tbuckley/cabot-search huggingface dataset:
Effects of soluble immune complexes on Fc receptor- and C3b receptor-mediated phagocytosis by macrophages.
Authors: F M Griffin
Journal: The Journal of Experimental Medicine (1980)

The effects of ingestion of soluble immune complexes upon macrophage phagocytic function was studied. Ingestion of immune complexes severely impaired the macrophage's ability to ingest IgG-coated particles but did not alter its ability to interact with particles by means other than its Fc receptors. Treatment of macrophages that had ingested immune complexes with supernates containing the previously described lymphokine that augments macrophage complement receptor function failed to enhance the cells' interaction with either IgG-coated erythrocytes or zymosan particles but markedly enhanced their ability to phagocytize via their complement receptors. The possible significance of these findings in immunologically mediated inflammation is discussed.
Lifetime Cost-Effectiveness of Calcineurin Inhibitor Withdrawal After De Novo Renal Transplantation
Authors: Stephanie R. Earnshaw, Christopher N. Graham, William D. Irish, Reiko Sato, Mark A. Schnitzler
Journal: Journal of the American Society of Nephrology (2008)

After renal transplantation, immunosuppressive regimens associated with high short-term survival rates are not necessarily associated with high long-term survival rates, suggesting that regimens may need to be optimized over time. Calcineurin inhibitor (CNI) withdrawal from a sirolimus-based immunosuppressive regimen may maximize the likelihood of long-term graft and patient survival by minimizing CNI-associated nephrotoxicity. In this study, a lifetime Markov model was created to compare the cost-effectiveness of a sirolimus-based CNI withdrawal regimen (sirolimus plus steroids) with other common CNI-containing regimens in adult de novo renal transplantation patients. Long-term graft survival was estimated by renal function and data from published studies and the US transplant registry, including short- and long-term outcomes, utility weights, and health-state costs were incorporated. Drug costs were based on average daily consumption and wholesale acquisition costs. The model suggests that treatment with sirolimus plus steroids is more efficacious and less costly than regimens consisting of a CNI, mycophenolate mofetil, and steroids; therefore, CNI withdrawal not only shows potential for long-term clinical benefits but also is expected to be cost-saving over a patient's life compared with the most commonly prescribed CNI-containing regimens.
Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss
Authors: K. Hallsworth, G. Fattakhova, K. G. Hollingsworth, C. Thoma, S. Moore, R. Taylor, C. P. Day, M. I. Trenell
Journal: Gut (2011)

Lifestyle interventions focusing on weight loss remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management. Despite this, the weight losses achieved in research trials are not easily replicated in the clinic and there is an urgent need for therapies independent of weight loss. Aerobic exercise is not well sustained and the effectiveness of the better tolerated resistance exercise upon liver lipid and mediators of liver lipid has not been assessed.Sedentary adults with clinically defined NAFLD were assigned to 8 weeks of resistance exercise (n=11) or continued normal treatment (n=8).8 weeks of resistance exercise elicited a 13% relative reduction in liver lipid (14.0 ± 9.1 vs. 12.2 ± 9.0; p<0.05). Lipid oxidation (submaximal RQ -0.020 ± 0.010 vs. -0.004 ± 0.003; p<0.05), glucose control (-12% vs. +12% change AUC; p<0.01) and homeostasis model assessment insulin resistance (5.9 ± 5.9 to 4.6 ± 4.6 vs. 4.7 ± 2.1 to 5.1 ± 2.5; p<0.05) were all improved. Resistance exercise had no effect on body weight, visceral adipose tissue volume, or whole body fat mass (p>0.05).This is the first study to demonstrate that resistance exercise specifically improves NAFLD independent of any change in body weight. These data demonstrate that resistance exercise may provide benefit for the management for non-alcoholic fatty liver, and the long-term impact of this now requires evaluation.
HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa
Authors: Jeffrey W. Eaton, Leigh F. Johnson, Joshua A. Salomon, Till Bärnighausen, Eran Bendavid, Anna Bershteyn, David E. Bloom, Valentina Cambiano, Christophe Fraser, Jan A. C. Hontelez, Salal Humair, Daniel J. Klein, Elisa F. Long, Andrew N. Phillips, Carel Pretorius, John Stover, Edward A. Wenger, Brian G. Williams, Timothy B. Hallett
Journal: PLoS Medicine (2012)

Background Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART. Methods and Findings Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results. Conclusions Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact. Please see later in the article for the Editors' Summary
SERCA upregulation: Breaking the positive feedback in heart failure?
Authors: J BASSANI, R BASSANI
Journal: Cardiovascular Research (2005)

See article by Maier et al.  [9]  (pages 636–646) in this issue .

