Showing papers by "Veterans Health Administration published in 2006"
TL;DR: Using metabolic function analyses of identified genes, the human genome is compared with the average content of previously sequenced microbial genomes and humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes.
Abstract: The human intestinal microbiota is composed of 10(13) to 10(14) microorganisms whose collective genome ("microbiome") contains at least 100 times as many genes as our own genome. We analyzed approximately 78 million base pairs of unique DNA sequence and 2062 polymerase chain reaction-amplified 16S ribosomal DNA sequences obtained from the fecal DNAs of two healthy adults. Using metabolic function analyses of identified genes, we compared our human genome with the average content of previously sequenced microbial genomes. Our microbiome has significantly enriched metabolism of glycans, amino acids, and xenobiotics; methanogenesis; and 2-methyl-d-erythritol 4-phosphate pathway-mediated biosynthesis of vitamins and isoprenoids. Thus, humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes.
4,111 citations
TL;DR: In conclusion, noninvasive tests can accurately predict hepatic fibrosis and may reduce the need for liver biopsy in the majority of HIV/HCV‐coinfected patients.
3,183 citations
Harlem Hospital Center1, Columbia University2, University of Copenhagen3, University of Minnesota4, Veterans Health Administration5, University of California, San Francisco6, University of Texas Health Science Center at Houston7, Medical Research Council8, Denver Health Medical Center9, University of New South Wales10, University of Cologne11, National Institutes of Health12, Henry Ford Health System13, University College London14
TL;DR: Episodic antiretroviral therapy guided by the CD4+ count significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antireteviral therapy, largely as a consequence of lowering theCD4+ cell count and increasing the viral load.
Abstract: Methods We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. Results A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P = 0.007) and 1.7 (95% CI, 1.1 to 2.5; P = 0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). Conclusions Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352.)
1,999 citations
TL;DR: The staging of intermediate-thickness primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy.
Abstract: Among 1269 patients with an intermediate-thickness primary melanoma, the mean (±SE) estimated 5-year disease-free survival rate for the population was 78.3±1.6% in the biopsy group and 73.1±2.1% in the observation group (hazard ratio for death, 0.74; 95% confidence interval [CI], 0.59 to 0.93; P = 0.009). Five-year melanoma-specific survival rates were similar in the two groups (87.1±1.3% and 86.6±1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3±4.6% among patients with tumor-positive sentinel nodes and 90.2±1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54 to 3.98; P<0.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group (P<0.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3±4.6% vs. 52.4±5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P = 0.004). Conclusions The staging of intermediate-thickness (1.2 to 3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. (ClinicalTrials.gov number, NCT00275496.)
1,616 citations
Duke University1, Tufts Medical Center2, Drexel University3, Harvard University4, University of Nebraska Medical Center5, Wayne State University6, University of California, San Francisco7, Cubist Pharmaceuticals8, University of California, Los Angeles9, Beaumont Hospital10, East Carolina University11, Dartmouth College12, Veterans Health Administration13, Denver Health Medical Center14, University of Maryland, Baltimore15, University of Cologne16, Lehigh Valley Hospital17, Cleveland Clinic18, Goethe University Frankfurt19, University of Hawaii at Manoa20, Johns Hopkins University21
TL;DR: Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis and met prespecified criteria for the noninferiority of daptomecin.
Abstract: Background Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed. Methods We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy. Results Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, −10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, a...
1,318 citations
University of Utah1, Veterans Health Administration2, National Institutes of Health3, University of Nebraska Medical Center4, Case Western Reserve University5, Indiana University6, New York University7, Cedars-Sinai Medical Center8, University of California, San Francisco9, Presbyterian Hospital of Dallas10, University of Alabama11, University of Pennsylvania12, University of Pittsburgh13, Virginia Mason Medical Center14, University of Arizona15, Northwestern University16, University of California, Los Angeles17
TL;DR: The GAIT trial as discussed by the authors evaluated the efficacy and safety of glucosamine and chondroitin sulfate as a treatment for knee pain from osteoarthritis in 1583 patients.
