant questions remain about durability of protection, when to start treating an infected partner (for instance, at diagnosis or at a specific CD4 level) and transmission of ART-resistant strains to partners.


Carrico A.W.,University of California at San Francisco
Life Sciences | Year: 2011

Prior to the era of highly active anti-retroviral therapy (HAART), cohort studies provided equivocal evidence to support the hypothesis that substance use predicts more rapid HIV disease progression. The present review examined the effects of substance use on HIV disease progression in cohort studies with follow-up that continued into the HAART era. Of the 20 studies included in this review, 16 observed that substance use predicted at least one indicator of HIV disease progression. Ten of the 11 studies that followed participants exclusively in the HAART era observed an effect of substance use on HIV disease progression. Findings across studies indicate that stimulant use promotes more rapid HIV disease progression and the effects of substance use on HIV disease progression can persist after controlling for self-reported HAART non-adherence. Future investigations that examine the bio-behavioral pathways whereby substance use promotes HIV disease progression should include: measures of HIV genotypic and phenotypic resistance, multi-method assessment of adherence, and assessment of co-morbid infections that are more prevalent among substance users. Although further mechanistic research is needed, findings from existing cohort studies have clear clinical implications. Implementing screening, brief intervention and referral to substance abuse treatment in HIV medical care could optimize health outcomes and decrease HIV transmission rates by boosting the effectiveness of "Test and Treat" approaches to HIV prevention. © 2010 Elsevier Inc. All rights reserved.


Aghajanova L.,University of California at San Francisco
Current Opinion in Obstetrics and Gynecology | Year: 2010

Purpose of review To review the recent literature on the involvement and importance of leukemia inhibitory factor (LIF) in the human implantation process, and the attempts using LIF-based interventions to improve assisted reproductive technologies (ARTs) outcome in women with recurrent implantation failure. Recent findings High LIF expression is an indicator of receptive endometrium in fertile women. However, in infertile individuals, the data on endometrial LIF expression and secretion are controversial. Even after ruling out other causes of infertility, such as tubal, endocrine, male factor, and endometriosis, LIF-only detection is not sufficient for assessment of implantation potential in women with unexplained infertility. This is obviously in contrast to evidence of the crucial role of LIF in mouse endometrial physiology. In a large multicenter study, recombinant human LIF failed to improve the outcome of IVF treatment in women with recurrent implantation failure. Summary A better comprehension of the mechanisms underlying endometrial receptivity and implantation should guide clinicians through proper management and treatment of infertility and implantation failure, and may eventually enable widespread adherence to single embryo transfer practices. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Criswell L.A.,University of California at San Francisco
Immunological Reviews | Year: 2010

During the past several years, substantial progress has been made in the identification of genetic variants that predispose to rheumatoid arthritis (RA) and other autoimmune disorders. Progress in this area has been facilitated by the availability of new technology that allows for a much more comprehensive screen of the genome than was possible before, in conjunction with large samples of RA patients with well-characterized disease. Recent RA genetic studies have identified genes with important functions related to intracellular signaling mechanisms, transcription factors, cytokines, membrane receptors, costimulatory molecules, and enzymes. In particular, recent discoveries highlight the importance of the CD40/NF-κB signaling pathway in RA, based on genetic association with several genes relevant to this pathway, including CD40, TRAF1, TNFAIP3, and REL. Progress in the identification of genes that contribute to RA is proceeding at a very rapid pace. These genetic discoveries shed light on underlying disease mechanisms in RA and provide targets for the development of novel diagnostic and therapeutic tools for future use in this chronic inflammatory disorder. © 2009 John Wiley & Sons A/S.


King T.L.,University of California at San Francisco
Seminars in Perinatology | Year: 2012

Some intrapartum care practices promote vaginal birth, whereas others may increase the risk for cesarean section. Electronic fetal monitoring and use of the Friedman graph to plot and monitor labor progress are associated with increasing the cesarean section rate. Continuous one-to-one support and midwifery management are associated with lower cesarean section rates. This article reviews the evidence that links specific intrapartum care practices to cesarean section. Strategies that can be implemented in the current social and cultural setting of obstetrics today are recommended. © 2012 Elsevier Inc.


Bikle D.D.,University of California at San Francisco
Reviews in Endocrine and Metabolic Disorders | Year: 2012

The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but in possessing both the enzymatic machinery to metabolize the vitamin D produced to active metabolites (in particular 1,25(OH) 2D) and the vitamin D receptor (VDR) that enables the keratinocytes to respond to the 1,25(OH) 2D thus generated. Numerous functions of the skin are regulated by vitamin D and/or its receptor. These include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, regulation of the hair follicle cycle, and suppression of tumor formation. Regulation of these actions is exerted by a number of different coregulator complexes including the coactivators vitamin D receptor interacting protein (DRIP) complex also known as Mediator and the steroid receptor coactivator (SRC) family (of which SRC 2 and 3 are found in keratincytes), the inhibitor hairless (Hr), and β-catenin whose impact on VDR function is complex. Different coregulators appear to be involved in different VDR regulated functions. This review will examine the various functions of vitamin D and its receptor in the skin, and explore the mechanisms by which these functions are regulated. © 2011 Springer Science+Business Media, LLC.


Ruggero D.,University of California at San Francisco
Science Signaling | Year: 2012

Key signaling pathways (such as phosphoinositide 3-kinase, Myc, and RAS) act as sensors of energy, stress, and nutrient availability and integrate these inputs to directly control ribosome production and gene expression at the translational level. This activity is normally directly coupled to cell growth, division, and survival. However, it remains poorly understood the extent to which changes in ribosome number and nucleolar integrity downstream of these key signaling pathways contribute to their oncogenic activity. Emerging studies provide interesting insight into how deregulations in RNA polymerase I activity may lead to tumorigenesis and suggest that new drugs targeting ribosomal DNA transcription may hold great promise for the treatment of cancer.


Brodsky F.M.,University of California at San Francisco
Annual Review of Cell and Developmental Biology | Year: 2012

Clathrin is considered the prototype vesicle coat protein whose self-assembly mediates sorting of membrane cargo and recruitment of lipid modifiers. Detailed knowledge of clathrin biochemistry, structure, and interacting proteins has accumulated since the first observation, almost 50 years ago, of its role in receptor-mediated endocytosis of yolk protein. This review summarizes that knowledge, and focuses on properties of the clathrin heavy and light chain subunits and interaction of the latter with Hip proteins, to address the diversity of clathrin function beyond conventional receptor-mediated endocytosis. The distinct functions of the two human clathrin isoforms (CHC17 and CHC22) are discussed, highlighting CHC22's specialized involvement in traffic of the GLUT4 glucose transporter and consequent role in human glucose metabolism. Analysis of clathrin light chain function and interaction with the actin-binding Hip proteins during bacterial inflection defines a novel actin-organizing function for CHC17 clathrin. By considering these diverse clathrin functions, along with intracellular sorting roles and inflluences on mitosis, further relevance of clathrin function to human health and disease is established. Copyright © 2012 by Annual Reviews. All rights reserved.


Bush J.O.,University of California at San Francisco | Soriano P.,The New School
Seminars in Cell and Developmental Biology | Year: 2012

The Eph receptor tyrosine kinases and their ephrin partners compose a large and complex family of signaling molecules involved in a wide variety of processes in development, homeostasis, and disease. The complexity inherent to Eph/ephrin signaling derives from several characteristics of the family. First, the large size and functional redundancy/compensation by family members presents a challenge in defining their in vivo roles. Second, the capacity for bidirectional signaling doubles the potential complexity, since every member has the ability to act both as a ligand and a receptor. Third, Ephs and ephrins can utilize a wide array of signal transduction pathways with a tremendous diversity of cell biological effect. The daunting complexity of Eph/ephrin signaling has increasingly prompted investigators to resort to multiple technological approaches to gain mechanistic insight. Here we review recent progress in the use of advanced mouse genetics in combination with proteomic and transcriptomic approaches to gain a more complete understanding of signaling mechanism in vivo. Integrating insights from such disparate approaches provides advantages in continuing to advance our understanding of how this multifarious group of signaling molecules functions in a diverse array of biological contexts. © 2011 Elsevier Ltd.


Rooney T.,University of California at San Francisco
Rheumatology (Oxford, England) | Year: 2011

Patients with RA have systemic inflammation and increased risk of cardiovascular (CV) events, including thrombosis. Levels of fibrinogen, a pro-thrombotic protein with predictive value for CV disease (CVD), are elevated during systemic inflammation. We compared circulating fibrinogen levels in patients with RA with healthy controls and evaluated the relationship with measures of disease activity. Patients with RA and controls were recruited at the University of California, San Francisco (UCSF). Disease activity was evaluated using standard composite indices. Fibrinogen, ESR, serum CRP, acute-phase serum amyloid A and levels of selected cytokines were quantified. A total of 105 RA patients and 62 controls were studied. Among patients with RA, disease activity ranged from quiescent to highly active disease. Circulating fibrinogen levels were significantly higher in RA than in controls [median (interquartile range) 466 (391-575) vs 367 (309-419) mg/dl, respectively, P < 0.0001]. This difference remained highly statistically significant after adjustment for demographic variables and BMI. Although fibrinogen correlated significantly with clinical measures of disease activity, significantly elevated levels were observed at low levels of activity, even in RA patients with no detectable swollen or tender joints. In multivariable models, ~ 80% of the increased fibrinogen in RA was accounted for by increases in CRP and ESR. Circulating levels of fibrinogen are elevated in RA and correlated with markers of inflammation, but only modestly correlate with clinical assessments of disease activity. Even RA patients with excellent clinical disease control exhibit elevated levels compared with controls.


Apodaca G.,University of Pittsburgh | Gallo L.I.,University of Pittsburgh | Bryant D.M.,University of California at San Francisco
Nature Cell Biology | Year: 2012

Epithelial cells have an apical-basolateral axis of polarity, which is required for epithelial functions including barrier formation, vectorial ion transport and sensory perception. Here we review what is known about the sorting signals, machineries and pathways that maintain this asymmetry, and how polarity proteins interface with membrane-trafficking pathways to generate membrane domains de novo. It is becoming apparent that membrane traffic does not simply reinforce polarity, but is critical for the generation of cortical epithelial cell asymmetry. © 2012 Macmillan Publishers Limited. All rights reserved.


Villasenor A.,University of California at San Francisco | Cleaver O.,University of Texas Southwestern Medical Center
Seminars in Cell and Developmental Biology | Year: 2012

Growth and development of embryonic organs goes hand in hand with development of the vascular system. Blood vessels have been known for centuries to supply nutrients and oxygen to all cell types in an organism, however, they have more recently been shown to provide specific cues required for the formation and functionality of a number of tissues. Here, we review the role of blood vessels during pancreas formation, from early specification of the initial pancreatic bud, to its growth and maturation. The overarching theme that emerges from the many studies carried out in the past decade is that the vasculature likely plays diverse and changing roles during pancreas organogenesis. Blood vessels are required for endocrine specification at the onset of pancreatic budding, while only a few days later, blood vessels suppress pancreatic branching and exocrine differentiation. In this review, we summarize our understanding to date about the crosstalk between the pancreas and its vasculature, and we provide a perspective on the promises and challenges of the field. © 2012 .


Vincenti F.,University of California at San Francisco | Dritselis A.,IMS Health
Nature Reviews Drug Discovery | Year: 2011

In June 2011, belatacept (Nulojix; Bristol-Myers Squibb), a fusion protein that inhibits T cell activation by binding to CD80 and CD86, was approved by the US Food and Drug Administration (FDA) for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. © 2011 Macmillan Publishers Limited. All rights reserved.


Verkman A.S.,University of California at San Francisco
Annual Review of Medicine | Year: 2012

The aquaporins are a family of membrane water channels, some of which also transport glycerol. They are involved in a wide range of physiological functions (including water/salt homeostasis, exocrine fluid secretion, and epidermal hydration) and human diseases (including glaucoma, cancer, epilepsy, and obesity). At the cellular level, aquaporin-mediated osmotic water transport across cell plasma membranes facilitates transepithelial fluid transport, cell migration, and neuroexcitation; aquaporin-mediated glycerol transport regulates cell proliferation, adipocyte metabolism, and epidermal water retention. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and congenital cataracts. The neuroinflammatory demyelinating disease neuromyelitis optica is marked by pathogenic autoantibodies against astrocyte water channel aquaporin-4. There remain broad opportunities for the development of aquaporin-based diagnostics and therapeutics. Disease-relevant aquaporin polymorphisms are beginning to be explored. There is great promise in the development of small-molecule aquaporin modulators for therapy of some types of refractory edema, brain swelling, neuroinflammation, glaucoma, epilepsy, cancer, pain, and obesity. © 2012 by Annual Reviews. All rights reserved.


Bilder D.,University of California at Berkeley | Haigo S.L.,University of California at Berkeley | Haigo S.L.,University of California at San Francisco
Developmental Cell | Year: 2012

Tissue and organ architectures are incredibly diverse, yet our knowledge of the morphogenetic behaviors that generate them is relatively limited. Recent studies have revealed unexpected mechanisms that drive axis elongation in the Drosophila egg, including an unconventional planar polarity signaling pathway,a distinctive type of morphogenetic movement termed " global tissue rotation," a molecular corset-like role of extracellular matrix, and oscillating basal cellular contractions. We review here what is known about Drosophila egg elongation, compare it to other instances of morphogenesis, and highlight several issues of general developmental relevance. © 2012 Elsevier Inc.


Smith-Bindman R.,University of California at San Francisco
Archives of Internal Medicine | Year: 2012

Susan G. Komen for the Cure asked the Institute of Medicine (IOM) to perform a comprehensive review of environmental causes and risk factors for breast cancer. Interestingly, none of the consumer products (ie, bisphenol A, phthalates), industrial chemicals (ie, benzene, ethylene oxide), or pesticides (ie, DDT/DDE) considered could be conclusively linked to an increased risk of breast cancer, although the IOM acknowledged that the available evidence was insufficient to draw firm conclusions for many of these exposures, calling for more research in these areas. The IOM found sufficient evidence to conclude that the 2 environmental factors most strongly associated with breast cancer were exposure to ionizing radiation and to combined postmenopausal hormone therapy. The IOM's conclusion of a causal relation between radiation exposure and cancer is consistent with a large and varied literature showing that exposure to radiation in the same range as used for computed tomography will increase the risk of cancer. It is the responsibility of individual health care providers who order medical imaging to understand and weigh the risk of any medical procedures against the expected benefit. ©2012 American Medical Association. All rights reserved.


