tbuckley/cabot-search huggingface dataset:
Association of Community-Acquired Pneumonia With Antipsychotic Drug Use in Elderly Patients
Authors: Gianluca Trifirò
Journal: Annals of Internal Medicine (2010)

Background: According to safety alerts from the U.S. Food and Drug Administration, pneumonia is one of the most frequently reported causes of death in elderly patients with dementia who are treated with antipsychotic drugs. However, epidemiologic evidence of the association between antipsychotic drug use and pneumonia is limited. Objective: To evaluate whether typical or atypical antipsychotic use is associated with fatal or nonfatal pneumonia in elderly persons. Design: Population-based, nested case–control study. Setting: Dutch Integrated Primary Care Information database. Patients: Cohort of persons who used an antipsychotic drug, were 65 years or older, and were registered in the IPCI database from 1996 to 2006. Case patients were all persons with incident community-acquired pneumonia. Up to 20 control participants were matched to each case patient on the basis of age, sex, and date of onset. Measurements: Risk for fatal or nonfatal community-acquired pneumonia with atypical and typical antipsychotic use. Antipsychotic exposure was categorized by type, timing, and daily dose, and the association with pneumonia was assessed by using conditional logistic regression. Results: 258 case patients with incident pneumonia were matched to 1686 control participants. Sixty-five (25%) of the case patients died in 30 days, and their disease was considered fatal. Current use of either atypical (odds ratio [OR], 2.61 [95% CI, 1.48 to 4.61]) or typical (OR, 1.76 [CI, 1.22 to 2.53]) antipsychotic drugs was associated with a dose-dependent increase in the risk for pneumonia compared with past use of antipsychotic drugs. Only atypical antipsychotic drugs were associated with an increase in the risk for fatal pneumonia (OR, 5.97 [CI, 1.49 to 23.98]). Limitations: Antipsychotic exposure was based on prescription files. Residual confounding due to unmeasured covariates or severity of disease was possible. Conclusion: The use of either atypical or typical antipsychotic drugs in elderly patients is associated in a dose-dependent manner with risk for community-acquired pneumonia. Primary Funding Source: None.
Lung transplantation in telomerase mutation carriers with pulmonary fibrosis
Authors: Leann L. Silhan, Pali D. Shah, Daniel C. Chambers, Laurie D. Snyder, Gerdt C. Riise, Christa L. Wagner, Eva Hellström-Lindberg, Jonathan B. Orens, Juliette F. Mewton, Sonye K. Danoff, Murat O. Arcasoy, Mary Armanios
Journal: European Respiratory Journal (2014)

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the USA, Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p&lt;0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients.
Homeostatic Competition Among T Cells Revealed by Conditional Inactivation of the Mouse <i>Cd4</i> Gene
Authors: Qi Wang, Julie Strong, Nigel Killeen
Journal: The Journal of Experimental Medicine (2001)

Absence of CD4 impairs the efficiency of T cell receptor (TCR) signaling in response to major histocompatibility complex (MHC) class II–presented peptides. Here we use mice carrying a conditional Cd4 allele to study the consequences of impaired TCR signaling after the completion of thymocyte development. We show that loss of CD4 decreases the steady-state proliferation of T cells as monitored by in vivo labeling with bromo-deoxyuridine. Moreover, T cells lacking CD4 compete poorly with CD4-expressing T cells during proliferative expansion after transfer into lymphopenic recipients. The data suggest that T cells compete with one another during homeostatic proliferation, and indicate that the basis of this competition is TCR signaling.
Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6.
Authors: K Mitsuyama, A Toyonaga, E Sasaki, O Ishida, H Ikeda, O Tsuruta, K Harada, H Tateishi, T Nishiyama, K Tanikawa
Journal: Gut (1995)

The in vivo appearance of soluble interleukin (IL)-6 receptor (sIL-6R) in serum from patients with inflammatory bowel disease was examined using an enzyme linked immunosorbent assay (ELISA). The serum sIL-6R concentrations in patients with active disease (ulcerative colitis, 148.4 (5.1); Crohn's disease, 142.3 (9.3) ng/ml; mean (SEM)) were significantly raised compared with those in patients with inactive disease (ulcerative colitis, 116.2 (7.2); Crohn's disease, 114.3 (7.1) ng/ml), some other type of colitis (104.8 (11.6) ng/ml), or in normal subjects (107.3 (2.4) ng/ml). These differences were also seen in paired samples examined during both active and inactive phases. Additionally, serum sIL-6R and IL-6 concentrations correlated significantly with C-reactive protein levels in both ulcerative colitis and Crohn's disease patients (r = 0.23 and 0.56, respectively; p < 0.05 for both). Furthermore, gel filtration analysis of serum from these patients showed two major peaks of immunoreactive IL-6-one peak corresponding to free IL-6 and another peak to sIL-6R-bound IL-6-this was further confirmed by a luminescence sandwich ELISA. These results, together with its in vitro effects, indicate that natural sIL-6R may function as a powerful enhancer of the IL-6-dependent immune processes observed in inflammatory bowel disease.
Risk of Celiac Disease in Children With Type 1 Diabetes Is Modified by Positivity for <i>HLA-DQB1*02-DQA1*05</i> and<i>TNF −308A</i>
Authors: Zdenek Sumnik, Ondrej Cinek, Nina Bratanic, Olga Kordonouri, Michal Kulich, Barnabas Roszai, Andras Arato, Jan Lebl, Gyula Soltesz, Thomas Danne, Tadej Battelino, Edit Schober
Journal: Diabetes Care (2006)