Abstract: Background Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. Methods We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. Results The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 perce...
1,199 citations
TL;DR: It is proposed that individuals who are prone to anxiety show an altered interoceptive prediction signal, i.e., manifest augmented detection of the difference between the observed and expected body state, which triggers an increase in anxious affect, worrisome thoughts and other avoidance behaviors.
1,168 citations
TL;DR: Results supported hypotheses regarding the relationship of resilience to personality dimensions and coping styles and augment the literature that seeks to better define resilience and provide evidence for the construct validity of the Connor-Davidson Resilience Scale.
1,130 citations
TL;DR: Medication nonadherence is prevalent among patients with diabetes mellitus and is associated with adverse outcomes, and interventions are needed to increase medication adherence so that patients can realize the full benefit of prescribed therapies.
Abstract: Background Medication nonadherence may reduce the effectiveness of therapies. To our knowledge, the association between medication nonadherence and mortality remains unexplored outside the context of clinical trials. Methods A retrospective cohort study of 11 532 patients with diabetes mellitus in a managed care organization. Medication adherence was calculated as the proportion of days covered for filled prescriptions of oral hypoglycemics, antihypertensives, and statin medications. The primary outcomes of interest were all-cause hospitalization and all-cause mortality. Multivariable regression analyses were performed to assess the independent association between medication adherence and outcomes. Results Nonadherent patients (proportion of days covered, P P P P Conclusions Medication nonadherence is prevalent among patients with diabetes mellitus and is associated with adverse outcomes. Interventions are needed to increase medication adherence so that patients can realize the full benefit of prescribed therapies.
1,041 citations
TL;DR: Predictors of successful aging varied yet point to several potentially modifiable targets for increasing the likelihood of successful Aging.
Abstract: Objective There is no consensual definition of "successful aging." Our aim was to review the literature on proportions of subjects meeting criteria and individual components of definitions of successful aging as well as correlates of these definitions. Methods We conducted a literature search for published English-language peer-reviewed reports of data-based studies of adults over age 60 that included an operationalized definition of successful aging. The authors categorized the components of these definitions and independent variables examined in relation to successful aging (e.g., gender, education, and social contacts). Results The authors identified 28 studies with 29 different definitions that met our criteria. Most investigations used large samples of community-dwelling older adults. The mean reported proportion of successful agers was 35.8% (standard deviation: 19.8) but varied widely (interquartile range: 31%). Multiple components of these definitions were identified, although 26 of 29 included disability/physical functioning. The most frequent significant correlates of the various definitions of successful aging were age (young-old), nonsmoking, and absence of disability, arthritis, and diabetes. Moderate support was found for greater physical activity, more social contacts, better self-rated health, absence of depression and cognitive impairment, and fewer medical conditions. Gender, income, education, and marital status generally did not relate to successful aging. Conclusion Despite variability among definitions, approximately one-third of elderly individuals were classified as aging successfully. The majority of these definitions were based on the absence of disability with lesser inclusion of psychosocial variables. Predictors of successful aging varied yet point to several potentially modifiable targets for increasing the likelihood of successful aging.
983 citations
TL;DR: A microRNA expression signature has been identified that is associated with pancreatic cancer and Aberrant microRNAs may offer new clues to pancreatic tumorigenesis and may provide diagnostic biomarkers for pancreatic adenocarcinoma.