Price J.,University of California at San Francisco
Topics in Antiviral Medicine | Year: 2014

virus (HCV) infection, non-HCV viral hepatitis remains an important cause of liver disease, especially among HIV-infected individuals. Hepatitis B virus (HBV) is the leading cause of cirrhosis worldwide, and approximately onequarter of patients with cirrhosis develop decompensated liver disease within 5 years. Initial treatment for chronic HBV infection includes peginterferon alfa, entecavir, and tenofovir. Approximately 15 million of the estimated 350 million individuals with chronic HBV infection have evidence of exposure to hepatitis D (delta) virus (HDV), which requires hepatitis B surface antigen for transmission and packaging. HBV/HDV coinfection is associated with more severe acute hepatitis and higher mortality than acute HBV monoinfection. Chronic coinfection is associated with a higher risk of cirrhosis and decompensated liver disease. The mainstay of treatment for HDV infection is peginterferon alfa for at least 48 weeks. Cases of hepatitis E virus (HEV) infection in HIV-infected persons have been reported. HEV infection can become chronic in immunosuppressed patients, and chronic infection is associated with rapid development of cirrhosis. There are no established guidelines for treating HEV infection in HIV-infected persons. © 2014, IAS-USA. All rights reserved.


Kajimura S.,University of California at San Francisco
Nature Reviews Molecular Cell Biology | Year: 2016

White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Goadsby P.J.,University of California at San Francisco
Annals of Neurology | Year: 2013

Migraine is a common, complex brain disorder whose biology is becoming better understood. Despite being the most disabling of the neurological disorders on a worldwide basis, headache disorders broadly, and migraine in particular, have poor research funding and a limited academic base. Given a modicum of investment, new targets, such as calcitonin gene-related peptide-based mechanisms, and entirely novel neuromodulation approaches illustrate that much can be done to improve patient care. Genetics and neuroimaging combined with excellent clinical phenotyping and translational neuroscience approaches are set to transform life for a cohort of patients with these common brain disorders. © 2013 American Neurological Association.


Mostovoy Y.,University of California at San Francisco
Nature Methods | Year: 2016

Despite tremendous progress in genome sequencing, the basic goal of producing a phased (haplotype-resolved) genome sequence with end-to-end contiguity for each chromosome at reasonable cost and effort is still unrealized. In this study, we describe an approach to performing de novo genome assembly and experimental phasing by integrating the data from Illumina short-read sequencing, 10X Genomics linked-read sequencing, and BioNano Genomics genome mapping to yield a high-quality, phased, de novo assembled human genome. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Nakamura K.,Gladstone | Nakamura K.,University of California at San Francisco
Neurotherapeutics | Year: 2013

Increased α-synuclein levels and mutations in mitochondria-associated proteins both cause familial Parkinson's disease (PD), and synuclein and mitochondria also play central, but poorly understood, roles in the pathogenesis of idiopathic PD. A fraction of synuclein interacts with mitochondria, and synuclein can produce mitochondrial fragmentation and impair mitochondrial complex I activity. However, the consequences of these mitochondrial changes for bioenergetic and other mitochondrial functions remain poorly defined, as does the role of synuclein-mitochondria interactions in the normal and pathologic effects of synuclein. Understanding the functional consequences of synuclein's interactions with mitochondria is likely to provide important insights into disease pathophysiology, and may also reveal therapeutic strategies. © 2013 The American Society for Experimental NeuroTherapeutics, Inc.


Chiu C.Y.,University of California at San Francisco | Chiu C.Y.,Abbott Laboratories
Current Opinion in Microbiology | Year: 2013

Viral pathogen discovery is of critical importance to clinical microbiology, infectious diseases, and public health. Genomic approaches for pathogen discovery, including consensus polymerase chain reaction (PCR), microarrays, and unbiased next-generation sequencing (NGS), have the capacity to comprehensively identify novel microbes present in clinical samples. Although numerous challenges remain to be addressed, including the bioinformatics analysis and interpretation of large datasets, these technologies have been successful in rapidly identifying emerging outbreak threats, screening vaccines and other biological products for microbial contamination, and discovering novel viruses associated with both acute and chronic illnesses. Downstream studies such as genome assembly, epidemiologic screening, and a culture system or animal model of infection are necessary to establish an association of a candidate pathogen with disease. © 2013 The Author.


Doherty D.,University of Washington | Millen K.J.,University of Washington | Barkovich A.J.,University of California at San Francisco
The Lancet Neurology | Year: 2013

Historically, the midbrain and hindbrain have been considered of secondary importance to the cerebrum, which has typically been acknowledged as the most important part of the brain. In the past, radiologists and pathologists did not regularly examine these structures-also known as the brainstem and cerebellum-because they are small and difficult to remove without damage. With recent developments in neuroimaging, neuropathology, and neurogenetics, many developmental disorders of the midbrain and hindbrain have emerged as causes of neurodevelopmental dysfunction. These research advances may change the way in which we treat these patients in the future and will enhance the clinical acumen of the practising neurologist and thereby improve the diagnosis and treatment of these patients. © 2013 Elsevier Ltd.


Matthay M.A.,University of California at San Francisco
American Journal of Respiratory and Critical Care Medicine | Year: 2014

In the last 30 years, we have learned much about the molecular, cellular, and physiological mechanisms that regulate the resolution of pulmonary edema in both the normal and the injured lung. Although the physiological mechanisms responsible for the formation of pulmonary edema were identifi ed by 1980, the mechanisms that explain the resolution of pulmonary edema were not well understood at that time. However, in the 1980s several investigators provided novel evidence that the primary mechanism for removal of alveolar edema fl uid depended on active ion transport across the alveolar epithelium. Sodium enters through apical channels, primarily the epithelial sodium channel, and is pumped into the lung interstitium by basolaterally located Na/K-ATPase, thus creating a local osmotic gradient to reabsorb the water fraction of the edema fluid from the airspaces of the lungs. The resolution of alveolar edema across the normally tight epithelial barrier can be up-regulated by cyclic adenosine monophosphate (cAMP)-dependent mechanisms through adrenergic or dopamine receptor stimulation, and by several cAMP-independent mechanisms, including glucocorticoids, thyroid hormone, dopamine, and growth factors. Whereas resolution of alveolar edema in cardiogenic pulmonary edema can be rapid, the rate of edema resolution in most patients with acute respiratory distress syndrome (ARDS) is markedly impaired, a finding that correlates with higher mortality. Several mechanisms impair the resolution of alveolar edema in ARDS, including cell injury from unfavorable ventilator strategies or pathogens, hypoxia, cytokines, and oxidative stress. In patients with severe ARDS, alveolar epithelial cell death is a major mechanism that prevents the resolution of lung edema. Copyright © 2014 by the American Thoracic Society.


Goodin D.S.,University of California at San Francisco
Handbook of Clinical Neurology | Year: 2014

Glucorticorticoids have both anti-inflammatory and immunosuppressive properties and both synthetic and natural glucocorticoid medications have been used to treat a number of inflammatory and autoimmune conditions, including the management of acute multiple sclerosis (MS) attacks. Many of the studies supporting the use of this approach to MS treatment have important limitations. Nevertheless, on balance, the data seem to support the notion that a brief glucocorticoid treatment regimen (~. 2 weeks) hastens recovery from an acute MS flare and that this treatment, in general, is well tolerated. However, such treatment does not seem to alter the final degree of recovery from the MS attack. Among the practice community, even within MS centers, there seems to be a general belief that the selection of the optimal agent, route of administration, and the duration of therapy can be made on the basis of personal experience and/or theoretic considerations. As a result, currently, there are a variety of idiosyncratic regimens (often vigorously defended), which are commonly used to treat patients. Nevertheless, it is important to recognize that the best route of administration, the optimal dose and duration of treatment, and the preferred agent or agents have yet to be firmly established. Moreover, although it may well turn out that some of these factors are more important than others, the best current evidence for the efficacy of glucocorticoid treatment in MS, by far, comes from the optic neuritis treatment trial, which used high-dose intravenous methylprednisolone for the first 3 days followed by an 11-day course of low-dose oral prednisone. © 2014 Elsevier B.V.


Lynch S.V.,University of California at San Francisco | Bruce K.D.,Kings College London
Cold Spring Harbor Perspectives in Medicine | Year: 2013

Repeated pulmonary exacerbation and progressive lung function decline characterize cystic fibrosis (CF) disease, and represents one of the leading causes of mortality in this patient population. Recent studies have shown, using culture-independent assays, that multiple microbial species can be detected in airway samples from CF patients. Moreover, specific groups of bacteria within these bacterial communities or microbiota, are highly associated with disease-associated factors such as antibiotic administration. This raises the possibility that, as in other human niches, pathogenic processes in the CFairways represent polymicrobial activities and that microbiome composition and perturbations to these communities define patient pulmonary health status. Airway samples are typically collected through the mouth, and are thus susceptible to contamination by upper airway secretions; hence, caution must be exercised in interpreting these data. Nonetheless, given the continuum of the upper and lower respiratory tract, understanding the contribution of these mixed-species assemblages to airway health is essential to improving CF patient care. This article aims to discuss recent advances in the field of CFairway microbiome research and interpret these findings in the context of CF pulmonary disease. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Julian L.J.,University of California at San Francisco
Neurologic Clinics | Year: 2011

In this article, the nature and course of cognitive dysfunction in MS are reviewed, particularly in the context of recent advances in our understanding of the diffuse nature of neuropathology in MS, and in the context of specific factors that may confer risk or protection for the development of cognitive impairment. In addition, assessment and screening approaches of MS-related cognitive dysfunction are discussed. MS is a condition not only restricted to the adult population, and this article includes a brief description of cognition in pediatric-onset MS. Finally, promising intervention approaches to treat cognitive problems in MS are summarized. © 2011 Elsevier Inc.


Karn C.F.,University of California at San Francisco
Clinical Trials | Year: 2013

Background Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. Results EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. Conclusions EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review. © 2013 The Author(s).


Luu M.,University of California at San Francisco
Skin therapy letter | Year: 2013

The exact role of biologics in the treatment of pediatric psoriasis remains undefined but is evolving. Biologics are an attractive option for use in children in part because they offer more convenient dosing regimens and less frequent laboratory monitoring than traditional systemic agents. Further, because their action is targeted, they theoretically lack many of the potential end-organ toxicities of traditional agents. However, compared to adult psoriasis populations, there is a relative lack of long-term safety data specific to the pediatric psoriasis population. Thus, the clear advantages of using biologic agents must be balanced with a measure of caution. This article will provide a summary of the cumulative pediatric safety and efficacy data for the anti-tumor necrosis factor-alpha (TNF-α) agents and interleukin (IL)-12 and IL-23 (IL12/23) pathway inhibitor and suggestions for a rational clinical approach to their use in children with psoriasis.


Orr M.T.,University of California at San Francisco
Current topics in microbiology and immunology | Year: 2011

The Ly49 receptors, which are expressed in a stochastic manner on subsets of murine natural killer (NK) cells, T cells, and other cells, are encoded by the Klra gene family and include receptors with either inhibitory or activating function. All of the inhibitory Ly49 receptors are characterized by an immunoreceptor tyrosine-based inhibitory motif in their cytoplasmic domain, which upon phosphorylation recruits tyrosine or lipid phosphatases to dampen signals transmitted through other activating receptors. Most of the inhibitory Ly49 receptors recognize polymorphic epitopes on major histocompatibility complex (MHC) class I proteins as ligands. Here, we review the polymorphism, ligand specificity, and signaling capacity of the inhibitory Ly49 receptors and discuss how these molecules regulate NK cell development and function.


Chen D.,Stanford University | Chen D.,Genentech | Mellman I.,University of California at San Francisco | Mellman I.,Genentech
Immunity | Year: 2013

The genetic and cellular alterations that define cancer provide the immune system with the means to generate Tcell responses that recognize and eradicate cancer cells. However, elimination of cancer by Tcells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell Tcell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer. © 2013 Elsevier Inc.


Clyman R.I.,University of California at San Francisco
Seminars in Perinatology | Year: 2013

A persistent left-to-right shunt through a patent ductus arteriosus (PDA) increases the rate of hydrostatic fluid filtration into the lung's interstitium, impairs pulmonary mechanics, and prolongs the need for mechanical ventilation. In preclinical trials, pharmacologic PDA closure leads to improved alveolarization and minimizes the impaired postnatal alveolar development that is the pathologic hallmark of the "new bronchopulmonary dysplasia (BPD)". Although early pharmacologic closure of the PDA decreases the incidence of pulmonary hemorrhage, intraventricular hemorrhage, and the need for PDA ligation, there is little evidence from controlled, clinical trials to support or refute a causal role for the PDA in the development of BPD. However, evidence from epidemiologic, preclinical, and randomized controlled clinical trials demonstrate that early ductus ligation is an independent risk factor for the development of BPD and may directly contribute to the neonatal morbidities it is trying to prevent. © 2013 Elsevier Inc.