OBJECTIVE—The overlap between genetic susceptibility to celiac disease (CD) and to type 1 diabetes is incomplete; therefore, some genetic polymorphisms may significantly modify the risk of CD in subjects with type 1 diabetes. This study aimed to investigate whether the susceptibility to CD in diabetic children is modified by positivity for HLA-DQB1*02-DQA1*05 and DQB1*0302-DQA1*03 and by alleles of single nucleotide polymorphisms within the genes encoding CTLA4, transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1, IL-2, IL-6, and IL-10. RESEARCH DESIGN AND METHODS—Genotypic data were compared between 130 case subjects (children with type 1 diabetes and CD diagnosed using endomysium antibodies) and 245 control subjects (children with type 1 diabetes only, optimally two per case, matched for center, age at type 1 diabetes onset, and type 1 diabetes duration). The subjects were recruited from 10 major European pediatric diabetes centers performing regular screening for CD. The polymorphisms were determined using PCR with sequence-specific primers, and the risk was assessed by building a step-up conditional logistic regression model using variables that were significantly associated with CD in the univariate analysis. RESULTS—The best-fitted model showed that risk of CD is increased by presence of HLA-DQB1*02-DQA1*05 (odds ratio 4.5 [95% CI 1.8–11], for homozygosity, and 2.0 [1.1–3.7], for a single dose) and also independently by TNF −308A (1.9 [1.1–3.2], for phenotypic positivity), whereas IL1-α −889T showed a weak negative association (0.6 [0.4–0.9]). CONCLUSIONS—The results indicate that the risk of CD in children with type 1 diabetes is significantly modified both by the presence of HLA-DQB1*02-DQA1*05 and by a variant of another gene within the major histocompatibility complex, the TNF −308A.
Use of the Patient Assessment of Chronic Illness Care (PACIC) With Diabetic Patients
Authors: Russell E. Glasgow, Holly Whitesides, Candace C. Nelson, Diane K. King
Journal: Diabetes Care (2005)

OBJECTIVE—There is a dearth of information on the extent to which diabetic patients receive care congruent with the chronic care model (CCM) and evidence-based behavioral counseling. This study evaluates a new instrument to fill this gap. RESEARCH DESIGN AND METHODS—A heterogeneous sample of 363 type 2 diabetic patients completed the original Patient Assessment of Chronic Illness Care (PACIC), along with additional items that allowed it to be scored according to the “5As” (ask, advise, agree, assist, and arrange) model of behavioral counseling. We evaluated relationships between survey scores and patient characteristics, quality of diabetes care, and self-management. RESULTS—Findings replicated those of the initial PACIC validation study but with a much larger sample of diabetic patients and more Latinos. Areas of CCM activities reported least often were goal setting/intervention tailoring and follow-up/coordination. The 5As scoring revealed that patients were least likely to receive assistance with problem solving and arrangement of follow-up support. Few demographic or medical characteristics were related to PACIC or 5As scores, but survey scores were significantly related to quality of diabetes care received and level of physical activity. CONCLUSIONS—The PACIC and the new 5As scoring method appear useful for diabetic patients. Its use is encouraged in future research and quality improvement studies.
Context Dependence, Ancestral Misidentification, and Spurious Signatures of Natural Selection
Authors: R. D. Hernandez, S. H. Williamson, C. D. Bustamante
Journal: Molecular Biology and Evolution (2007)