Abstract: microRNAs are functional, 22 nt, noncoding RNAs that negatively regulate gene expression. Disturbance of microRNA expression may play a role in the initiation and progression of certain diseases. A microRNA expression signature has been identified that is associated with pancreatic cancer. This has been accomplished with the application of real-time PCR profiling of over 200 microRNA precursors on specimens of human pancreatic adenocarcinoma, paired benign tissue, normal pancreas, chronic pancreatitis and nine pancreatic cancer cell lines. Hierarchical clustering was able to distinguish tumor from normal pancreas, pancreatitis and cell lines. The PAM algorithm correctly classified 28 of 28 tumors, 6 of 6 normal pancreas and 11 of 15 adjacent benign tissues. One hundred microRNA precursors were aberrantly expressed in pancreatic cancer or desmoplasia (p < 0.01), including microRNAs previously reported as differentially expressed in other human cancers (miR-155, miR-21, miR-221 and miR-222) as well as those not previously reported in cancer (miR-376a and miR-301). Most of the top aberrantly expressed miRNAs displayed increased expression in the tumor. Expression of the active, mature microRNA was validated using a real-time PCR assay to quantify the mature microRNA and Northern blotting. Reverse transcription in situ PCR showed that three of the top differentially expressed miRNAs (miR-221, -376a and -301) were localized to tumor cells and not to stroma or normal acini or ducts. Aberrant microRNA expression may offer new clues to pancreatic tumorigenesis and may provide diagnostic biomarkers for pancreatic adenocarcinoma.
TL;DR: Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients, and Administration of any dose of paricalcitol was associated with improved survival in time-varying models.
Centers for Disease Control and Prevention1, Vanderbilt University2, Connecticut Agricultural Experiment Station3, University of California, Berkeley4, Oregon Department of Human Services5, Johns Hopkins University6, University of Rochester7, Emory University8, Veterans Health Administration9, University of Texas at San Antonio10
TL;DR: The rate of antibiotic-resistant invasive pneumococcal infections decreased in young children and older persons after the introduction of the conjugate vaccine, and there was an increase in infections caused by serotypes not included in the vaccine.
Abstract: BACKGROUND Five of seven serotypes in the pneumococcal conjugate vaccine, introduced for infants in the United States in 2000, are responsible for most penicillin-resistant infections. We examined the effect of this vaccine on invasive disease caused by resistant strains. METHODS We used laboratory-based data from Active Bacterial Core surveillance to measure disease caused by antibiotic-nonsusceptible pneumococci from 1996 through 2004. Cases of invasive disease, defined as disease caused by pneumococci isolated from a normally sterile site, were identified in eight surveillance areas. Isolates underwent serotyping and susceptibility testing. RESULTS Rates of invasive disease caused by penicillin-nonsusceptible strains and strains not susceptible to multiple antibiotics peaked in 1999 and decreased by 2004, from 6.3 to 2.7 cases per 100,000 (a decline of 57 percent; 95 percent confidence interval, 55 to 58 percent) and from 4.1 to 1.7 cases per 100,000 (a decline of 59 percent; 95 percent confidence interval, 58 to 60 percent), respectively. Among children under two years of age, disease caused by penicillin-nonsusceptible strains decreased from 70.3 to 13.1 cases per 100,000 (a decline of 81 percent; 95 percent confidence interval, 80 to 82 percent). Among persons 65 years of age or older, disease caused by penicillin-nonsusceptible strains decreased from 16.4 to 8.4 cases per 100,000 (a decline of 49 percent). Rates of resistant disease caused by vaccine serotypes fell 87 percent. An increase was seen in disease caused by serotype 19A, a serotype not included in the vaccine (from 2.0 to 8.3 per 100,000 among children under two years of age). CONCLUSIONS The rate of antibiotic-resistant invasive pneumococcal infections decreased in young children and older persons after the introduction of the conjugate vaccine. There was an increase in infections caused by serotypes not included in the vaccine.
TL;DR: An understanding of the natural history of hepatitis C is essential to effectively manage, treat, and counsel individuals with HCV infection.
Abstract: Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, as well as the most common indication for liver transplantation in many countries. Although the incidence of hepatitis C infection has dramatically decreased during the past decade, the worldwide reservoir of chronically infected persons is estimated at 170 million, or 3% of the global population. There is much controversy surrounding the natural history of hepatitis C infection. The rate of chronic HCV infection is affected by a person's age, gender, race, and viral immune response. Approximately 75%-85% of HCV-infected persons will progress to chronic HCV infection, and are at risk for the development of extrahepatic manifestations, compensated and decompensated cirrhosis, and hepatocellular carcinoma (HCC). The rate of progression to cirrhosis is highly variable, and is influenced by several factors, including the amount of alcohol consumption, age of initial HCV infection, degree of inflammation and fibrosis on liver biopsy, HIV and HBV coinfection, and comordid conditions. An estimated 10%-15% of HCV-infected persons will advance to cirrhosis within the first 20 years. Persons with cirrhosis are at increased risk of developing HCC. An understanding of the natural history of hepatitis C is essential to effectively manage, treat, and counsel individuals with HCV infection.