Cleaver J.E.,University of California at San Francisco
Photochemistry and Photobiology | Year: 2011

The phosphorylation of H2Ax on its S139 site, γH2Ax, is important for the assembly of repair complexes at DNA double strand breaks (DSBs). The formation and functional role of γH2Ax after other kinds of DNA damage, especially UV light, where DSBs are rare, is less clear. Following UV light in the UVB and UVC ranges, complex distributions of γH2Ax can be identified, quite unlike the discrete enumerable foci seen after ionizing radiation. Several distinct distributions of γH2Ax occur: a low level nuclear-wide distribution of γH2Ax occurs during nucleotide excision repair; irregular focal distributions occur at arrested replication forks; high intensity nuclear-wide γH2Ax occurs in association with S-phase apoptosis. The intensity and distributions of γH2Ax vary according to the activity of excision repair, bypass polymerase and apoptotic caspases. The frequency of DSBs at arrested replication forks is low but highly variable in different cell types, and probably caused by enzymatic action. Despite the prominence of S139 phosphorylation following UV damage, mutation of this site has no influence on the UV damage response indicating that γH2Ax is a biomarker but not a participant in the UV-DNA damage response. Source for image:. The figure was created by the user EMW, userpage:.ââNucleosomal structure showing the looping of DNA around the histone core and the extended tail of γH2Ax that is phosphorylated during the DNA damage response. Serine 139 is phosphorylated in response to DNA damage, whereas tyrosine 142 is phosphorylated constitutively and dephosphorylated in response to DNA damage. Whereas serine 139 phosphorylation supports repair of DNA double strand breaks, in response to UV damage it appears to be a biomarker for lethal blocked replication forks and apoptosis. Other nucleosomal histones are also subject to secondary modification by phosphorylation, acetylation, methylation and ubiquitination that generates binding sites for many regulatory proteins. © 2011 Wiley Periodicals, Inc.


Fox R.K.,University of California at San Francisco
Medical Clinics of North America | Year: 2014

With rising rates of end-stage liver disease and hepatocellular carcinoma, there is a growing demand for liver transplantation. The decision to allocate a liver to a patient is an extensive process in a transplant center, but the timing of initial referral for transplant evaluation will commonly be the responsibility of the primary care physician. This article discusses the indications and contraindications for liver transplantation. The criteria to determine timing of transplant referral are reviewed, and integration of these criteria into long-term management of patients with cirrhosis is emphasized. © 2014 Elsevier Inc.


Carbone E.T.,University of California at San Francisco
Journal of the American Association for Laboratory Animal Science : JAALAS | Year: 2012

Buprenorphine HCl is a common analgesic for laboratory mice undergoing surgical procedures. The documented duration of action of buprenorphine HCl is as short as 3 to 5 h in mice, potentially necessitating readministration for continued analgesia. A long-acting buprenorphine formulation would reduce handling-associated stress and provide uninterrupted analgesia. This study used the hot-plate assay to assess the antinociceptive effects of a single injection of sustained-release buprenorphine (bup-SR), buprenorphine-HCl (bup-HCl), and saline over 72 h in young adult male BALB/cJ and SWR/J mice. SWR/J mice had shorter baseline latencies than did BALB/cJ mice, possibly reflecting greater sensitivity to thermal nociception. Relative increase from baseline latency (% maximal possible effect) was significant for buprenorphine-SR at 2, 6, and 12 h compared with saline. According to results from a hot-plate assay, the analgesic efficacy of buprenorphine-SR appears to last at least 12 h in male BALB/cJ and SWR/J mice.


Slavotinek A.M.,University of California at San Francisco
Molecular Genetics and Metabolism | Year: 2011

Anophthalmia and microphthalmia (A/M) are significant eye defects because they can have profound effects on visual acuity. A/M is associated with non-ocular abnormalities in an estimated 33-95% of cases and around 25% of patients have an underlying genetic syndrome that is diagnosable. Syndrome recognition is important for targeted molecular genetic testing, prognosis and for counseling regarding recurrence risks. This review provides clinical and molecular information for several of the commonest syndromes associated with A/M: Anophthalmia-Esophageal-Genital syndrome, caused by SOX2 mutations, Anophthalmia and pituitary abnormalities caused by OTX2 mutations, Matthew-Wood syndrome caused by STRA6 mutations, oculofaciocardiodental syndrome and Lenz microphthalmia caused by BCOR mutations, Microphthalmia Linear Skin pigmentation syndrome caused by HCCS mutations, Anophthalmia, pituitary abnormalities, polysyndactyly caused by BMP4 mutations and Waardenburg anophthalmia caused by mutations in SMOC1. In addition, we briefly discuss the ocular and extraocular phenotypes associated with several other important eye developmental genes, including GDF6, VSX2, RAX, SHH, SIX6 and PAX6. © 2011 Elsevier Inc.


Background: At our institution, serum testosterone in adult males is measured by immunoassay while female and pediatric specimens are sent to a reference laboratory for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis due to low concentrations. As this is of significant cost, a testosterone LC-MS/MS assay was developed in-house. Methods: A 5500 QTRAP® using electrospray ionization and a Shimadzu Prominence with a C18 column were used. Gradient elution with formic acid, water and methanol:acetonitrile at 0.5. ml/min had a 7-min run-time. A liquid-liquid extraction with hexane:ethyl acetate was carried out on 200μl of serum. Multiple reaction monitoring was employed. Results: Sample preparation took ~. 80. min for 21 samples. Six calibrators were used (0-1263. ng/dl; concentration assigned by NIST SRM 971) with 3 quality controls (9, 168 and 532. ng/dl). The limits of detection and quantitation were 1 and 2. ng/dl respectively. Extraction recovery was ~. 90% and ion suppression ~. 5%. Within-run and total precision studies yielded <15% CV at the limit of quantitation and <7% CV through the rest of the linear range. Isobaric interferences were baseline separated from testosterone. Method comparisons between this assay, an immunoassay, and another LC-MS/MS assay were completed. Conclusions: An accurate and sensitive LC-MS/MS assay for total testosterone was developed. Bringing this assay in-house reduces turnaround time for clinicians and patients and saves our institution funds. © 2012 Elsevier B.V.


Ruggero D.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2013

The link between perturbations in translational control and cancer etiology is becoming a primary focus in cancer research. It has now been established that genetic alterations in several components of the translational apparatus underlie spontaneous cancers as well as an entire class of inherited syndromes known as "ribosomopathies" associated with increased cancer susceptibility. These discoveries have illuminated the importance of deregulations in translational control to very specific cellular processes that contribute to cancer etiology. In addition, a growing body of evidence supports the view that deregulation of translational control is a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development. Indeed, activation of these key oncogenic pathways induces rapid and dramatic translational reprogramming both by increasing overall protein synthesis and by modulating specific mRNA networks. These translational changes promote cellular transformation, impacting almost every phase of tumor development. This paradigm represents a new frontier in the multihit model of cancer formation and offers significant promise for innovative cancer therapies. Current research, in conjunction with cutting edge technologies, will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Chiu C.S.,University of California at San Francisco
Current Opinion in Ophthalmology | Year: 2014

PURPOSE OF REVIEW: Posterior capsular rupture (PCR) is an infrequent complication of cataract surgery that can lead to significant ocular morbidity and permanent vision loss. In the setting of PCR, the primary objective is the safe and thorough evacuation of vitreous and lens fragments from the anterior segment. The secondary objective is the stable placement of an intraocular lens (IOL) selected for best refractive outcomes. Expedited referral to vitreoretinal specialists is recommended for management of posteriorly dislocated lens material and surveillance for retinal injury. It is the intention of this review to present current guidelines for the management of PCR. RECENT FINDINGS: There are new techniques available to anterior and posterior segment surgeons in the setting of PCR. Endoillumination may facilitate visualization during anterior vitrectomy and the IOL may be used as a pupillary barrier to prevent loss of lens fragments. When secondary procedures are needed, early return to the operating room and small-gauge pars plana techniques may reduce patient morbidity. SUMMARY: When approached carefully and systematically, patients may have good outcomes in the setting of PCR. Recent advancements in instrumentation and technique encourage further study and may lead to new standards of care. © Lippincott Williams and Wilkins.


Debnath A.,University of California at San Francisco
Gut microbes | Year: 2013

Recently, we developed a novel automated, high throughput screening (HTS) methodology for the anaerobic intestinal parasite Entamoeba histolytica. We validated this HTS platform by screening a chemical library containing US Food and Drug Administration (FDA)-approved drugs and bioactive compounds. We identified an FDA-approved drug, auranofin, as most active against E. histolytica both in vitro and in vivo. Our cell culture and animal studies indicated that thioredoxin reductase, an enzyme involved in reactive oxygen species detoxification, was the target for auranofin in E. histolytica. Here, we discuss the rationale for drug development for three parasites which are major causes of diarrhea worldwide, E. histolytica, Giardia lamblia and Cryptosporidium parvum and extend our current finding of antiparasitic activity of auranofin to Entamoeba cysts, G. lamblia and C. parvum. These studies support the use of HTS assays and reprofiling FDA-approved drugs for new therapy for neglected tropical diseases.


Nelson S.J.,University of California at San Francisco
NMR in Biomedicine | Year: 2011

MRI is routinely used for diagnosis, treatment planning and assessment of response to therapy for patients with glioma. Gliomas are spatially heterogeneous and infiltrative lesions that are quite variable in terms of their response to therapy. Patients classified as having low-grade histology have a median overall survival of 7 years or more, but need to be monitored carefully to make sure that their tumor does not upgrade to a more malignant phenotype. Patients with the most aggressive grade IV histology have a median overall survival of 12-15 months and often undergo multiple surgeries and adjuvant therapies in an attempt to control their disease. Despite improvements in the spatial resolution and sensitivity of anatomic images, there remain considerable ambiguities in the interpretation of changes in the size of the gadolinium-enhancing lesion on T 1-weighted images as a measure of treatment response, and in differentiating between treatment effects and infiltrating tumor within the larger T 2 lesion. The planning of focal therapies, such as surgery, radiation and targeted drug delivery, as well as a more reliable assessment of the response to therapy, would benefit considerably from the integration of metabolic and physiological imaging techniques into routine clinical MR examinations. Advanced methods that have been shown to provide valuable data for patients with glioma are diffusion, perfusion and spectroscopic imaging. Multiparametric examinations that include the acquisition of such data are able to assess tumor cellularity, hypoxia, disruption of normal tissue architecture, changes in vascular density and vessel permeability, in addition to the standard measures of changes in the volume of enhancing and nonenhancing anatomic lesions. This is particularly critical for the interpretation of the results of Phase I and Phase II clinical trials of novel therapies, which are increasingly including agents that are designed to have anti-angiogenic and anti-proliferative properties as opposed to having a direct effect on tumor cell viability. © 2011 John Wiley & Sons, Ltd.


Matthay M.A.,University of California at San Francisco
Annals of the American Thoracic Society | Year: 2015

Based on preclinical data, cell-based therapy with bone marrow-derived mesenchymal stem (stromal) cells (MSCs) is a potentially attractive new therapeutic option for treating patients with the acute respiratory distress syndrome. Small and large animal models of acute lung injury from endotoxin, live bacteria, and sepsis have shown that MSCs can decrease lung injury and increase survival. The mechanisms for benefit are mediated in part by paracrine release of several antiinfl ammatory cytokines, keratinocyte growth factor, angiopoietin-1, as well as the release of antimicrobial peptides. There is also evidence that MSCs can transfer mitochondria and restore normal bioenergetics to injured alveolar epithelium. Some of the beneficial effects are mediated by microvesicles. A phase 1 safety and dose-escalation trial was completed and a randomized, double-blind clinical trial is currently underway. Copyright © 2015 by the American Thoracic Society.


Hiatt R.A.,University of California at San Francisco
American Journal of Epidemiology | Year: 2015

The concept of translational cancer epidemiology has evolved since its early beginnings in 1937 with the establishment of the National Cancer Institute. Conceptual models of cancer control research have also evolved over the last 30 years, to the point where we now have 4 stages of translational research (T0-T4). The current review by Lam et al. (Am J Epidemiol. 2015;181(7):451-458) covers cancer epidemiology research supported by the National Cancer Institute and a selected sample of the cancer epidemiology literature. It suggests that most cancer epidemiology in the last 10 years has been in pure discovery research. Current drivers of cancer epidemiology research, including new technologies, team science multilevel research, and knowledge integration, are not strongly represented in the review. However, the use of epidemiology in the latter stages of translation may not have been captured by the scope of this review. The closer epidemiologists get to advanced stages of translation, the more likely they are to work with investigators in other disciplines in other sectors of society. An argument can be made that regardless of whether this kind of research is not happening or was just missed by the current review, the field of cancer epidemiology can expand its scope and further evolve towards more effective applications in population health. © 2015 The Author.


Deo R.C.,University of California at San Francisco
Circulation | Year: 2015

Spurred by advances in processing power, memory, storage, and an unprecedented wealth of data, computers are being asked to tackle increasingly complex learning tasks, often with astonishing success. Computers have now mastered a popular variant of poker, learned the laws of physics from experimental data, and become experts in video games - tasks that would have been deemed impossible not too long ago. In parallel, the number of companies centered on applying complex data analysis to varying industries has exploded, and it is thus unsurprising that some analytic companies are turning attention to problems in health care. The purpose of this review is to explore what problems in medicine might benefit from such learning approaches and use examples from the literature to introduce basic concepts in machine learning. It is important to note that seemingly large enough medical data sets and adequate learning algorithms have been available for many decades, and yet, although there are thousands of papers applying machine learning algorithms to medical data, very few have contributed meaningfully to clinical care. This lack of impact stands in stark contrast to the enormous relevance of machine learning to many other industries. Thus, part of my effort will be to identify what obstacles there may be to changing the practice of medicine through statistical learning approaches, and discuss how these might be overcome. © 2015 American Heart Association, Inc.


Lord C.,Cornell College | Bishop S.L.,University of California at San Francisco
Annual Review of Clinical Psychology | Year: 2015

This article provides a selective review of advances in scientific knowledge about autism spectrum disorder (ASD), using DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, fifth edition) diagnostic criteria as a framework for the discussion. We review literature that prompted changes to the organization of ASD symptoms and diagnostic subtypes in DSM-IV, and we examine the rationale for new DSM-5 specifiers, modifiers, and severity ratings as well as the introduction of the diagnosis of social (pragmatic) communication disorder. Our goal is to summarize and critically consider the contribution of clinical psychology research, along with that of other disciplines, to the current conceptualization of ASD. © 2015 by Annual Reviews. All rights reserved.