Much effort has been devoted to devising approaches that may improve survival and the quality of life for the millions of people afflicted by heart failure (HF) all over the world. Because HF develops in association with different etiologies, its treatment represents a challenge for clinicians and investigators. The consistent observation of defective Ca2+ cycling in the failing myocardium has led to the notion that improvement of cardiac Ca2+ handling might be a suitable approach to minimize the systolic and diastolic dysfunction and possibly also the electrophysiological abnormalities that characterize HF.

Changes in Ca2+ handling in HF include partial Ca2+ depletion of the sarcoplasmic reticulum (SR), abnormal behavior of SR Ca2+ release channels, increased diastolic SR Ca2+ leak, upregulation of the sarcolemmal Na+–Ca2+ exchanger, and downregulation of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) [1–6]. It is likely that SR dysfunction may arise from the excessive demand on the heart due to prolonged activation of compensatory mechanisms that lead to changes in gene transcription and metabolism, thus representing part of the vicious circle that precipitates HF [7].

Gene therapy aimed at improving SR function has been … 

*Corresponding author. Centro de Engenharia Biomedica/UNICAMP, Caixa Postal 6040, 13084-971 Campinas, SP, Brazil. Tel.: +55 19 3788 9274; fax: +55 19 3289 3346. Email address: bassani{at}ceb.unicamp.br
Common Genetic Variation and Antidepressant Efficacy in Major Depressive Disorder: A Meta-Analysis of Three Genome-Wide Pharmacogenetic Studies
Authors: Rudolf Uher, Katherine E. Tansey, Neven Henigsberg, Maier Wolfgang, Ole Mors, Joanna Hauser, Anna Placentino, Daniel Souery, Anne Farmer, Katherine J. Aitchison, Ian Craig, McGuffin Peter, Cathryn M. Lewis, Marcus Ising, Susanne Lucae, Elisabeth B. Binder, Stefan Kloiber, Florian Holsboer, Bertram Müller-Myhsok, Stephan Ripke, Steven P. Hamilton, Jared Soundy, Gonzalo Laje, Francis J. McMahon, Maurizio Fava, A. John Rush, Roy H. Perlis
Journal: American Journal of Psychiatry (2013)

Objective Indirect evidence suggests that common genetic variation contributes to individual differences in antidepressant efficacy among individuals with major depressive disorder, but previous studies may have been underpowered to detect these effects. Method A meta-analysis was performed on data from three genome-wide pharmacogenetic studies (the Genome-Based Therapeutic Drugs for Depression [GENDEP] project, the Munich Antidepressant Response Signature [MARS] project, and the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study), which included 2,256 individuals of Northern European descent with major depressive disorder, and antidepressant treatment outcomes were prospectively collected. After imputation, 1.2 million single-nucleotide polymorphisms were tested, capturing common variation for association with symptomatic improvement and remission after up to 12 weeks of antidepressant treatment. Results No individual association met a genome-wide threshold for statistical significance in the primary analyses. A polygenic score derived from a meta-analysis of GENDEP and MARS participants accounted for up to approximately 1.2% of the variance in outcomes in STAR*D, suggesting a weakly concordant signal distributed over many polymorphisms. An analysis restricted to 1,354 individuals treated with citalopram (STAR*D) or escitalopram (GENDEP) identified an intergenic region on chromosome 5 associated with early improvement after 2 weeks of treatment. Conclusions Despite increased statistical power accorded by meta-analysis, the authors identified no reliable predictors of antidepressant treatment outcome, although they did identify modest, direct evidence that common genetic variation contributes to individual differences in antidepressant response.
Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture
Authors: J. Brent Richards
Journal: Annals of Internal Medicine (2009)

Background: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Design: Large-scale meta-analysis of genome-wide association data. Setting: 5 international, multicenter, population-based studies. Participants: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. Measurements: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. Results: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. Conclusion: In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD. Primary Funding Source: European Union, Netherlands Organisation for Scientific Research, Research Institute for Diseases in the Elderly, Netherlands Genomics Initiative, Wellcome Trust, National Institutes of Health, deCODE Genetics, and Canadian Institutes of Health Research.
Changes in Microvascular Diameter and Oxygen Tension Induced by Carbon Dioxide
Authors: BRIAN R. DULING
Journal: Circulation Research (1973)