TL;DR: Using a novel single-molecule PCR approach to quantify the total burden of mitochondrial DNA molecules with deletions, it is shown that a high proportion of individual pigmented neurons in the aged human substantia nigra contain very high levels of mtDNA deletions.
Abstract: Using a novel single-molecule PCR approach to quantify the total burden of mitochondrial DNA (mtDNA) molecules with deletions, we show that a high proportion of individual pigmented neurons in the aged human substantia nigra contain very high levels of mtDNA deletions. Molecules with deletions are largely clonal within each neuron; that is, they originate from a single deleted mtDNA molecule that has expanded clonally. The fraction of mtDNA deletions is significantly higher in cytochrome c oxidase (COX)-deficient neurons than in COX-positive neurons, suggesting that mtDNA deletions may be directly responsible for impaired cellular respiration.
TL;DR: This trial provides some of the most encouraging results of PTSD treatment for veterans with chronic PTSD and supports increased use of cognitive- behavioral treatments in this population.
Abstract: Sixty veterans (54 men, 6 women) with chronic military-related posttraumatic stress disorder (PTSD) participated in a wait-list controlled trial of cognitive processing therapy (CPT). The overall dropout rate was 16.6% (20% from CPT, 13% from waiting list). Random regression analyses of the intention-to-treat sample revealed significant improvements in PTSD and comorbid symptoms in the CPT condition compared with the wait-list condition. Forty percent of the intention-to-treat sample receiving CPT did not meet criteria for a PTSD diagnosis, and 50% had a reliable change in their PTSD symptoms at posttreatment assessment. There was no relationship between PTSD disability status and outcomes. This trial provides some of the most encouraging results of PTSD treatment for veterans with chronic PTSD and supports increased use of cognitive- behavioral treatments in this population.
TL;DR: It is reported that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation.
Abstract: The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.
TL;DR: Treatments aimed at reducing insulin resistance have had some success, but larger placebo-controlled studies are needed to fully establish the efficacy of these interventions and possibly others in reducing the deleterious effects of fat accumulation in the liver.
Abstract: Context: Insulin resistance is an almost universal finding in nonalcoholic fatty liver disease (NAFLD). This review outlines the evidence linking insulin resistance and NAFLD, explores whether liver fat is a cause or consequence of insulin resistance, and reviews the current evidence for treatment of NAFLD. Evidence Acquisition: Evidence from epidemiological, experimental, and clinical research studies investigating NAFLD and insulin resistance was reviewed. Evidence Synthesis: Insulin resistance in NAFLD is characterized by reductions in whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Insulin resistance may enhance hepatic fat accumulation by increasing free fatty acid delivery and by the effect of hyperinsulinemia to stimulate anabolic processes. The impact of weight loss, metfo...
TL;DR: Study findings suggest that CM is among the more effective approaches to promoting abstinence during the treatment of substance use disorders, thereby allowing clients to take fuller advantage of other clinical treatment components.
Abstract: Aims To examine the effectiveness of contingency management (CM) techniques in treating substance use disorders (i.e. illicit drugs, alcohol, tobacco).
Design Meta-analysis was used to determine the average effect size and potential moderators in 47 comparisons of the effectiveness of CM from studies based on a treatment–control group design and published between 1970 and 2002.
Findings The mean effect size (ES) of CM was positive, with a magnitude of d = 0.42 using a fixed effects model. The magnitude of the ES declined over time, following treatment. CM was more effective in treating opiate use (d = 0.65) and cocaine use (d = 0.66), compared with tobacco (d = 0.31) or multiple drugs (d = 0.42). Larger effect sizes were associated with higher researcher involvement, earlier studies and shorter treatment duration.