Irby D.M.,University of California at San Francisco
Academic Medicine | Year: 2016

Current controversies in medical education associated with professionalism, including disagreements about curriculum, pedagogy, and assessment, are rooted in part in the differing frameworks that are used to address professionalism. Three dominant frameworks, which have evolved in the medical education community, are described. The oldest framework is virtue based and focuses on the inner habits of the heart, the development of moral character and reasoning, plus humanistic qualities of caring and compassion: The good physician is a person of character. The second framework is behavior based, which emphasizes milestones, competencies, and measurement of observable behaviors: The good physician is a person who consistently demonstrates competence in performing patient care tasks. The third framework is identity formation, with a focus on identity development and socialization into a community of practice: The good physician integrates into his or her identity a set of values and dispositions consonant with the physician community and aspires to a professional identity reflected in the very best physicians. Although each professionalism framework is useful and valid, the field of medical education is currently engaged in several different discourses resulting in misunderstanding and differing recommendations for strategies to facilitate professionalism. In this article, the assumptions and contributions of each framework are described to provide greater insight into the nature of professionalism. By examining each discourse in detail, underlying commonalities and differences can be highlighted to assist educators in more effectively creating professionalism curricula, pedagogy, and assessment. © 2016 by the Association of American Medical Colleges


Rosenstein M.G.,University of California at San Francisco
Obstetrics and gynecology | Year: 2012

To estimate the multiple dimensions of risk faced by pregnant women and their health care providers when comparing the risks of stillbirth at term with the risk of infant death after birth. This is a retrospective cohort study that included all nonanomalous, term deliveries in the state of California from 1997 to 2006 (N=3,820,826). The study compared infant mortality rates after delivery at each week of term pregnancy with the rates of a composite fetal-infant mortality that would occur after expectant management for 1 additional week. The risk of stillbirth at term increases with gestational age from 2.1 per 10,000 ongoing pregnancies at 37 weeks of gestation up to 10.8 per 10,000 ongoing pregnancies at 42 weeks of gestation. At 38 weeks of gestation, the risk of expectant management carries a similar risk of death as delivery, but at each later gestational age, the mortality risk of expectant management is higher than the risk of delivery (39 weeks of gestation: 12.9 compared with 8.8 per 10,000; 40 weeks of gestation: 14.9 compared with 9.5 per 10,000; 41 weeks of gestation: 17.6 compared with 10.8 per 10,000). Infant mortality rates at 39, 40, and 41 weeks of gestation are lower than the overall mortality risk of expectant management for 1 week.


Marshall W.F.,University of California at San Francisco
Annual Review of Biophysics | Year: 2016

The cell represents a highly organized state of living matter in which numerous geometrical parameters are under dynamic regulation in order to match the form of a cell with its function. Cells appear capable of regulating not only the total quantity of their internal organelles, but also the size and number of those organelles. The regulation of three parameters, size, number, and total quantity, can in principle be accomplished by regulating the production or growth of organelles, their degradation or disassembly, and their partitioning among daughter cells during division. Any or all of these steps could in principle be under regulation. But if organelle assembly or disassembly is regulated by number or size, how would the cell know how many copies of an organelle it has, or how big they are? Copyright © 2016 by Annual Reviews. All rights reserved.


Potter M.B.,University of California at San Francisco
Annual Review of Public Health | Year: 2013

Colorectal cancer is a significant cause of mortality in the United States and globally. In the United States, increased access to screening and effective treatment has contributed to a reduction in colorectal cancer incidence and mortality for the general population, though significant disparities persist. Worldwide, the disparities are even more pronounced, with vastly different colorectal cancer mortality rates and trends among nations. Newly organized colorectal cancer screening programs in economically developed countries with a high burden of colorectal cancer may provide pathways to reduce these disparities over time. This article provides an overview of colorectal cancer incidence, mortality, screening, and disparities in the United States and other world populations. Promising strategies and resources are identified to address colorectal cancer screening rates and disparities in the United States and worldwide. © 2013 by Annual Reviews. All rights reserved.


Stachowiak J.C.,University of Texas at Austin | Brodsky F.M.,University of California at San Francisco | Miller E.A.,Columbia University
Nature Cell Biology | Year: 2013

Many cellular membrane-bound structures exhibit distinct curvature that is driven by the physical properties of their lipid and protein constituents. Here we review how cells manipulate and control this curvature in the context of dynamic events such as vesicle-mediated membrane traffic. Lipids and cargo proteins each contribute energy barriers that must be overcome during vesicle formation. In contrast, protein coats and their associated accessory proteins drive membrane bending using a variety of interdependent physical mechanisms. We survey the energy costs and drivers involved in membrane curvature, and draw a contrast between the stochastic contributions of molecular crowding and the deterministic assembly of protein coats. These basic principles also apply to other cellular examples of membrane bending events, including important disease-related problems such as viral egress. © 2013 Macmillan Publishers Limited. All rights reserved.


Bainbridge K.E.,U.S. National Institutes of Health | Wallhagen M.I.,University of California at San Francisco
Annual Review of Public Health | Year: 2014

Despite contributing substantially to disability in the United States, age-related hearing loss is an underappreciated public health concern. Loss of hearing sensitivity has been documented in two-thirds of adults aged 70 years and older and has been associated with communication difficulties, lower health-related quality of life, and decreased physical and cognitive function. Management strategies for age-related hearing loss are costly, yet the indirect costs due to lost productivity among people with communication difficulties are also substantial and likely to grow. Hearing aids can improve health-related quality of life, but the majority of people with documented hearing loss do not report using them. Uncovering effective means to improve the utilization of hearing health care services is essential for meeting the hearing health care demands of our aging population. The importance of hearing for general well-being warrants an effort to enhance awareness among the general population of the indications of hearing loss and options for assistance. ©2014 by Annual Reviews. All rights reserved.


Hsu J.C.,University of California at San Francisco
Journal of the American Heart Association | Year: 2013

Transseptal puncture is a critical step in achieving left atrial (LA) access for a variety of cardiac procedures. Although the mechanical Brockenbrough needle has historically been used for this procedure, a needle employing radiofrequency (RF) energy has more recently been approved for clinical use. We sought to investigate the comparative effectiveness of an RF versus conventional needle for transseptal LA access. In this prospective, single-blinded, controlled trial, 72 patients were randomized in a 1:1 fashion to an RF versus conventional (BRK-1) transseptal needle. In an intention-to-treat analysis, the primary outcome was time required for transseptal LA access. Secondary outcomes included failure of the assigned needle, visible plastic dilator shavings from needle introduction, and any procedural complication. The median transseptal puncture time was 68% shorter using the RF needle compared with the conventional needle (2.3 minutes [interquartile range {IQR}, 1.7 to 3.8 minutes] versus 7.3 minutes [IQR, 2.7 to 14.1 minutes], P = 0.005). Failure to achieve transseptal LA access with the assigned needle was less common using the RF versus conventional needle (0/36 [0%] versus 10/36 [27.8%], P < 0.001). Plastic shavings were grossly visible after needle advancement through the dilator and sheath in 0 (0%) RF needle cases and 12 (33.3%) conventional needle cases (P < 0.001). There were no differences in procedural complications (1/36 [2.8%] versus 1/36 [2.8%]). Use of an RF needle resulted in shorter time to transseptal LA access, less failure in achieving transseptal LA access, and fewer visible plastic shavings.


Thiam A.R.,Yale University | Thiam A.R.,Ecole Normale Superieure de Paris | Farese Jr. R.V.,Gladstone | Farese Jr. R.V.,University of California at San Francisco | Walther T.C.,Yale University
Nature Reviews Molecular Cell Biology | Year: 2013

Lipid droplets are intracellular organelles that are found in most cells, where they have fundamental roles in metabolism. They function prominently in storing oil-based reserves of metabolic energy and components of membrane lipids. Lipid droplets are the dispersed phase of an oil-in-water emulsion in the aqueous cytosol of cells, and the importance of basic biophysical principles of emulsions for lipid droplet biology is now being appreciated. Because of their unique architecture, with an interface between the dispersed oil phase and the aqueous cytosol, specific mechanisms underlie their formation, growth and shrinkage. Such mechanisms enable cells to use emulsified oil when the demands for metabolic energy or membrane synthesis change. The regulation of the composition of the phospholipid surfactants at the surface of lipid droplets is crucial for lipid droplet homeostasis and protein targeting to their surfaces. © 2013 Macmillan Publishers Limited. All rights reserved.


Bain-Brickley D.,University of California at San Francisco
Cochrane database of systematic reviews (Online) | Year: 2011

Achieving and maintaining high levels of medication adherence are required to achieve the full benefits of antiretroviral therapy (ART), yet suboptimal adherence among children is common in both developed and developing countries. To conduct a systematic review of the literature of evaluations of interventions for improving paediatric ART adherence. We created a comprehensive search strategy in order to identify all studies relevant to this topic. In July 2010, we searched the following electronic databases: EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, LILACS, Web of Science, Web of Social Science, NLM Gateway (supplemented by a manual search of the most recent abstracts not included in the Gateway database). We searched abstracts from the International AIDS Conference from 2002 to 2010, the International AIDS Society Conference on Pathogenesis, Treatment and Prevention from 2003 to 2009, and from the Conference on Retroviruses and Opportunistic Infections from 1997 to 2010. We used search strategies determined by the Cochrane Review Group on HIV/AIDS. We also contacted researchers who work in this field and checked reference lists of related systematic reviews and of all included studies. Randomised and non-randomised controlled trials of interventions to improve adherence to ART among children and adolescents (age ≤18 years) were included. Studies had to report adherence to ART as an outcome. After one author performed an initial screening to exclude citations that did not meet the inclusion criteria, two authors did a second screening of those citations that likely met the criteria. For all articles that passed the second screening, full articles were pulled in order to make a final determination. Two authors then extracted data and graded methodological quality independently. Differences were resolved through discussion. Four studies met the inclusion criteria. No single intervention was evaluated by more than one trial. Two studies were conducted in low-income countries. Two studies were randomised controlled trials (RCT), and two were non-randomised trials. An RCT of a home-based nursing programme showed a positive effect of the intervention on knowledge and medication refills (p=.002), but no effect on CD4 count and viral load. A second RCT of caregiver medication diaries showed that the intervention group had fewer participants reporting no missed doses compared to the control group (85% vs. 92%, respectively), although this difference was not statistically significant (p=.08). The intervention had no effect on CD4 percentage or viral load. A non-randomised trial of peer support group therapy for adolescents demonstrated no change in self-reported adherence, yet the percentage of participants with suppressed viral load increased from 30% to 80% (p=.06). The second non-randomised trial found that the percentage of children achieving >80% adherence was no different between children on a lopinavir-ritonavir (LPV/r) regimen compared to children on a non-nucleoside reverse transcriptase regimen (p=.781). However, the proportion of children achieving virological suppression was significantly greater for children on the LPV/r regimen than for children on the NNRTI-containing regimen (p=.002). A home-based nursing intervention has the potential to improve ART adherence, but more evidence is needed. Medication diaries do not appear to have an effect on adherence or disease outcomes. Two interventions, an LPV/r-containing regimen and peer support therapy for adolescents, did not demonstrate improvements in adherence, yet demonstrated greater viral load suppression compared to control groups, suggesting a different mechanism for improved health outcomes. Well-designed evaluations of interventions to improve paediatric adherence to ART are needed.


Henderson N.C.,Queens Medical Research Institute | Sheppard D.,University of California at San Francisco
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Fibrosis is a major cause of morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only effective treatment for end-stage fibrotic disease. However, demand for donor organs greatly outstrips supply, and so effective anti-fibrotic treatments are urgently required. In recent years, the integrin family of cell adhesion receptors has gained prominence as key regulators of chronic inflammation and fibrosis. Fibrosis models in multiple organs have demonstrated that integrins have profound effects on the fibrotic process. There is now abundant in vivo data demonstrating critical regulatory roles for integrins expressed on different cell types during tissue fibrogenesis. In this review, we will examine the ways in which integrins regulate these processes and discuss how the manipulation of integrins using function blocking antibodies and small molecule inhibitors may have clinical utility in the treatment of patients with a broad range of fibrotic diseases. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. © 2012 Elsevier B.V.


Kraus M.W.,University of California at San Francisco
Psychological science : a journal of the American Psychological Society / APS | Year: 2010

Recent research suggests that lower-class individuals favor explanations of personal and political outcomes that are oriented to features of the external environment. We extended this work by testing the hypothesis that, as a result, individuals of a lower social class are more empathically accurate in judging the emotions of other people. In three studies, lower-class individuals (compared with upper-class individuals) received higher scores on a test of empathic accuracy (Study 1), judged the emotions of an interaction partner more accurately (Study 2), and made more accurate inferences about emotion from static images of muscle movements in the eyes (Study 3). Moreover, the association between social class and empathic accuracy was explained by the tendency for lower-class individuals to explain social events in terms of features of the external environment. The implications of class-based patterns in empathic accuracy for well-being and relationship outcomes are discussed.


Bern C.,University of California at San Francisco
Current Opinion in Infectious Diseases | Year: 2012

Purpose of Review: This review examines recent literature on Chagas disease in the immunosuppressed host. Recent Findings: Chagas disease in immunosuppressed patients may represent acute transmission in an organ recipient, or reactivation of chronic infection in an HIV-infected individual or patient receiving cardiac transplantation for Chagas cardiomyopathy. Transplantation of the kidney or liver from an infected donor resulted in transmission in 18-19 and 29%, respectively. Prospective monitoring usually detects acute infection before symptom onset; early treatment is highly effective. In heart transplant patients, reactivation symptoms include fever, myocarditis and skin lesions, and may mimic rejection. Approximately 20% of HIV-Trypanosoma cruzi infected patients experience reactivation; manifestations include meningoencephalitis and/or myocarditis. Summary: Transplantation of the heart from a T. cruzi-infected donor is contraindicated; use of other organs can be considered. Guidelines recommend prospective monitoring rather than prophylactic treatment in recipients. Posttransplant monitoring for acute infection or reactivation relies on PCR, culture and microscopy of blood specimens regularly for at least 6 months. Treatment employs standard courses of benznidazole or nifurtimox, and immune reconstitution for the HIV-coinfected patient. Case reports suggest some HIV-T. cruzi-infected patients may benefit from secondary prophylaxis, but more data are needed to determine efficacy and specific regimens. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Webb B.,University of California at San Francisco
Methods in molecular biology (Clifton, N.J.) | Year: 2014

Genome sequencing projects have resulted in a rapid increase in the number of known protein sequences. In contrast, only about one-hundredth of these sequences have been characterized at atomic resolution using experimental structure determination methods. Computational protein structure modeling techniques have the potential to bridge this sequence-structure gap. In this chapter, we present an example that illustrates the use of MODELLER to construct a comparative model for a protein with unknown structure. Automation of a similar protocol has resulted in models of useful accuracy for domains in more than half of all known protein sequences.


