Showing papers by "University of Maryland, Baltimore published in 2011"

Vaginal microbiome of reproductive-age women

Abstract: The means by which vaginal microbiomes help prevent urogenital diseases in women and maintain health are poorly understood. To gain insight into this, the vaginal bacterial communities of 396 asymptomatic North American women who represented four ethnic groups (white, black, Hispanic, and Asian) were sampled and the species composition characterized by pyrosequencing of barcoded 16S rRNA genes. The communities clustered into five groups: four were dominated by Lactobacillus iners, L. crispatus, L. gasseri, or L. jensenii, whereas the fifth had lower proportions of lactic acid bacteria and higher proportions of strictly anaerobic organisms, indicating that a potential key ecological function, the production of lactic acid, seems to be conserved in all communities. The proportions of each community group varied among the four ethnic groups, and these differences were statistically significant [χ(2)(10) = 36.8, P < 0.0001]. Moreover, the vaginal pH of women in different ethnic groups also differed and was higher in Hispanic (pH 5.0 ± 0.59) and black (pH 4.7 ± 1.04) women as compared with Asian (pH 4.4 ± 0.59) and white (pH 4.2 ± 0.3) women. Phylotypes with correlated relative abundances were found in all communities, and these patterns were associated with either high or low Nugent scores, which are used as a factor for the diagnosis of bacterial vaginosis. The inherent differences within and between women in different ethnic groups strongly argues for a more refined definition of the kinds of bacterial communities normally found in healthy women and the need to appreciate differences between individuals so they can be taken into account in risk assessment and disease diagnosis.

International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases

Abstract: A Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the 1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine. The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects of antimicrobial therapy (collateral damage) were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations.

MDAnalysis: A Toolkit for the Analysis of Molecular Dynamics Simulations

Abstract: MDAnalysis is an object-oriented library for structural and temporal analysis of molecular dynamics (MD) simulation trajectories and individual protein structures. It is written in the Python language with some performance-critical code in C. It uses the powerful NumPy package to expose trajectory data as fast and efficient NumPy arrays. It has been tested on systems of millions of particles. Many common file formats of simulation packages including CHARMM, Gromacs, Amber, and NAMD and the Protein Data Bank format can be read and written. Atoms can be selected with a syntax similar to CHARMM's powerful selection commands. MDAnalysis enables both novice and experienced programmers to rapidly write their own analytical tools and access data stored in trajectories in an easily accessible manner that facilitates interactive explorative analysis. MDAnalysis has been tested on and works for most Unix-based platforms such as Linux and Mac OS X. It is freely available under the GNU General Public License from http://mdanalysis.googlecode.com.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Effect of nesiritide in patients with acute decompensated heart failure.

Abstract: A b s t r ac t Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, −0.4 percentage points; 95% CI, −1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.)

Moving pictures of the human microbiome.

Abstract: Background Understanding the normal temporal variation in the human microbiome is critical to developing treatments for putative microbiome-related afflictions such as obesity, Crohn's disease, inflammatory bowel disease and malnutrition. Sequencing and computational technologies, however, have been a limiting factor in performing dense time series analysis of the human microbiome. Here, we present the largest human microbiota time series analysis to date, covering two individuals at four body sites over 396 timepoints.

Azithromycin for Prevention of Exacerbations of COPD

Abstract: A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exac erbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among par ticipants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerba tions per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P = 0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithro mycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P = 0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P = 0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P = 0.04). Conclusions Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.)

Origins of the E. coli Strain Causing an Outbreak of Hemolytic–Uremic Syndrome in Germany

Abstract: Background A large outbreak of diarrhea and the hemolytic–uremic syndrome caused by an unusual serotype of Shiga-toxin–producing Escherichia coli (O104:H4) began in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin–producing E. coli have been reported — 3167 without the hemolytic–uremic syndrome (16 deaths) and 908 with the hemolytic–uremic syndrome (34 deaths) — indicating that this strain is notably more virulent than most of the Shiga-toxin–producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. Methods We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference st...

Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9

Abstract: Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

Abstract: Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (,26%– 27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ,2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p,5610 28 ) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

The BATTLE Trial: Personalizing Therapy for Lung Cancer

Abstract: The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non–small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant- KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. ([ClinicalTrials.gov][1] numbers: [NCT00409968][2], [NCT00411671][3], [NCT00411632][4], [NCT00410059][5], and [NCT00410189][6].) Significance: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with “real-time” biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment. Cancer Discovery; 1(1); 44–53. © 2011 AACR. Read the Commentary on this article by Sequist et al., [p. 14][7] Read the Commentary on this article by Rubin et al., [p. 17][8] This article is highlighted in the In This Issue feature, [p. 4][9] [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00409968&atom=%2Fcandisc%2F1%2F1%2F44.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00411671&atom=%2Fcandisc%2F1%2F1%2F44.atom [4]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00411632&atom=%2Fcandisc%2F1%2F1%2F44.atom [5]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00410059&atom=%2Fcandisc%2F1%2F1%2F44.atom [6]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00410189&atom=%2Fcandisc%2F1%2F1%2F44.atom [7]: /lookup/volpage/1/14?iss=1 [8]: /lookup/volpage/1/17?iss=1 [9]: /lookup/volpage/1/4?iss=1

Staphylococcus aureus biofilms: properties, regulation, and roles in human disease.

Abstract: Increasing attention has been focused on understanding bacterial biofilms and this growth modality's relation to human disease. In this review we explore the genetic regulation and molecular components involved in biofilm formation and maturation in the context of the Gram-positive cocci, Staphylococcus aureus. In addition, we discuss diseases and host immune responses, along with current therapies associated with S. aureus biofilm infections and prevention strategies.

General Principles of Antimicrobial Therapy

Abstract: Antimicrobial agents are some of the most widely, and often injudiciously, used therapeutic drugs worldwide. Important considerations when prescribing antimicrobial therapy include obtaining an accurate diagnosis of infection; understanding the difference between empiric and definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-effective oral agents for the shortest duration necessary; understanding drug characteristics that are peculiar to antimicrobial agents (such as pharmacodynamics and efficacy at the site of infection); accounting for host characteristics that influence antimicrobial activity; and in turn, recognizing the adverse effects of antimicrobial agents on the host. It is also important to understand the importance of antimicrobial stewardship, to know when to consult infectious disease specialists for guidance, and to be able to identify situations when antimicrobial therapy is not needed. By following these general principles, all practicing physicians should be able to use antimicrobial agents in a responsible manner that benefits both the individual patient and the community.

Non-prescription antimicrobial use worldwide: a systematic review

Abstract: In much of the world antimicrobial drugs are sold without prescription or oversight by health-care professionals. The scale and effect of this practice is unknown. We systematically reviewed published works about non-prescription antimicrobials from 1970-2009, identifying 117 relevant articles. 35 community surveys from five continents showed that non-prescription use occurred worldwide and accounted for 19-100% of antimicrobial use outside of northern Europe and North America. Safety issues associated with non-prescription use included adverse drug reactions and masking of underlying infectious processes. Non-prescription use was common for non-bacterial disease, and antituberculosis drugs were available in many areas. Antimicrobial-resistant bacteria are common in communities with frequent non-prescription use. In a few settings, control efforts that included regulation decreased antimicrobial use and resistance. Non-prescription antimicrobial and antituberculosis use is common outside of North America and northern Europe and must be accounted for in public health efforts to reduce antimicrobial resistance.

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Abstract: The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more at...

Comparison of multi-subject ICA methods for analysis of fMRI data.

Abstract: Spatial independent component analysis (ICA) applied to functional magnetic resonance imaging (fMRI) data identifies functionally connected networks by estimating spatially independent patterns from their linearly mixed fMRI signals. Several multi-subject ICA approaches estimating subject-specific time courses (TCs) and spatial maps (SMs) have been developed, however, there has not yet been a full comparison of the implications of their use. Here, we provide extensive comparisons of four multi-subject ICA approaches in combination with data reduction methods for simulated and fMRI task data. For multi-subject ICA, the data first undergo reduction at the subject and group levels using principal component analysis (PCA). Comparisons of subject-specific, spatial concatenation, and group data mean subject-level reduction strategies using PCA and probabilistic PCA (PPCA) show that computationally intensive PPCA is equivalent to PCA, and that subject-specific and group data mean subject-level PCA are preferred because of well-estimated TCs and SMs. Second, aggregate independent components are estimated using either noise-free ICA or probabilistic ICA (PICA). Third, subject-specific SMs and TCs are estimated using back-reconstruction. We compare several direct group ICA (GICA) back-reconstruction approaches (GICA1-GICA3) and an indirect back-reconstruction approach, spatio-temporal regression (STR, or dual regression). Results show the earlier group ICA (GICA1) approximates STR, however STR has contradictory assumptions and may show mixed-component artifacts in estimated SMs. Our evidence-based recommendation is to use GICA3, introduced here, with subject-specific PCA and noise-free ICA, providing the most robust and accurate estimated SMs and TCs in addition to offering an intuitive interpretation.