Conclusions Study findings suggest that CM is among the more effective approaches to promoting abstinence during the treatment of substance use disorders. CM improves the ability of clients to remain abstinent, thereby allowing them to take fuller advantage of other clinical treatment components.
University of North Carolina at Chapel Hill1, Columbia University2, Rush University Medical Center3, American Diabetes Association4, American Heart Association5, University of Colorado Denver6, Tulane University7, McMaster University8, University of Texas Southwestern Medical Center9, Lahey Hospital & Medical Center10, Harvard University11, Veterans Health Administration12, University of California, Los Angeles13, Northwestern University14
TL;DR: This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.
Abstract: The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.
TL;DR: It is hoped that future medical informatics studies will implement higher level quasi-experimental study designs that yield more convincing evidence for causal links between medical informatic interventions and outcomes.
TL;DR: In addition, diminished expression of outer membrane proteins, mutations in topoisomerases, and up-regulation of efflux pumps play an important part in antibiotic resistance as discussed by the authors. Unfortunately, the accumulation of multiple mechanisms of resistance leads to the development of multiply resistant or even "panresistant" strains.
Abstract: Acinetobacter species and Pseudomonas aeruginosa are noted for their intrinsic resistance to antibiotics and for their ability to acquire genes encoding resistance determinants. Foremost among the mechanisms of resistance in both of these pathogens is the production of beta -lactamases and aminoglycoside-modifying enzymes. Additionally, diminished expression of outer membrane proteins, mutations in topoisomerases, and up-regulation of efflux pumps play an important part in antibiotic resistance. Unfortunately, the accumulation of multiple mechanisms of resistance leads to the development of multiply resistant or even "panresistant" strains.
TL;DR: A significant role for NETs in neutrophil-mediated innate immunity is demonstrated, and a novel therapeutic target against invasive GAS infection is identified.
TL;DR: It is suggested that high circulating FSH causes hypogonadal bone loss and that Osteoclasts and their precursors possess G(i2alpha)-coupled FSHRs that activate MEK/Erk, NF-kappaB, and Akt to result in enhanced osteoclast formation and function.
Veterans Health Administration1, University of Kentucky2, Nagoya City University3, Vanderbilt University4, University of Florida5, University of California, Davis6, Michigan State University7, Johns Hopkins University8, University of Alabama at Birmingham9, James Cook University10, University of Wisconsin-Madison11, University of Aberdeen12, University of Pennsylvania13, University of Tokyo14, Genentech15, National Research Council16
TL;DR: This paper showed that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice.
Abstract: Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.
TL;DR: The need to improve the transition of care from the hospital to outpatient setting to ensure that patients continue to take evidence-based medications that have mortality benefit is suggested.
Abstract: Background: Nonadherence to medications is common, but the determinants and consequences are poorly defined. The objectives of this study were to identify patient and myocardial infarction (MI) treatment factors associated with medication therapy discontinuation and to assess the impact of medication discontinuation 1 month after MI on 12-month mortality. Methods: This was a multicenter prospective cohort of patients with MI enrolled in the Prospective Registry Evaluating Myocardial Infarction: Event and Recovery study.Theoutcomeswereuseofaspirin,-blockers,and statins at 1 month after MI hospitalization among patients discharged with all 3 medications as well as 12month mortality. Results: Of 1521 patients discharged with all 3 medications,184discontinueduseofall3medications,56discontinued use of 2 medications, 272 discontinued use of 1 medication, and 1009 continued taking all 3 medications at 1 month. In multivariable analyses, patients not graduating from high school (odds ratio [OR], 1.76; 95%confidenceinterval[CI],1.20-2.60)weremorelikely to discontinue use of all medications. The effect of increasing age on medication therapy discontinuation was greater for females (OR, 1.77; 95% CI, 1.34-2.34) than males (OR, 1.23; 95% CI, 1.02-1.47). Patients who discontinued use of all medications at 1 month had lower 1-yearsurvival(88.5%vs97.7%;log-rankP.001)comparedwithpatientswhocontinuedtotake1ormoremedication(s). In multivariable survival analysis, medication therapy discontinuation was independently associated with higher mortality (hazards ratio, 3.81; 95% CI, 1.887.72). Results were consistent when evaluating discontinuation of use of aspirin, -blockers, and statins separately.