Jeker L.T.,University of California at San Francisco
Cold Spring Harbor perspectives in medicine | Year: 2012

Type 1 Diabetes (T1D), also called juvenile diabetes because of its classically early onset, is considered an autoimmune disease targeting the insulin-producing β cells in the pancreatic islets of Langerhans. T1D reflects a loss of tolerance to tissue self-antigens caused by defects in both central tolerance, which aims at eliminating potentially autoreactive lymphocytes developing in the thymus, and peripheral tolerance, which normally controls autoreactive T cells that escaped the thymus. Like in other autoimmune diseases, the mechanisms leading to T1D are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in the breakdown of peripheral tolerance. In this article, we discuss the contribution of these factors in the development of the autoimmune response targeting pancreatic islets in T1D and the therapeutic strategies currently being explored to correct these defects.


Carrico A.W.,University of California at San Francisco
AIDS (London, England) | Year: 2011

Research on the role psychiatric factors in HIV disease management has yielded discrepant findings, possibly because prior studies did not include comprehensive psychiatric screeners. This study administered a validated screener to examine psychiatric correlates of highly active antiretroviral therapy (HAART) utilization and viral load. Community-recruited, HIV-positive impoverished persons provided sociodemographic information, completed a Diagnostic Interview Schedule that screened for psychiatric disorders, and provided a blood sample to measure HIV disease markers. In this cross-sectional investigation with 227 participants, a multiple logistic regression model examined correlates of HAART utilization compared to a reference group that was eligible for (i.e. CD4(+) cell count <350 cells/μl) but not taking HAART. A multiple linear regression model examined correlates of HIV viral load among 147 participants on HAART. Sleeping on the street [adjusted OR (AOR) = 0.06; 95% confidence interval (CI) = 0.01-0.26] and screening positive for a stimulant use disorder (AOR = 0.29; 95% CI = 0.13-0.65) were independently associated with lower odds of HAART utilization. Conversely, enrollment in the AIDS Drug Assistance Program (AOR = 3.94; 95% CI = 1.45-10.73) and receipt of mental health treatment (AOR = 4.78; 95% CI = 1.77-12.87) were independently associated with increased odds of HAART utilization. Among those on HAART, screening positive for a severe mental illness was independently associated with a six-fold higher viral load. Providing psychiatric treatment could optimize health outcomes among HIV-positive impoverished persons and boost the effectiveness of 'test and treat' approaches to HIV prevention.


Yao T.,University of California at San Francisco
Cancer causes & control : CCC | Year: 2012

This study estimated secondhand smoke (SHS) exposure at home among nonsmoking children (age 0-18) and adults (age ≥ 19) in rural China, and examined associated socio-demographic factors. A total of 5,442 nonsmokers (including 1,456 children and 3,986 adults) living in six rural areas in China were interviewed in person. The standardized questionnaire obtained information on their demographic characteristics and SHS exposure at home. Differences in SHS exposure were assessed by use of the chi-squared test. Logistic regression analysis was used to examine the associated factors. Occurrence of SHS exposure at home among nonsmoking children and adults was 68.0 and 59.3%, respectively. Logistic regression analysis found that children living in households with married, low-education, and low-income heads of household, and those who resided in the Qinghai province of China were more likely to be exposed to SHS. Among adults, those who were female, aged 19-34, single, low-education, and low-income, and those who lived in Qinghai province were more likely to be exposed to SHS at home. Our findings of substantial SHS exposure at home in rural China emphasize the importance of implementing interventions to reduce SHS exposure among this population.


Sanders S.J.,University of California at San Francisco
Nature Genetics | Year: 2016

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Bhattacharya J.,Columbia University | Matthay M.A.,University of California at San Francisco
Annual Review of Physiology | Year: 2013

Considerable progress has been made in understanding the basic mechanisms that regulate fluid and protein exchange across the endothelial and epithelial barriers of the lung under both normal and pathological conditions. Clinically relevant lung injury occurs most commonly from severe viral and bacterial infections, aspiration syndromes, and severe shock. The mechanisms of lung injury have been identified in both experimental and clinical studies. Recovery from lung injury requires the reestablishment of an intact endothelial barrier and a functional alveolar epithelial barrier capable of secreting surfactant and removing alveolar edema fluid. Repair mechanisms include the participation of endogenous progenitor cells in strategically located niches in the lung. Novel treatment strategies include the possibility of cell-based therapy that may reduce the severity of lung injury and enhance lung repair. Copyright © 2013 by Annual Reviews. All rights reserved.


Uchida K.,University of California at San Francisco
Nature Chemical Biology | Year: 2016

To drive lymphocyte proliferation and differentiation, common γ-chain (γc) cytokine receptors require hours to days of sustained stimulation. JAK1 and JAK3 kinases are found together in all γc-receptor complexes, but how their respective catalytic activities contribute to signaling over time is not known. Here we dissect the temporal requirements for JAK3 kinase activity with a selective covalent inhibitor (JAK3i). By monitoring phosphorylation of the transcription factor STAT5 over 20 h in CD4+ T cells stimulated with interleukin 2 (IL-2), we document a second wave of signaling that is much more sensitive to JAK3i than the first wave. Selective inhibition of this second wave is sufficient to block cyclin expression and entry to S phase. An inhibitor-resistant JAK3 mutant (C905S) rescued all effects of JAK3i in isolated T cells and in mice. Our chemical genetic toolkit elucidates a biphasic requirement for JAK3 kinase activity in IL-2–driven T cell proliferation and will find broad utility in studies of γc-receptor signaling. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Bikle D.D.,University of California at San Francisco
Photochemical and Photobiological Sciences | Year: 2012

Non-melanoma skin cancers (NMSC) are the most common type of cancer, occurring at a rate of over 1 million per year in the United States. Although their metastatic potential is generally low, they can and do metastasize, especially in the immune compromised host, and their surgical treatment is often quite disfiguring. Ultraviolet radiation (UVR) as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVR is also required for vitamin D synthesis in the skin. Based on our own data and that reported in the literature, we hypothesize that the vitamin D produced in the skin serves to suppress UVR epidermal tumor formation. In this review we will first discuss the evidence supporting the conclusion that the vitamin D receptor (VDR), with or without its ligand 1,25-dihydroxyvitamin D, limits the propensity for cancer formation following UVR. We will then explore three potential mechanisms for this protection: inhibition of proliferation and stimulation of differentiation, immune regulation, and stimulation of DNA damage repair (DDR). This journal is © The Royal Society of Chemistry and Owner Societies 2012.


Marshall W.F.,University of California at San Francisco
Current Opinion in Plant Biology | Year: 2012

The mechanisms that determine the shape and organization of cells remain largely unknown. Green algae such as Chlamydomonas provide excellent model systems for studying cell geometry owing to their highly reproducible cell organization. Structural and genetic studies suggest that asymmetry of the centriole (basal body) plays a critical determining role in organizing the internal organization of algal cells, through the attachment of microtubule rootlets and other large fiber systems to specific sets of microtubule triplets on the centriole. Thus to understand cell organization, it will be critical to understand how the different triplets of the centriole come to have distinct molecular identities. © 2012 Elsevier Ltd.


Collisson E.A.,University of California at San Francisco
Clinical Cancer Research | Year: 2015

The treatment of resected lung adenocarcinoma has ample room for improvement. Can genomic characterization aid us in deciding how and when to apply adjuvant therapy in the smallest resected tumors? © 2015 AACR.


Marques S.C.,University of California at San Francisco
Human genomics | Year: 2010

Over the past decade, the number of pharmacogenetic tests has increased considerably, allowing for the development of our knowledge of their clinical application. The uridine diphosphate glucuronosyltransferase 1A1 gene ( UGT1A1 ) assay is an example of a pharmacogenetic test. Numerous variants have been found in UGT1A1 , the main conjugating enzyme of bilirubin and drugs such as the anticancer drug irinotecan. Recently, the US Food and Drug Administration (FDA) recommended testing for the presence of UGT1A1*28 , an allele correlated with decreased transcriptional activity, to predict patients at risk of irinotecan toxicity. The administration of other drugs - such as inhibitors of the UGT1A1 enzyme - can clinically mimic the *28 phenotype, whereas inducers of UGT1A1 can increase the glucuronidation rate of the enzyme. The *28 polymorphism is not present in all ethnicities at a similar frequency, which suggests that it is important to study different populations to determine the clinical relevance of testing for UGT1A1*28 and to identify other clinically relevant UGT1A1 variants. Environmental factors such as lifestyle can also affect UGT1A1 activity. This review is a critical analysis of studies on drugs that can be affected by the presence of UGT1A1*28 , the distribution of this polymorphism around the globe, distinct variants that may be clinically significant in African and Asian populations and how lifestyle can affect treatment outcomes that depend on UGT1A1 activity.


Huang A.J.,University of California at San Francisco
JAMA Internal Medicine | Year: 2013

Source of Review This review was commissioned by the Agency for Healthcare Research and Quality(AHRQ) and conducted by the University of Minnesota Evidence-Based Practice Center for theAHRQComparative Effectiveness Review series.1 Background Urinary incontinence affects more than a quarter ofwomenand can have adverse effects on women's physical, psychological, and social well-being. Clinicians rely to varying extents on patientreported measures and clinical tests to diagnose incontinence and guide treatment in the ambulatory setting. Available nonsurgical treatments include pharmacological therapies such as antimuscarinic, serotonin-noradrenalin reuptake inhibitor, and estrogenbased medications, as well as nonpharmacological treatments such as lifestyle changes, pelvic floor muscle training, bladder training, electrical stimulation, magnetic stimulation, and intravaginal or intraurethral devices. Objectives The objectives of this review were to (1) determine what constitutes an adequate diagnostic evaluation on which to base nonsurgical treatment of urinary incontinence in women in the ambulatory care setting and (2) determine the benefits and harms of available pharmacological and nonpharmacological treatments for incontinence in women.


Hwang E.S.,University of California at San Francisco
Journal of the National Cancer Institute - Monographs | Year: 2010

Mastectomy has been the historical mainstay of treatment for ductal carcinoma in situ (DCIS), but over time, there have been significant changes in its use for preinvasive breast cancer. Although there was an early reduction in mastectomy rates for DCIS with the introduction of breast-conserving surgery, in some groups, the rates of both mastectomy and contralateral mastectomy for DCIS have increased in recent years. Due to advances in breast cancer screening as well as improvements in breast reconstruction, mastectomy will continue to be an important and acceptable treatment option. Recurrence is rare following mastectomy for DCIS. Nevertheless, there remains a need to follow patients for in-breast, nodal, or contralateral breast events, which can occur long after the index DCIS has been treated. Since up to 70% of women with newly diagnosed DCIS have disease that can be managed with breast-conserving surgery, patient counseling is imperative to ensure the best use of this option for DCIS, given that mastectomy does not significantly impact survival in this setting. © The Author 2010. Published by Oxford University Press. All rights reserved.


Cedars M.I.,University of California at San Francisco
Fertility and Sterility | Year: 2015

Men and women are increasingly delaying childbearing to the late 30s, the 40s and beyond. The implications of this societal change on childhood health and well-being have only recently been a focus of research. There are known increased perinatal risks associated with increasing maternal age, while paternal age seems to have a potentially greater negative impact on childhood health. Understanding the mechanisms underlying the aging of sperm and eggs, and how these changes impact offspring, is a critical next step as we work to help patients build healthy families. © 2015 American Society for Reproductive Medicine.


Distal middle cerebral artery (MCA) aneurysms frequently have nonsaccular morphology that necessitates trapping and bypass. Bypasses can be difficult because efferent arteries lie deep in the opercular cleft and may not be easily identifiable. We introduce the "flash fluorescence" technique, which uses videoangiography with indocyanine green (ICG) dye to identify an appropriate recipient artery on the cortical surface for the bypass, enabling a more superficial and easier anastomosis. Flash fluorescence requires 3 steps: (1) temporary clip occlusion of the involved afferent artery; (2) videoangiography demonstrating fluorescence in uninvolved arteries on the cortical surface; and (3) removal of the temporary clip with flash fluorescence in the involved efferent arteries on the cortical surface, thereby identifying a recipient. Alternatively, temporary clips can occlude uninvolved arteries, and videoangiography will demonstrate initial fluorescence in efferent arteries during temporary occlusion and flash fluorescence in uninvolved arteries during reperfusion. From a consecutive series of 604 MCA aneurysms treated microsurgically, 22 (3.6%) were distal aneurysms and 11 required a bypass. The flash fluorescence technique was used in 3 patients to select the recipient artery for 2 superficial temporal artery-to-MCA bypasses and 1 MCA-MCA bypass. The correct recipient was selected in all cases. The flash fluorescence technique provides quick, reliable localization of an appropriate recipient artery for bypass when revascularization is needed for a distal MCA aneurysm. This technique eliminates the need for extensive dissection of the efferent artery and enables a superficial recipient site that makes the anastomosis safer, faster, and less demanding.