A research agenda to underpin malaria eradication.

Abstract: The interruption of malaria transmission worldwide is one of the greatest challenges for international health and development communities. The current expert view suggests that, by aggressively scaling up control with currently available tools and strategies, much greater gains could be achieved against malaria, including elimination from a number of countries and regions; however, even with maximal effort we will fall short of global eradication. The Malaria Eradication Research Agenda (malERA) complements the current research agenda—primarily directed towards reducing morbidity and mortality—with one that aims to identify key knowledge gaps and define the strategies and tools that will result in reducing the basic reproduction rate to less than 1, with the ultimate aim of eradication of the parasite from the human population. Sustained commitment from local communities, civil society, policy leaders, and the scientific community, together with a massive effort to build a strong base of researchers from the endemic areas will be critical factors in the success of this new agenda.

Advanced practice nurse outcomes 1990-2008: a systematic review.

Abstract: Advanced practice registered nurses have assumed an increasing role as providers in the health care system, particularly for underserved populations. The aim of this systematic review was to answer the following question: Compared to other providers (physicians or teams without APRNs) are APRN patient outcomes of care similar? This systematic review of published literature between 1990 and 2008 on care provided by APRNs indicates patient outcomes of care provided by nurse practitioners and certified nurse midwives in collaboration with physicians are similar to and in some ways better than care provided by physicians alone for the populations and in the settings included. Use of clinical nurse specialists in acute care settings can reduce length of stay and cost of care for hospitalized patients. These results extend what is known about APRN outcomes from previous reviews by assessing all types of APRNs over a span of 18 years, using a systematic process with intentionally broad inclusion of outcomes, patient populations, and settings. The results indicate APRNs provide effective and high-quality patient care, have an important role in improving the quality of patient care in the United States, and could help to address concerns about whether care provided by APRNs can safely augment the physician supply to support reform efforts aimed at expanding access to care.

Minimum information about a marker gene sequence (MIMARKS) and minimum information about any (x) sequence (MIxS) specifications.

Abstract: Here we present a standard developed by the Genomic Standards Consortium (GSC) for reporting marker gene sequences—the minimum information about a marker gene sequence (MIMARKS). We also introduce a system for describing the environment from which a biological sample originates. The ‘environmental packages’ apply to any genome sequence of known origin and can be used in combination with MIMARKS and other GSC checklists. Finally, to establish a unified standard for describing sequence data and to provide a single point of entry for the scientific community to access and learn about GSC checklists, we present the minimum information about any (x) sequence (MIxS). Adoption of MIxS will enhance our ability to analyze natural genetic diversity documented by massive DNA sequencing efforts from myriad ecosystems in our ever-changing biosphere.

The Brief Negative Symptom Scale: Psychometric Properties

Abstract: The participants in the NIMH-MATRICS Consensus Development Conference on Negative Symptoms recommended that an instrument be developed that measured blunted affect, alogia, asociality, anhedonia, and avolition. The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains. The interrater, test-retest, and internal consistency of the instrument were strong, with respective intraclass correlation coefficients of 0.93 for the BNSS total score and values of 0.89-0.95 for individual subscales. Comparisons with positive symptoms and other negative symptom instruments supported the discriminant and concurrent validity of the instrument.

Reframing sexual differentiation of the brain

Abstract: In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.

Cluster-randomized trial of a mobile phone personalized behavioral intervention for blood glucose control.

Abstract: OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with standard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A cluster-randomized clinical trial, the Mobile Diabetes Intervention Study, randomly assigned 26 primary care practices to one of three stepped treatment groups or a control group (usual care). A total of 163 patients were enrolled and included in analysis. The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period. Secondary outcomes were changes in patient-reported diabetes symptoms, diabetes distress, depression, and other clinical (blood pressure) and laboratory (lipid) values. Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support. Patients received automated, real-time educational and behavioral messaging in response to individually analyzed blood glucose values, diabetes medications, and lifestyle behaviors communicated by mobile phone. Providers received quarterly reports summarizing patient’s glycemic control, diabetes medication management, lifestyle behaviors, and evidence-based treatment options. RESULTS The mean declines in glycated hemoglobin were 1.9% in the maximal treatment group and 0.7% in the usual care group, a difference of 1.2% ( P = 0.001) over 12 months. Appreciable differences were not observed between groups for patient-reported diabetes distress, depression, diabetes symptoms, or blood pressure and lipid levels (all P > 0.05). CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data, lifestyle behaviors, and patient self-management data individually analyzed and presented with evidence-based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year.