TL;DR: It is indicated that lamins A and C are important contributors to the mechanical stiffness of nuclei, whereas lamin B1 contributes to nuclear integrity but not stiffness.
TL;DR: The predicted attenuation ofβ-amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1.
TL;DR: The staging concept of LSG followed by LRYGBP is a safe and effective surgical approach for high-risk patients seeking bariatric surgery.
Abstract: The surgical treatment of obesity in the high-risk, high-body-mass-index (BMI) (>60) patient remains a challenge. Major morbidity and mortality in these patients can approach 38% and 6%, respectively. In an effort to achieve more favorable outcomes, we have employed a two-stage approach to such high-risk patients. This study evaluates our initial outcomes with this technique. In this study, patients underwent laparoscopic sleeve gastrectomy (LSG) as a first stage during the period January 2002–February 2004. After achieving significant weight loss and reduction in co-morbidities, these patients then proceeded with the second stage, laparoscopic Roux-en-Y gastric bypass (LRYGBP). During this time, 126 patients underwent LSG (53% female). The mean age was 49.5 ± 0.9 years, and the mean BMI was 65.3 ± 0.8 (range 45–91). Operative risk assessment determined that 42% were American Society of Anesthesiologists physical status score (ASA) III and 52% were ASA IV. The mean number of co-morbid conditions per patient was 9.3 ± 0.3 with a median of 10 (range 3–17). There was one distant mortality and the incidence of major complications was 13%. Mean excess weight after LSG at 1 year was 46%. Thirty-six patients with a mean BMI of 49.1 ± 1.3 (excess weight loss, EWL, 38%) had the second-stage LRYGBP. The mean number of co-morbidities in this group was 6.4 ± 0.1 (reduced from 9). The ASA class of the majority of patients had been downstaged at the time of LRYGB. The mean time interval between the first and second stages was 12.6 ± 0.8 months. The mean and median hospital stays were 3 ± 1.7 and 2.5 (range 2–7) days, respectively. There were no deaths, and the incidence of major complications was 8%. The staging concept of LSG followed by LRYGBP is a safe and effective surgical approach for high-risk patients seeking bariatric surgery.
TL;DR: A cluster analysis of 75 persons with schizophrenia spectrum disorders based on single measures of insight using the Positive and Negative Syndrome Scale, internalized stigma using the Internalized Stigma of Mental Illness Scale, and compared groups on concurrent assessments of hope and self-esteem revealed that the high insight/moderate stigma group had significantly the lowest levels of hope on the Beck Hopelessness Scale andSelf-esteem using the Multidimensional Self-esteem Inventory.
Abstract: Research has paradoxically linked awareness of illness to both better function outcomes and lesser hope and self-esteem. One possible explanation for these findings is that acceptance of having schizophrenia may impact outcomes differently depending on the meanings the person attaches to this acceptance, particularly whether he or she accepts stigmatizing beliefs about mental illness. To explore this possibility we performed a cluster analysis of 75 persons with schizophrenia spectrum disorders based on single measures of insight using the Positive and Negative Syndrome Scale, internalized stigma using the Internalized Stigma of Mental Illness Scale, and compared groups on concurrent assessments of hope and self-esteem. Three groups were produced by the cluster analyses: low in sight/mild stigma (n = 23), high insight/minimal stigma (n = 25), and high insight/moderate stigma (n = 27). As predicted, analysis of variance-comparing groups revealed that the high insight/moderate stigma group had significantly the lowest levels of hope on the Beck Hopelessness Scale and self-esteem using the Multidimensional Self-esteem Inventory. As predicted, the high insight/minimal stigma group also had significantly less impaired social function than the other groups. Implications for assisting persons to come to cope with awareness of illness and stigma are discussed.