Lateral supracerebellar-infratentorial approaches are established for lesions in ambient cistern and posterolateral midbrain, but published surgical experiences do not describe results with this approach in the sitting position. Gravity retraction of the cerebellum opens this surgical corridor and dramatically alters exposure, creating 2 variations of the lateral supracerebellar-infratentorial approach: the supracerebellar-supratrochlear approach and the infratentorial-infratrochlear approach. We reviewed our experience treating cavernous malformations and arteriovenous malformations (AVMs) of the posteroinferior thalamus and posterolateral midbrain by use of supracerebellar-supratrochlear and infratentorial-infratrochlear approaches. Microsurgical technique, clinical data, radiographic features, and neurological outcomes were evaluated. During an 11-year surgical experience with 341 cavernous malformation patients and 402 AVM patients, 8 patients were identified, 6 with cavernous malformations and 2 with AVMs. Infratentorial-infratrochlear approaches were used in 4 patients (50%), including 3 with inferolateral midbrain cavernous malformations. Supracerebellar-supratrochlear approaches were used in 4 patients (50%), including 2 with posterior thalamic lesions surfacing on pulvinar. Resections were radiographically complete in all cases. There were no new, permanent neurological deficits, nor were there any medical or surgical complications. There has been no evidence of rebleeding or recurrence. Gravity retraction of the cerebellum transforms the lateral supracerebellar-infratentorial approach, enhancing exposure and approach trajectories that can be achieved with patients in prone or lateral positions. The increased upward viewing angle of the supracerebellar-supratrochlear approach accesses the posteroinferior thalamus. The increased downward-viewing angle of the infratentorial-infratrochlear approach accesses cerebellomesencephalic fissure and posterolateral midbrain. These approaches open wide corridors for safe surgical resection of symptomatic cavernous malformations and AVMs.


Bastian B.C.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Melanomas comprise multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ-line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain-of-function mutations in one of several primary oncogenes, which typically lead to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor-suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about the pathogenesis and clinical, histologic, and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. © 2014 by Annual Reviews. All rights reserved.


Fox E.P.,University of California at San Francisco
Transcription | Year: 2012

Candida albicans is a commensal microorganism of the human microbiome; it is also the most prevalent fungal pathogen of humans. Many infections caused by C. albicans are a direct consequence of its proclivity to form biofilms--resilient, surface-associated communities of cells where individual cells acquire specialized properties that are distinct from those observed in suspension cultures. We recently identified the transcriptional network that orchestrates the formation of biofilms in C. albicans. These results set the stage for understanding how biofilms are formed and, once formed, how the specialized properties of biofilms are elaborated. This information will provide new insight for understanding biofilms in more detail and may lead to improvements in preventing and treating biofilm-based infections in the future.


Schachter J.,University of California at San Francisco
Expert Review of Molecular Diagnostics | Year: 2013

Evaluation of: Roberts CH, Last A, Molina-Gonzalez S et al. Development and evaluation of a next-generation digital PCR diagnostic assay for ocular chlamydia trachomatis infections. J. Clin. Microbiol. 51(7), 2195-2203 (2013). Trachoma is the leading infectious cause of blindness in developing countries. Currently, there is no program to eliminate blinding trachoma as a public health problem. We need better diagnostic tests for research and to assess progress in control programs. Roberts et al. adapted droplet digital PCR (ddPCR), an emulsion PCR process that performs absolute quantitation of nucleic acids, to detect and quantify Chlamydia trachomatis infections. They compared the results with ddPCR on conjunctival swab specimens collected in trachoma-endemic area to results using Roche's Amplicor® C. trachomatis/Neisseria gonorrhoeae (CT/NG) PCR and found that ddPCR sensitivity was 73.3%. The authors concluded that 'ddPCR is an effective diagnostic technology suitable for both research and clinical use in diagnosing ocular C. trachomatis infections'. This reviewer disagrees, feeling that if the stated sensitivity is accurate, it is too low, and suggests there may be good reasons to adapt commercially available tests for this purpose. © 2013 Informa UK Ltd.


Verkman A.S.,University of California at San Francisco
Physical Biology | Year: 2013

Diffusion of solutes and macromolecules in the extracellular space (ECS) in brain is important for non-synaptic intercellular communication, extracellular ionic buffering, and delivery of drugs and metabolites. Diffusion in tumor ECS is important for delivery of anti-tumor drugs. The ECS in brain comprises ∼20% of brain parenchymal volume and contains cell-cell gaps down to ∼50 nm. We have developed fluorescence methods to quantify solute diffusion in the ECS, allowing measurements deep in solid tissues using microfiberoptics with micron tip size. Diffusion through the tortuous ECS in brain is generally slowed by ∼3-5-fold compared with that in water, with approximately half of the slowing due to tortuous ECS geometry and half due to the mildly viscous extracellular matrix (ECM). Mathematical modeling of slowed diffusion in an ECS with reasonable anatomical accuracy is in good agreement with experiment. In tumor tissue, diffusion of small macromolecules is only mildly slowed (<3-fold slower than in water) in superficial tumor, but is greatly slowed (>10-fold) at a depth of few millimeters as the tumor tissue becomes more compact. Slowing by ECM components such as collagen contribute to the slowed diffusion. Therefore, as found within cells, cellular crowding and highly tortuous transport can produce only minor slowing of diffusion in the ECS. © 2013 IOP Publishing Ltd.


Matthay K.K.,University of California at San Francisco
Clinical Cancer Research | Year: 2013

Isotretinoin (13-cis-retinoic acid; 13-cisRA) has been shown to significantly improve survival for children with high-risk neuroblastoma. Pharmacokinetics of isotretinoin may be negatively affected by the mode of drug administration and the dosing formula. © 2012 AACR.


Papa F.R.,University of California at San Francisco
Cold Spring Harbor Perspectives in Medicine | Year: 2012

Overwhelming of protein folding in the endoplasmic reticulum (ER)-referred to as "ER stress"-activates a set of intracellular signaling pathways termed the unfolded protein response (UPR). Beneficial outputs of the UPR promote adaptation in cells experiencing manageably low levels of ER stress. However, if ER stress reaches critically high levels, the UPR uses destructive outputs to trigger programmed cell death. Genetic mutations in various UPR components cause inherited syndromes of diabetes mellitus in both rodents and humans, implicating the UPR in the proper functioning and survival of pancreatic islet β cells. Markers of chronically elevated ER stress, terminal UPR signaling, and apoptosis are evident in β cells in these rare disorders; these markers are similarly present in islets of human patients with common forms of diabetes. These findings promise to enhance our molecular understanding of human diabetes significantly and may lead to new and effective therapies. © 2012 Cold Spring Harbor Laboratory Press.


Minzenberg M.J.,University of California at San Francisco
Neuropsychopharmacology | Year: 2014

Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4-30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4-30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control.Neuropsychopharmacology advance online publication, 23 July 2014; doi:10.1038/npp.2014.155.


Shin S.Y.,University of California at San Francisco
Arthritis care & research | Year: 2013

Research shows a gap between perceived cognitive dysfunction and objective neuropsychological performance in persons with chronic diseases. We explored this relationship in persons with rheumatoid arthritis (RA). Individuals from a longitudinal cohort study of RA participated in a study visit that included physical, psychosocial, cognitive, and biologic metrics. Subjective cognitive dysfunction was assessed using the Perceived Deficits Questionnaire (PDQ; range 0-20, where higher scores = greater perceived impairment). Objective cognitive impairment was assessed using a battery of 12 standardized neuropsychological measures yielding 16 indices. On each test, subjects were classified as impaired if they performed 1 SD below the age-based population norms. Total cognitive function scores were calculated by summing the transformed scores (range 0-16, where higher scores = greater impairment). Multiple linear regression analyses determined the relationship of the total cognitive function score with the PDQ score, controlling for sex, race, marital status, income, education, disease duration, disease severity, depression, and fatigue. One hundred twenty subjects (mean ± SD age 58.5 ± 11.0 years) were included. Mean ± SD scores of total cognitive function and the PDQ were 2.5 ± 2.2 (range 0-10) and 5.8 ± 3.8 (range 0-16), respectively. In multivariate analysis, there was no significant relationship between the total cognitive function score and the PDQ score. However, depression and fatigue (β = 0.32, P < 0.001 and β = 0.31, P = 0.001, respectively) were significantly associated with the PDQ score. The findings emphasize the gap between subjective and objective measures of cognitive impairment and the importance of considering psychological factors within the context of cognitive symptoms in clinical settings. Copyright © 2013 by the American College of Rheumatology.


Julian L.J.,University of California at San Francisco
Arthritis care & research | Year: 2011

Depression and cardiovascular disease are common and debilitating comorbidities associated with systemic lupus erythematosus (SLE). In this study, history of cardiovascular events, cardiovascular risk factors, and SLE disease-related factors were evaluated as longitudinal predictors of depression in a large cohort of patients with SLE. Data were derived from 663 adult participants in the 2004-2008 Lupus Outcomes Study, who were followed for up to 5 annual interviews. Multivariate logistic regression analyses using generalized estimating equations were used to determine predictors of the development of increased depressive symptom severity over a 12-month period (Center for Epidemiologic Studies Depression Scale [CES-D] score of 23 or greater), yielding 2,224 paired observations. Predictors included sociodemographics, traditional cardiovascular risk factors (reported presence of heart disease, history of stroke or myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus, obesity, smoking status, and family history), and SLE-specific risk factors (glucocorticoid use, renal involvement, disease duration, and disease activity). The annual incidence of depression was 12% in this cohort. Multivariate predictors of new-onset depression included younger age (ages 20-39 years: odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.3-3.9; ages 40-59 years: OR 1.8, 95% CI 1.1-2.7), Hispanic/Latino ethnicity (OR 1.8, 95% CI 1.2-2.8), having some college education (OR 1.8, 95% CI 1.1-3.0), baseline CES-D score (OR per point 1.1, 95% CI 1.1-1.2), presence of diabetes mellitus (OR 1.8, 95% CI 1.1-2.8), and baseline SLE disease activity (OR 1.2, 95% CI 1.1-1.4). These results suggest that, in addition to known sociodemographic factors, the presence of diabetes mellitus and SLE disease activity may play a role in the development of depression in SLE. Copyright © 2011 by the American College of Rheumatology.


Venook A.P.,University of California at San Francisco
The oncologist | Year: 2010

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the burden of this devastating cancer is expected to increase further in coming years. The collection and analysis of epidemiologic HCC data will play a critical role in guiding future disease prevention strategies and optimizing patient management. Previous epidemiologic studies have highlighted striking global variations in the incidence of HCC, which is particularly high in much of east Asia and sub-Saharan Africa, and lower, but on the increase, in North America and most of Europe. This variation appears to be related to the complex etiology of HCC, with different risk factors, primarily infection with hepatitis B or hepatitis C virus, responsible for driving HCC incidence rates in different regions. Although previous studies have contributed considerably to the knowledge of HCC epidemiology, there are limitations associated with the currently available data, which arise from studies performed at different times in the past, using varying methodologies, and with diverse patient populations. A new and global approach to the study of HCC epidemiology is required if HCC disease prevention and treatment strategies are to be adequately directed and supported in coming years.


Reeves S.,University of California at San Francisco
The Cochrane database of systematic reviews | Year: 2013

The delivery of effective, high-quality patient care is a complex activity. It demands health and social care professionals collaborate in an effective manner. Research continues to suggest that collaboration between these professionals can be problematic. Interprofessional education (IPE) offers a possible way to improve interprofessional collaboration and patient care. To assess the effectiveness of IPE interventions compared to separate, profession-specific education interventions; and to assess the effectiveness of IPE interventions compared to no education intervention. For this update we searched the Cochrane Effective Practice and Organisation of Care Group specialised register, MEDLINE and CINAHL, for the years 2006 to 2011. We also handsearched the Journal of Interprofessional Care (2006 to 2011), reference lists of all included studies, the proceedings of leading IPE conferences, and websites of IPE organisations. Randomised controlled trials (RCTs), controlled before and after (CBA) studies and interrupted time series (ITS) studies of IPE interventions that reported objectively measured or self reported (validated instrument) patient/client or healthcare process outcomes. At least two review authors independently assessed the eligibility of potentially relevant studies. For included studies, at least two review authors extracted data and assessed study quality. A meta-analysis of study outcomes was not possible due to heterogeneity in study designs and outcome measures. Consequently, the results are presented in a narrative format. This update located nine new studies, which were added to the six studies from our last update in 2008. This review now includes 15 studies (eight RCTs, five CBA and two ITS studies). All of these studies measured the effectiveness of IPE interventions compared to no educational intervention. Seven studies indicated that IPE produced positive outcomes in the following areas: diabetes care, emergency department culture and patient satisfaction; collaborative team behaviour and reduction of clinical error rates for emergency department teams; collaborative team behaviour in operating rooms; management of care delivered in cases of domestic violence; and mental health practitioner competencies related to the delivery of patient care. In addition, four of the studies reported mixed outcomes (positive and neutral) and four studies reported that the IPE interventions had no impact on either professional practice or patient care. This updated review reports on 15 studies that met the inclusion criteria (nine studies from this update and six studies from the 2008 update). Although these studies reported some positive outcomes, due to the small number of studies and the heterogeneity of interventions and outcome measures, it is not possible to draw generalisable inferences about the key elements of IPE and its effectiveness. To improve the quality of evidence relating to IPE and patient outcomes or healthcare process outcomes, the following three gaps will need to be filled: first, studies that assess the effectiveness of IPE interventions compared to separate, profession-specific interventions; second, RCT, CBA or ITS studies with qualitative strands examining processes relating to the IPE and practice changes; third, cost-benefit analyses.


Gelfand A.A.,University of California at San Francisco
Current Opinion in Neurology | Year: 2013

Purpose of Review: This review covers recent advances in our understanding of migraine and childhood periodic syndromes in children and adolescents, as well as the treatment of these disorders. Recent Findings: The childhood periodic syndromes include benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine, and cyclic vomiting syndrome. Recent research suggests infant colic may also fit into this category. Migraine headache is common in children and adolescents, and chronic migraine effects 0.8-1.8% of adolescents and 0.6% of children. Two triptans are now FDA-approved for the acute treatment of migraine in pediatric patients. For preventive therapy, a number of medications have been studied and a major national trial is ongoing. Summary: Childhood periodic syndromes are thought to be early life expressions of those genes that later in life are expressed as migraine headache. Future research into mechanisms of identifying children with these disorders prior to extensive and often invasive testing would be of benefit to these families and children. Migraine-specific therapies are now approved for the acute treatment of migraine in pediatric patients. Preventive migraine therapy is indicated in appropriate patients, although which medications are most effective in children is an area of active research. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Lowell C.A.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2011

The response of innate immune cells to growth factors, immune complexes, extracellular matrix proteins, cytokines, pathogens, cellular damage, and many other stimuli is regulated by a complex net of intracellular signal transduction pathways. The majority of these pathways are either initiated or modulated by Src-family or Syk tyrosine kinases present in innate cells. The Src-family kinases modulate the broadest range of signaling responses, including regulating immunoreceptors, C-type lectins, integrins, G-protein-coupled receptors, and many others. Src-family kinases also modulate the activity of other kinases, including the Tec-family members as well as FAK and Pyk2. Syk kinase is required for initiation of signaling involving receptors that utilize immunoreceptor tyrosine activation (ITAM) domains. This article reviews the major activating and inhibitory signaling pathways regulated by these cytoplasmic tyrosine kinases, illuminating the many examples of signaling cross talk between pathways. © 2011 Cold Spring Harbor Laboratory Press.