Cutting Edge: Tissue-Retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection

Abstract: We identify in this article a new class of lung tissue-resident memory CD4 T cells that exhibit tissue tropism and retention independent of Ag or inflammation. Tissue-resident memory CD4 T cells in the lung did not circulate or emigrate from the lung in parabiosis experiments, were protected from in vivo Ab labeling, and expressed elevated levels of CD69 and CD11a compared with those of circulating memory populations. Importantly, influenza-specific lung-resident memory CD4 T cells served as in situ protectors to respiratory viral challenge, mediating enhanced viral clearance and survival to lethal influenza infection. By contrast, memory CD4 T cells isolated from spleen recirculated among multiple tissues without retention and failed to mediate protection to influenza infection, despite their ability to expand and migrate to the lung. Our results reveal tissue compartmentalization as a major determining factor for immune-mediated protection in a key mucosal site, important for targeting local protective responses in vaccines and immunotherapies.

Evidence-based guideline: Treatment of painful diabetic neuropathy Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

Abstract: Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?” Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL. Neurology ® 2011;76:1–1

CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate-protein modeling.

Abstract: Monosaccharide derivatives such as xylose, fucose, N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GlaNAc), glucuronic acid, iduronic acid, and N-acetylneuraminic acid (Neu5Ac) are important components of eukaryotic glycans. The present work details development of force-field parameters for these monosaccharides and their covalent connections to proteins via O-linkages to serine or threonine sidechains and via N-linkages to asparagine sidechains. The force field development protocol was designed to explicitly yield parameters that are compatible with the existing CHARMM additive force field for proteins, nucleic acids, lipids, carbohydrates, and small molecules. Therefore, when combined with previously developed parameters for pyranose and furanose monosaccharides, for glycosidic linkages between monosaccharides, and for proteins, the present set of parameters enables the molecular simulation of a wide variety of biologically-important molecules such as complex carbohydrates and glycoproteins. Parametrization included fitting to quantum mechanical (QM) geometries and conformational energies of model compounds, as well as to QM pair interaction energies and distances of model compounds with water. Parameters were validated in the context of crystals of relevant monosaccharides, as well NMR and/or x-ray crystallographic data on larger systems including oligomeric hyaluronan, sialyl Lewis X, O- and N-linked glycopeptides, and a lectin:sucrose complex. As the validated parameters are an extension of the CHARMM all-atom additive biomolecular force field, they further broaden the types of heterogeneous systems accessible with a consistently-developed force-field model.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Abstract: Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10−3. We found significant previously unidentified signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Live attenuated malaria vaccine designed to protect through hepatic CD8+ T cell immunity

Abstract: Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens shown to induce such protection in humans Such protection is thought to be mediated by CD8+ T cells in the liver that secrete interferon-γ (IFN-γ) We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8+, IFN-γ–producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice) Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria

X-ROS signaling: rapid mechano-chemo transduction in heart.

Abstract: We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where NOX2 is located and sensitizes nearby ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). This triggers a burst of Ca(2+) sparks, the elementary Ca(2+) release events in heart. Although this stretch-dependent "tuning" of RyRs increases Ca(2+) signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca(2+) sparks to trigger arrhythmogenic Ca(2+) waves. In the mouse model of Duchenne muscular dystrophy, hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca(2+) release from the SR. X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca(2+) release in the heart and offers fresh therapeutic possibilities.

The mouse forced swim test.

Abstract: The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental manipulations that are aimed at rendering or preventing depressive-like states. Mice are placed in an inescapable transparent tank that is filled with water and their escape related mobility behavior is measured. The forced swim test is straightforward to conduct reliably and it requires minimal specialized equipment. Successful implementation of the forced swim test requires adherence to certain procedural details and minimization of unwarranted stress to the mice. In the protocol description and the accompanying video, we explain how to conduct the mouse version of this test with emphasis on potential pitfalls that may be detrimental to interpretation of results and how to avoid them. Additionally, we explain how the behaviors manifested in the test are assessed.