Microvascular diameters in the hamster cheek pouch were measured with a Vickers image-shearing eyepiece, and oxygen tension (Po 2 ) was measured amperometrically with 2-6µ microcathodes. Perivascular Po 2 was dependent on both the type of microvessel observed and the composition of the solution bathing the tissue. During application of a solution with a mean Po 2 of 17 mm Hg and a Pco 2 of 0 mm Hg, a longitudinal gradient in perivascular Po 2 was observed: Po 2 decreased from 44 ± 2 ( SE ) mm Hg at the large arterioles to 18 ± 2 mm Hg at the capillary origin. Tissue Po 2 was 10 ± 1 mm Hg. Suffusion of the cheek pouch with a solution with approximately the same Po 2 and a Pco 2 of 32 mm Hg resulted in an elevation of perivascular Po 2 at all sites. Large arteriolar Po 2 under these circumstances was 47 ± 2 mm Hg, capillary origin Po 2 was 29 ± 3 mm Hg, and tissue Po 2 was 17 ± 3 mm Hg. CO 2 also produced vasodilation: the average vascular diameter increased 18 ± 7% when the solution Pco 2 was increased from 0 to 32 mm Hg. The tissue showed evidence of regulation of tissue O 2 supply both with and without CO 2 in the suffusion solution. The effects of CO 2 on the distribution of O 2 were compared with the effects of other vasodilators, and it was found that the tissue Po 2 was not consistently changed by the application of the vasodilators, whereas it was elevated 70% by CO 2 . This difference is attributed in part to the effect of CO 2 on the oxyhemoglobin dissociation curve.
Patient commentary: social media provides patients with support, information, and friendship
Authors: Amanda Greene
Journal: BMJ (2015)

When I was diagnosed with systemic lupus erythematosus 32 years ago, aged 15, social media did not exist. After months of diagnostic tests, I was happy to find out that my condition had a name. Six months after diagnosis, I attended my first lupus support group, where the topic for discussion was funeral planning. Questions posed included “what prayers and flowers do you want?”

For me dying was not an option. My mother and I looked at all the treatment options. We told the doctor that I was going to be a long term lupus survivor. My doctor took …
THE BEHAVIOR OF POX VIRUSES IN THE RESPIRATORY TRACT
Authors: John B. Nelson
Journal: The Journal of Experimental Medicine (1941)

Fowl pox virus from active skin lesions was established in the upper respiratory tract of normal chickens by nasal instillation and maintained for 12 successive passages. The nasal infection was not communicable by direct contact but did afford protection, for at least 6 weeks, against subsequent development of the virus in the skin. Multiplication of the virus in the nasal passages was only irregularly attended by specific mucosal changes and was not accompanied by the vigorous counter-reaction engendered by the causal agents of roup. The same strain of virus on propagation in embryonated eggs also survived and multiplied in the nasal tract but with somewhat reduced activity, the 34th egg transfer failing to afford complete protection. Nasal instillation in mice was followed only by a reaction in the lung from which the virus was recoverable through the 7th day.
Interferon -1a in ulcerative colitis: a placebo controlled, randomised, dose escalating study
Authors: S Nikolaus
Journal: Gut (2003)

<b>Background and aims:</b> Administration of interferon (IFN)-β may represent a rational approach to the treatment of ulcerative colitis through its immunomodulatory and anti-inflammatory effects. The present study was performed to evaluate the efficacy and tolerability of IFN-β-1a. <b>Methods:</b> Patients (n=18) with moderately active ulcerative colitis were randomised to receive IFN-β-1a or placebo. IFN-β-1a was started at a dose of 22 μg three times a week subcutaneously, and the dose was increased at two week intervals to 44 μg and then to 88 μg if no response was observed. The maximum duration of treatment was eight weeks. End points were clinical treatment response, defined as a decrease of at least 3 points from baseline in the ulcerative colitis scoring system (UCSS) symptoms score and induction of endoscopically confirmed remission. <b>Results:</b> Baseline characteristics and disease severity were similar in both groups. Data from 17 patients are included in this report (10 patients in the IFN-β-1a group and seven patients in the placebo group). Clinical response was achieved in five patients (50%) in the IFN-β-1a group and in one (14%) in the placebo group (<i>P</i>=0.14). Remission was achieved in three patients in the IFN-β-1a group and in none in the placebo group (p=0.02). Most adverse reactions associated with IFN-β-1a were influenza-like symptoms or injection site reactions, and were mild or moderate in severity. <b>Conclusions:</b> IFN-β-1a may represent a promising novel treatment approach in ulcerative colitis.
Host Determinants in Staphylococcal Disease
Authors: J Verhoef, H A Verbrugh
Journal: Annual Review of Medicine (1981)