Whooley M.A.,University of California at San Francisco | Wong J.M.,University of California at Irvine
Annual Review of Clinical Psychology | Year: 2013

During the past two decades, research in the field of depression and cardiovascular disorders has exploded. Multiple studies have demonstrated that depression is more prevalent in populations with cardiovascular disease, is a robust risk factor for the development of cardiovascular disease in healthy populations, and is predictive of adverse outcomes (such as myocardial infarction and death) among populations with preexisting cardiovascular disease. Mechanistic studies have shown that poor health behaviors, such as physical inactivity, medication nonadherence, and smoking, strongly contribute to this association. Small randomized trials have found that antidepressant therapies may improve cardiac outcomes. Based on this accumulating evidence, the American Heart Association has recommended routine screening for depression in all patients with coronary heart disease. This review examines the key epidemiological literature on depression and cardiovascular disorders and discusses our current understanding of the mechanisms responsible for this association. We also examine current recommendations for screening, diagnosis, and management of depression. We conclude by highlighting new research areas and discussing therapeutic management of depression in patients with cardiovascular disorders. Copyright © 2013 by Annual Reviews.


Anderson M.S.,University of California at San Francisco | Su M.A.,University of North Carolina at Chapel Hill
Current Opinion in Immunology | Year: 2011

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a crucial role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified. © 2010 Elsevier Ltd.


Bindman A.B.,University of California at San Francisco
Journal of the American College of Radiology | Year: 2014

CMS is testing a range of payment policy options, including pay for performance, bundled payments, and shared savings through accountable care organizations. Radiologists can anticipate that the basis for how they are paid by Medicare will change and that they will need to play a greater role than has been required of them in the traditional fee-for-service payment system to demonstrate that imaging studies are used safely and efficiently. © 2014 Published by Elsevier on behalf of American College of Radiology.


Fauci A.S.,National Institute of Allergy and Infectious Diseases | Marovich M.A.,National Institute of Allergy and Infectious Diseases | Dieffenbach C.W.,National Institute of Allergy and Infectious Diseases | Hunter E.,Emory University | Buchbinder S.P.,University of California at San Francisco
Science | Year: 2014

Future HIV vaccine research should consider the balance between responses that favor protection and those that lead to susceptibility to infection.


Colby D.W.,University of California at San Francisco
Cold Spring Harbor perspectives in biology | Year: 2011

The discovery of infectious proteins, denoted prions, was unexpected. After much debate over the chemical basis of heredity, resolution of this issue began with the discovery that DNA, not protein, from pneumococcus was capable of genetically transforming bacteria (Avery et al. 1944). Four decades later, the discovery that a protein could mimic viral and bacterial pathogens with respect to the transmission of some nervous system diseases (Prusiner 1982) met with great resistance. Overwhelming evidence now shows that Creutzfeldt-Jakob disease (CJD) and related disorders are caused by prions. The prion diseases are characterized by neurodegeneration and lethality. In mammals, prions reproduce by recruiting the normal, cellular isoform of the prion protein (PrP(C)) and stimulating its conversion into the disease-causing isoform (PrP(Sc)). PrP(C) and PrP(Sc) have distinct conformations: PrP(C) is rich in α-helical content and has little β-sheet structure, whereas PrP(Sc) has less α-helical content and is rich in β-sheet structure (Pan et al. 1993). The conformational conversion of PrP(C) to PrP(Sc) is the fundamental event underlying prion diseases. In this article, we provide an introduction to prions and the diseases they cause.


Thompson H.R.,University of California at San Francisco
Preventing chronic disease | Year: 2013

School physical education (PE) has been identified as a critical public health tool to increase physical activity among youths. We sought to objectively assess compliance with PE quantity mandates and quality recommendations in a large urban California school district. We collected PE schedules and systematically observed PE lessons (n=154) in 20 elementary, 4 middle, and 4 high schools from February through May 2011. On the basis of schools' master schedules, 83% of elementary schools met the California state mandate of 100 PE minutes per week. Teachers' actual schedules indicated that 20% of schools met the mandate, and observation showed that only 5% were in compliance. All middle and high schools met the mandated 200 minutes per week. On average, classes at all school levels met the recommended 50% of PE lesson time in moderate-to-vigorous physical activity. No teacher- or school-level factors significantly predicted PE quantity, but credentialed elementary PE teachers spent more time building students' motor skills. Our results suggest that current national estimates of PE, which are based on schools' self-report, overestimate the amount of PE provided in elementary schools. Although more than half of PE class time was spent in moderate-to-vigorous physical activity, total physical activity in elementary schools from PE is minimal and may do little to contribute to students' overall health.


Miller W.L.,University of California at San Francisco | Auchus R.J.,University of Texas Southwestern Medical Center
Endocrine Reviews | Year: 2011

Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. Whereas most endocrine texts discuss adrenal, ovarian, testicular, placental, and other steroidogenic processes in a gland-specific fashion, steroidogenesis is better understood as a single process that is repeated in each gland with cell-type-specific variations on a single theme. Thus, understanding steroidogenesis is rooted in an understanding of the biochemistry of the various steroidogenic enzymes and cofactors and the genes that encode them. The first and rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone by a single enzyme, P450scc (CYP11A1), but this enzymatically complex step is subject to multiple regulatory mechanisms, yielding finely tuned quantitative regulation. Qualitative regulation determining the type of steroid to be produced is mediated by many enzymes and cofactors. Steroidogenic enzymes fall into two groups: cytochrome P450 enzymes and hydroxysteroid dehydrogenases. A cytochrome P450 may be either type 1 (in mitochondria) or type 2 (in endoplasmic reticulum), and a hydroxysteroid dehydrogenase may belong to either the aldo-keto reductase or short-chain dehydrogenase/reductase families. The activities of these enzymes are modulated by posttranslational modifications and by cofactors, especially electron-donating redox partners. The elucidation of the precise roles of these various enzymes and cofactors has been greatly facilitated by identifying the genetic bases of rare disorders of steroidogenesis. Some enzymes not principally involved in steroidogenesis may also catalyze extraglandular steroidogenesis, modulating the phenotype expected to result from some mutations. Understanding steroidogenesis is of fundamental importance to understanding disorders of sexual differentiation, reproduction, fertility, hypertension, obesity, and physiological homeostasis. Copyright © 2011 by The Endocrine Society.


Link T.M.,University of California at San Francisco
Radiology | Year: 2012

Osteoporosis is becoming an increasingly important public health issue, and effective treatments to prevent fragility fractures are available. Osteoporosis imaging is of critical importance in identifying individuals at risk for fractures who would require pharmacotherapy to reduce fracture risk and also in monitoring response to treatment. Dual x-ray absorptiometry is currently the state-of-the-art technique to measure bone mineral density and to diagnose osteoporosis according to the World Health Organization guidelines. Motivated by a 2000 National Institutes of Health consensus conference, substantial research efforts have focused on assessing bone quality by using advanced imaging techniques. Among these techniques aimed at better characterizing fracture risk and treatment effects, high-resolution peripheral quantitative computed tomography (CT) currently plays a central role, and a large number of recent studies have used this technique to study trabecular and cortical bone architecture. Other techniques to analyze bone quality include multidetector CT, magnetic resonance imaging, and quantitative ultrasonography. In addition to quantitative imaging techniques measuring bone density and quality, imaging needs to be used to diagnose prevalent osteoporotic fractures, such as spine fractures on chest radiographs and sagittal multidetector CT reconstructions. Radiologists need to be sensitized to the fact that the presence of fragility fractures will alter patient care, and these fractures need to be described in the report. This review article covers state-of-the-art imaging techniques to measure bone mineral density, describes novel techniques to study bone quality, and focuses on how standard imaging techniques should be used to diagnose prevalent osteoporotic fractures. © RSNA, 2012.


BACKGROUND: Previous studies have characterized an increasing trend of double burden households, or households with individuals experiencing both undernutrition and obesity, in countries undergoing a nutrition transition. Although most prior studies indicate the prevalence of double burden households is highest in middle-income countries, there is some support for an increase in double burden households in sub-Saharan African countries as well.METHOD: Using data from the Demographic Health Surveys (DHS) and the World Health Organization (WHO), the prevalence of double burden households in sub-Saharan African countries was calculated and the associations between prevalence of overweight/obese adults and underweight, stunted and wasted children were evaluated at the country and household (DHS only) levels. Restricted analyses and frequencies were calculated using urban-only datasets. Surveys from 28 African countries were available using WHO data and 26 from the DHS surveys. Only surveys that were conducted after 2000 were included in analyses.RESULTS: Using the WHO datasets, there were inverse associations between the prevalence of overweight and obesity in adults and underweight, stunting and wasting in children. Correspondingly, there were positive associations between adult underweight and child underweight, stunting and wasting. These associations were not significant in a smaller sample size using urban-only surveys. The prevalence of double burden households in DHS datasets was low: under 5 percent for obese mothers and underweight, stunted or wasted child pairs with a slightly higher percentage for overweight mothers and children with undernutrition. Restricting the analysis to urban only populations did not increase the frequencies of double burden households significantly.CONCLUSION: There was a low prevalence of double burden households in recent data from sub-Saharan Africa. Countries that have a high prevalence of child undernutrition correspondingly have a high prevalence of adult underweight and low prevalence of adult overweight and obesity.


Stannard D.,University of California at San Francisco
Pain Management Nursing | Year: 2012

For more than a century, acetaminophen has been recognized worldwide as a safe and effective agent for relieving pain and reducing fever in a wide range of patients. However, until recently, acetaminophen was available in the United States only in oral and rectal suppository formulations. In November 2010, the United States Food and Drug Administration granted approval for the use of a new intravenous (IV) formulation of acetaminophen for: 1) the management of mild to moderate pain; 2) the management of moderate to severe pain with adjunctive opioid analgesics; and 3) the reduction of fever in adults and children (age ≥2 years). This case-illustrated review of IV acetaminophen begins with a discussion of the rationale for the drug's development and proceeds to analyze the clinical pharmacology, efficacy, safety, and nursing implications of its use, both as monotherapy and in combination with other agents as part of a multimodal pain therapy strategy. © 2012 American Society for Pain Management Nursing.


Bourne H.R.,University of California at San Francisco
eLife | Year: 2013

The relentless expansion that threatens the sustainability of biomedical research in the US takes a heavy toll on young researchers.


Bernstein H.S.,University of California at San Francisco
Pediatric research | Year: 2012

Congenital heart disease occurs in 1% of liveborn infants, making it the most common birth defect worldwide. Many of these children develop heart failure. In addition, both genetic and acquired forms of dilated cardiomyopathy are a significant source of heart failure in the pediatric population. Heart failure occurs when the myocardium is unable to meet the body's metabolic demands. Unlike some organs, the heart has limited, if any, capacity for repair after injury. Heart transplantation remains the ultimate approach to treating heart failure, but this is costly and excludes patients who are poor candidates for transplantation given their comorbidities, or for whom a donor organ is unavailable. Stem cell therapy represents the first realistic strategy for reversing the effects of what has until now been considered terminal heart damage. We will discuss potential sources of cardiac-specific stem cells, including mesenchymal, resident cardiac, embryonic, and induced pluripotent stem cells. We will consider efforts to enhance cardiac stem cell engraftment and survival in damaged myocardium, the incorporation of cardiac stem cells into tissue patches, and techniques for creating bioartificial myocardial tissue as well as whole organs. Finally, we will review progress being made in assessing functional improvement in animals and humans after cellular transplant.


Terrault N.,University of California at San Francisco
American Journal of Gastroenterology | Year: 2013

Improvements in the outcomes of patients transplanted for hepatitis B virus (HBV) have been substantial in the past two decades. With current therapies, the vast majority of transplant recipients are protected against recurrent and/or progressive liver disease. Effective prophylactic therapies include hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues (NAs) and NA therapy alone (without HBIG). Definitions of recurrence in the setting of prophylaxis are evolving - persistence or reappearance of hepatitis B surface antigen in serum remains a marker of reinfection, but is not necessarily a marker of progressive hepatitis. The level of HBV DNA at the time of transplant remains the most consistent factor predicting risk of recurrent HBV. An individualized, rather than a one size fits all, approach to prophylaxis that is based on risk of reinfection and/or risk of progressive disease, if reinfected, is the optimal means of insuring optimal graft survival for HBV-infected patients. ©2013 by the American College of Gastroenterology.


Mayadas T.N.,Harvard University | Cullere X.,Harvard University | Lowell C.A.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Neutrophils and neutrophil-like cells are the major pathogen-fighting immune cells in organisms ranging from slime molds to mammals. Central to their function is their ability to be recruited to sites of infection, to recognize and phagocytose microbes, and then to kill pathogens through a combination of cytotoxic mechanisms. These include the production of reactive oxygen species, the release of antimicrobial peptides, and the recently discovered expulsion of their nuclear contents to form neutrophil extracellular traps. Here we discuss these primordial neutrophil functions, which also play key roles in tissue injury, by providing details of neutrophil cytotoxic functions and congenital disorders of neutrophils. In addition, we present more recent evidence that interactions between neutrophils and adaptive immune cells establish a feed-forward mechanism that amplifies pathologic inflammation. These newly appreciated contributions of neutrophils are described in the setting of several inflammatory and autoimmune diseases. © 2014 by Annual Reviews. All rights reserved.