Despite impressive gains in knowledge about the microbe and the host, the understanding and control of infections caused by staphylococci are still far from complete. Staphylococcus aureus continues to cause serious infectious diseases with a relative high morbidity and mortality. These are classical examples of opportunistic infections: deviations from the state in which the host controls bacterial colonization and prevents tissue invasion. The staphylococcus possesses numerous virulence factors that can act independently to induce a variety of symptoms and lesions. Therefore, clinical disease caused by staphylococci may vary widely. Although staphy­ lococci have a special preference for invasion of soft tissues and bones, every organ system can be affected ( 1, 2). This paper reviews progress made in understanding the interaction be­ tween virulence factors of staphylococci and defense mechanisms of the host as they relate to colonization and invasion. In addition, defects in host resistance are discussed, as these may indicate the relative importance of host determinants in staphylococcal disease� The potential virulence fac­ tors of staphylococci and their effects on host defense are summarized in Table 1.
Correlated Evolution of Androgen Receptor and Aromatase Revisited
Authors: A. M. Reitzel, A. M. Tarrant
Journal: Molecular Biology and Evolution (2010)

Conserved interactions among proteins or other molecules can provide strong evidence for coevolution across their evolutionary history. Diverse phylogenetic methods have been applied to identify potential coevolutionary relationships. In most cases, these methods minimally require comparisons of orthologous sequences and appropriate controls to separate effects of selection from the overall evolutionary relationships. In vertebrates, androgen receptor (AR) and cytochrome p450 aromatase (CYP19) share an affinity for androgenic steroids, which serve as receptor ligands and enzyme substrates. In a recent study, Tiwary and Li (Tiwary BK, Li W-H. 2009. Parallel evolution between aromatase and androgen receptor in the animal kingdom. Mol Biol Evol. 26:123–129) reported that AR and CYP19 displayed a signature of ancient and conserved interactions throughout all the Eumetazoa (i.e., cnidarians, protostomes, and deuterostomes). Because these findings conflicted with a number of previous studies, we reanalyzed the data set used by Tiwary and Li. First, our analyses demonstrate that the invertebrate genes used in the previous analysis are not orthologous sequences but instead represent a diverse set of nuclear receptors and CYP enzymes with no confirmed or hypothesized relationships with androgens. Second, we show that 1) their analytical approach, which measures correlations in evolutionary distances between proteins, potentially led to spurious significant relationships due simply to conserved domains and 2) control comparisons provide positive evidence for a strong influence of evolutionary history. We discuss how corrections to this method and analysis of key taxa (e.g., duplications in the teleost fish and suiform lineages) can inform investigations of the coevolutionary relationships between AR and aromatase.
Variants in the <i>SIRT1</i> Gene May Affect Diabetes Risk in Interaction With Prenatal Exposure to Famine
Authors: Ilse P.G. Botden, M. Carola Zillikens, Susanne R. de Rooij, Janneke G. Langendonk, A.H. Jan Danser, Eric J.G. Sijbrands, Tessa J. Roseboom
Journal: Diabetes Care (2012)

OBJECTIVE To investigate whether SIRT1, a nutrient-sensing histone deacetylase, influences fetal programming during malnutrition. RESEARCH DESIGN AND METHODS In 793 individuals of the Dutch Famine Birth Cohort, we analyzed the interaction between three SIRT1 single nucleotide polymorphisms (SNPs) and prenatal exposure to famine on type 2 diabetes risk. RESULTS In the total population (exposed and unexposed), SIRT1 variants were not associated with type 2 diabetes. A significant interaction was found between two SIRT1 SNPs and exposure to famine in utero on type 2 diabetes risk (P = 0.03 for rs7895833; P = 0.01 for rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of type 2 diabetes only in individuals who had been exposed to famine prenatally (odds ratio for rs7895833 0.50 [95% CI 0.24–1.03], P = 0.06; for rs1467568 0.48 [0.25–0.91], P = 0.02). CONCLUSIONS SIRT1 may be an important genetic factor involved in fetal programming during malnutrition, influencing type 2 diabetes risk later in life.