Podust L.M.,University of California at San Francisco | Sherman D.H.,University of Michigan
Natural Product Reports | Year: 2012

Covering: 1985 to 2012 Diverse oxygenation patterns of natural products generated by secondary metabolic pathways in microorganisms and plants are largely achieved through the tailoring reactions catalysed by cytochrome P450 enzymes (P450s). P450s are a large family of oxidative hemoproteins found in all life forms from prokaryotes to humans. Understanding the reactivity and selectivity of these fascinating C-H bond-activating catalysts will advance their use in generating valuable pharmaceuticals and products for medicine, agriculture and industry. A major strength of this P450 group is its set of established enzyme-substrate relationships, the source of the most detailed knowledge on how P450 enzymes work. Engineering microbial-derived P450 enzymes to accommodate alternative substrates and add new functions continues to be an important near- and long-term practical goal driving the structural characterization of these molecules. Understanding the natural evolution of P450 structure-function should accelerate metabolic engineering and directed evolutionary approaches to enhance diversification of natural product structures and other biosynthetic applications. This journal is © The Royal Society of Chemistry 2012.


Loh M.L.,University of California at San Francisco
British Journal of Haematology | Year: 2011

Myeloid neoplasms derive from the pathological clonal expansion of an abnormal stem cell and span a diverse spectrum of phenotypes including acute myeloid leukaemia (AML), myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). Expansion of myeloid blasts with suppression of normal haematopoiesis is the hallmark of AML, whereas MPN is associated with over-proliferation of one or more lineages that retain the capacity to differentiate, and MDS is characterized by cytopenias and aberrant differentiation. MPD and MDS can progress to AML, which is likely due to the acquisition of cooperative mutations. Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap MPN/MDS by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukaemia, a similar disease in adults. While the current standard of care for patients with JMML relies on allogeneic haematopoietic stem cell transplant (HSCT), relapse is the most frequent cause of treatment failure. This review outlines our understanding of the genetic underpinnings of JMML with a recent update on the discovery of novel CBL mutations, as well as a brief review on current therapeutic approaches. © 2011 Blackwell Publishing Ltd.


ABSTRACT As in other organisms, CRISPR/Cas9 methods provide a powerful approach for genome editing in the nematode Caenorhabditis elegans. Oligonucleotides are excellent repair templates for introducing substitutions and short insertions, as they are cost effective, require no cloning, and appear in other organisms to target changes by homologous recombination at DNA double-strand breaks (DSBs). Here, I describe a methodology in C. elegans to efficiently knock in epitope tags in 8–9 days, using a temperature-sensitive lethal mutation in the pha-1 gene as a co-conversion marker. I demonstrate that 60mer oligos with 29 bp of homology drive efficient knock-in of point mutations, and that disabling nonhomologous end joining by RNAi inactivation of the cku-80 gene significantly improves knock-in efficiency. Homology arms of 35–80 bp are sufficient for efficient editing and DSBs up to 54 bp away from the insertion site produced knock-ins. These findings will likely be applicable for a range of genome editing approaches in C. elegans, which will improve editing efficiency and minimize screening efforts. © 2015 by the Genetics Society of America


Rauen K.A.,University of California at San Francisco
Annual Review of Genomics and Human Genetics | Year: 2013

The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration. Copyright © 2013 by Annual Reviews. All rights reserved.


Prusiner S.B.,University of California at San Francisco
Annual Review of Genetics | Year: 2013

Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests. © 2013 by Annual Reviews. All rights reserved.


Martin P.M.,University of California at San Francisco
Translational psychiatry | Year: 2013

Wnt signaling, which encompasses multiple biochemical pathways that regulate neural development downstream of extracellular Wnt glycoprotein ligands, has been suggested to contribute to major psychiatric disorders including autism spectrum disorders (ASD). We used next-generation sequencing and Sequenom genotyping technologies to resequence 10 Wnt signaling pathway genes in 198 ASD patients and 240 matched controls. Results for single-nucleotide polymorphisms (SNPs) of interest were confirmed in a second set of 91 ASD and 144 control samples. We found a significantly increased burden of extremely rare missense variants predicted to be deleterious by PolyPhen-2, distributed across seven genes in the ASD sample (3.5% in ASD vs 0.8% in controls; Fisher's exact test, odds ratio (OR)=4.37, P=0.04). We also found a missense variant in WNT1 (S88R) that was overrepresented in the ASD sample (8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048; OR=8.2 and P=0.053 after correction for population stratification). Functional analysis revealed that WNT1-S88R is more active than wild-type WNT1 in assays for the Wnt/β-catenin signaling pathway. Our findings of a higher burden in ASD of rare missense variants distributed across 7 of 10 Wnt signaling pathway genes tested, and of a functional variant at the WNT1 locus associated with ASD, support that dysfunction of this pathway contributes to ASD susceptibility. Given recent findings of common molecular mechanisms in ASD, schizophrenia and affective disorders, these loci merit scrutiny in other psychiatric conditions as well.


Wu A.H.,University of California at San Francisco
Archives of pathology & laboratory medicine | Year: 2013

Pharmacogenetic testing is becoming increasingly important for drugs such as irinotecan, warfarin, clopidogrel, codeine, and the tricyclic antidepressant drugs. Laboratories certified to perform pharmacogenetic testing must demonstrate successful performance on proficiency testing surveys. To examine the performance of laboratories subscribing to pharmacogenetic proficiency testing surveys for genes that encode CYP2C9, VKORC1, UGT1A1, CYP2C19, and CYP2D6. College of American Pathologists Pharmacogenetic Proficiency Survey (PGX), 2007-2011. For all 5 genes challenged, there was good performance among participating laboratories for reporting wild types (95.4%-99.1% correct). For CYP2C9, VKORC1, and UGT1A1, there was no statistical difference in the percentage correctly detected for variant alleles compared to wild type. For CYP2C19, participating laboratories were greater than 90% successful in detecting variant genotypes of *1/*2, *1/*8, and *2/*3. However, several laboratories failed to detect *2/*2, *2/*4 and *1/*17 variant genotypes. For CYP2D6, laboratories were successful in detecting the most important variant genotypes (*1/*4, *1/*2, *4/*10, *10/*10, *2/*4, *2/*10) but not some of the less frequently encountered variant genotypes (*1/*10, *2/*3, *1/*35, *4/*5, and *1/*1XN). The interpretation of phenotypes by participating laboratories was largely consistent with the genotypes reported, with errors in genotyping leading to errors in phenotype assignment. Improvements in genotyping accuracy are needed for some pharmacogenetics laboratories with reference to CYP2C19 and CYP2D6.


Bikle D.D.,University of California at San Francisco
Experimental Dermatology | Year: 2011

Vitamin D has been produced by plants and animals almost from the time life began. The ability to transport and metabolize vitamin D to more active forms evolved as the structures of plants and animals became more complex, and the cells within these organisms took on more specialized functions. In higher-order animals, the vitamin D receptor (VDR) is found in nearly every cell, and the ability of the cell to produce the active hormone, 1,25(OH)2D, is also widely distributed. Furthermore, the physiological functions with which vitamin D signalling is now associated are as diverse as the tissues in which the VDR is located. Why is this, and is there a common theme? This viewpoint article argues that there is. All cells maintain a fairly constant and submicromolar concentration of free calcium. Calcium is an important regulator of many processes within the cell. The ebb and flow of calcium within cells is controlled by calcium pumps, antiporters and channels. Animals with calcified exo or endoskeletons have an additional need for calcium, a need that changes during the life cycle of the organism. In this article, I make the case that vitamin D signalling evolved to enable the organism to effectively regulate calcium flux, storage and signalling and that such regulation is critical for the evolutionary process. © 2010 John Wiley & Sons A/S.


Chalkley R.J.,University of California at San Francisco | Clauser K.R.,The Broad Institute of MIT and Harvard
Molecular and Cellular Proteomics | Year: 2012

Using enrichment strategies many research groups are routinely producing large data sets of post-translationally modified peptides for proteomic analysis using tandem mass spectrometry. Although search engines are relatively effective at identifying these peptides with a defined measure of reliability, their localization of site/s of modification is often arbitrary and unreliable. The field continues to be in need of a widely accepted metric for false localization rate that accurately describes the certainty of site localization in published data sets and allows for consistent measurement of differences in performance of emerging scoring algorithms. In this article are discussed the main strategies currently used by software for modification site localization and ways of assessing the performance of these different tools. Methods for representing ambiguity are reviewed and a discussion of how the approaches transfer to different data types and modifications is presented. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Foster E.,University of California at San Francisco
New England Journal of Medicine | Year: 2010

A 44-year-old man presents with dyspnea and new atrial fibrillation. He received a diagnosis of mitral regurgitation at 28 years of age, after physical examination revealed a midsystolic click and late-systolic murmur; echocardiography performed at that time showed mitral-valve prolapse with mild late-systolic mitral regurgitation and normal left ventricular size and function. He has not seen a physician in many years. Physical examination reveals a holosystolic murmur and a soft S3 sound. Repeat echocardiography shows a flail posterior leaflet and moderately severe mitral regurgitation. How should this case be managed? Copyright © 2010 Massachusetts Medical Society.


Cheung K.J.,Johns Hopkins University | Gabrielson E.,Johns Hopkins University | Werb Z.,University of California at San Francisco | Ewald A.J.,Johns Hopkins University
Cell | Year: 2013

Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led collective invasion in the major human breast cancer subtypes. Importantly, luminal cancer cells were observed to convert phenotypically to invasive leaders following induction of basal epithelial genes. Although only a minority of cells within luminal tumors expressed basal epithelial genes, knockdown of either K14 or p63 was sufficient to block collective invasion. Our data reveal that heterotypic interactions between epithelial subpopulations are critical to collective invasion. We suggest that targeting the basal invasive program could limit metastatic progression. © 2013 Elsevier Inc.


Horvath T.,University of California at San Francisco
Cochrane database of systematic reviews (Online) | Year: 2012

More than 34 million people are presently living with HIV infection. Antiretroviral therapy (ART) can help these people to live longer, healthier lives, but adherence to ART can be difficult. Mobile phone text-messaging has the potential to help promote adherence in these patients. To determine whether mobile phone text-messaging is efficacious in enhancing adherence to ART in patients with HIV infection. Using the Cochrane Collaboration's validated search strategies for identifying randomised controlled trials and reports of HIV interventions, along with appropriate keywords and MeSH terms, we searched a range of electronic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), MEDLINE (via PubMed), PsycINFO, Web of Science, and the World Health Organization (WHO) Global Index Medicus. The date range was from  01 January 1980 to 01 November 2011. There were no limits to language or publication status. Randomised controlled trials (RCTs) in which patients or their caregivers (in the case of infants and children) of any age, in any setting, and receiving ART were provided with mobile phone text messages as a means of promoting adherence to ART. Two authors independently examined the abstracts of all identified trials. We initially identified 243 references. Seventeen full-text articles were closely reviewed. Both authors abstracted data independently, using a pre-designed, standardised data collection form. When appropriate, data were combined in meta-analysis. Two RCTs from Kenya were included in the review. One trial compared short weekly text messages against standard care. The other trial compared short daily, long daily, short weekly and long weekly messages against standard care. Both trials were with adult patients.In the trial comparing only short weekly messages to standard care, text messaging was associated with a lower risk of non-adherence at 12 months (RR 0.77, 95% CI 0.63 to 0.93) and with the non-occurrence of virologic failure at 12 months (RR 0.83, 95% CI 0.69 to 0.99).In the trial that compared different intervals and lengths for text-messaging to standard care, long weekly text-messaging was not significantly associated with a lower risk of non-adherence compared to standard care (RR 0.79, 95% CI 0.60 to 1.04). Patients receiving weekly text-messages of any length were at lower risk of non-adherence at 48 weeks than were patients receiving daily messages of any length (RR 0.79, 95% CI 0.64 to 0.99). There were no significant differences between weekly text-messaging of any length (RR 1.01, 95% CI 0.75 to 1.37) and between short or long messaging at either interval (RR 0.99, 95% CI 0.78 to 1.27). Compared to standard care, any daily text-messaging, whether short or long, did not reduce the risk for non-adherence (RR 0.99, 95% CI 0.82 to 1.20).In meta-analysis of both trials, any weekly text-messaging (i.e. whether short or long messages) was associated with a lower risk of non-adherence at 48-52 weeks (RR 0.78, 95% CI 0.68 to 0.89). The effect of short weekly text-messaging was also significant (RR 0.77, 95% CI 0.67 to 0.89). There is high-quality evidence from the two RCTs that mobile phone text-messaging at weekly intervals is efficacious in enhancing adherence to ART, compared to standard care. There is high quality evidence from one trial that weekly mobile phone text-messaging is efficacious in improving HIV viral load suppression. Policy-makers should consider funding programs proposing to provide weekly mobile phone text-messaging as a means for promoting adherence to antiretroviral therapy. Clinics and hospitals should consider implementing such programs. There is a need for large RCTs of this intervention in adolescent populations, as well as in high-income countries.


Albertson D.G.,University of California at San Francisco
Journal of Pathology | Year: 2012

The determination of oestrogen receptor α (ERα) expression in breast cancers has been for many years the standard of care for guiding patient management. In 2007, Holst and colleagues published the previously unappreciated observation that the ERα gene, ESR1, was amplified in 21% of breast cancers, and that ESR1 gene amplification identified those individuals with high ERα expression in their tumours and who were likely to respond to hormonal manipulation. This has been a controversial area. Others have tried to reproduce these findings but the results have been mixed with respect to amplification frequency, and even contradictory with respect to prognostic and predictive value. The controversy may have now been resolved. Ooi et al, in this issue of the journal, show that the large clustered FISH signals that have been interpreted as ESR1 amplification are sensitive to RNase treatment, indicating that FISH is detecting accumulation of ESR1 transcripts in the nucleus of breast cancer cells expressing high levels of ERα, rather than gene amplification events. This story has important lessons for translational cancer research, and in particular FISH studies of gene copy number. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Puck J.M.,University of California at San Francisco
Annals of the New York Academy of Sciences | Year: 2011

Early detection of primary immunodeficiency is recognized as important for avoiding infectious complications that co