Population genetic analyses often use polymorphism data from one species, and orthologous genomic sequences from closely related outgroup species. These outgroup sequences are frequently used to identify ancestral alleles at segregating sites and to compare the patterns of polymorphism and divergence. Inherent in such studies is the assumption of parsimony, which posits that the ancestral state of each single nucleotide polymorphism (SNP) is the allele that matches the orthologous site in the outgroup sequence, and that all nucleotide substitutions between species have been observed. This study tests the effect of violating the parsimony assumption when mutation rates vary across sites and over time. Using a context-dependent mutation model that accounts for elevated mutation rates at CpG dinucleotides, increased propensity for transitional versus transversional mutations, as well as other directional and contextual mutation biases estimated along the human lineage, we show (using both simulations and a theoretical model) that enough unobserved substitutions could have occurred since the divergence of human and chimpanzee to cause many statistical tests to spuriously reject neutrality. Moreover, using both the chimpanzee and rhesus macaque genomes to parsimoniously identify ancestral states causes a large fraction of the data to be removed while not completely alleviating problem. By constructing a novel model of the context-dependent mutation process, we can correct polymorphism data for the effect of ancestral misidentification using a single outgroup.
Interventions to improve water quality for preventing diarrhoea: systematic review and meta-analysis
Authors: Thomas Clasen, Wolf-Peter Schmidt, Tamer Rabie, Ian Roberts, Sandy Cairncross
Journal: BMJ (2007)

<b>Objective</b> To assess the effectiveness of interventions to improve the microbial quality of drinking water for preventing diarrhoea. <b>Design</b> Systematic review. <b>Data sources</b> Cochrane Infectious Diseases Group9s trials register, CENTRAL, Medline, Embase, LILACS; hand searching; and correspondence with experts and relevant organisations. <b>Study selection</b> Randomised and quasirandomised controlled trials of interventions to improve the microbial quality of drinking water for preventing diarrhoea in adults and in children in settings with endemic disease. <b>Data extraction</b> Allocation concealment, blinding, losses to follow-up, type of intervention, outcome measures, and measures of effect. Pooled effect estimates were calculated within the appropriate subgroups. <b>Data synthesis</b> 33 reports from 21 countries documenting 42 comparisons were included. Variations in design, setting, and type and point of intervention, and variations in defining, assessing, calculating, and reporting outcomes limited the comparability of study results and pooling of results by meta-analysis. In general, interventions to improve the microbial quality of drinking water are effective in preventing diarrhoea. Effectiveness was not conditioned on the presence of improved water supplies or sanitation in the study setting and was not enhanced by combining the intervention with instructions on basic hygiene, a water storage vessel, or improved sanitation or water supplies—other common environmental interventions intended to prevent diarrhoea. <b>Conclusion</b> Interventions to improve water quality are generally effective for preventing diarrhoea in all ages and in under 5s. Significant heterogeneity among the trials suggests that the level of effectiveness may depend on a variety of conditions that research to date cannot fully explain.
Hyperandrogenic anovulation (the polycystic ovary syndrome) - back to the ovary?
Authors: I Ben-Shlomo
Journal: Human Reproduction Update (1998)

Hyperandrogenic anovulation is characterized by polycystic appearance of the ovaries, elevated free serum testosterone with decreased concentrations of serum sex hormone binding globulin, an increased ratio of luteinizing hormone to follicle stimulating hormone and varying degrees of insulin resistance. We hypothesize that this is the result of variably increased 'ovarian androgenic insulin responsiveness' acting in combination with body mass. Women who develop hyperandrogenism and anovulation when lean (having normal serum insulin concentrations) represent the more severely affected individuals, whereas those who can resume ovulation by losing weight (and lowering their elevated serum insulin) represent a milder form. The tendency of these women to develop ovarian hyperstimulation syndrome despite hypophyseal desensitization suggests a primary ovarian defect which is apparently more pronounced in lean subjects. The unique ability of surgical damage to the ovary to induce ovulation, raises the possibility that inflammatory-like tissue remodelling has a major role in rescuing follicles from androgen-induced atresia. Approaches that may facilitate the study of this possible mechanism may include examination of in-vitro perfused, post-surgery mammalian ovaries and the elucidation of signal transduction mechanism(s) of insulin in the ovary, with special reference to cells emanating from affected women.
Public Health Interventions Need to Meet the Same Standards of Medical Ethics as Individual Health Interventions
Authors: Michael Keane
Journal: The American Journal of Bioethics (2010)

ways of regulating a particular public health risk that have a better balance of moral benefits over moral costs. Costs to liberty are only one of the relevant factors. The very probable large costs to human life through waiting to see whether education and labeling policies are effective ways of reducing trans fat intake is also a relevant factor. Resnik provides no reason to think that the moral costs associated with these very probable deaths are smaller than those associated with the infringement of liberty. Moreover, invoking the “principle of the least restrictive alternative” in public health regulation seems to be either almost entirely superfluous, or to involve an illicit form of double counting. If it means that we should adopt the least restrictive alternative out of the ones that have already been singled out as offering the best balance of moral benefits over moral costs, then presumably it can only operate as a tie breaker, and so will be unable to do the work Resnik requires. 1 But if it is supposed to play a substantive role (as Resnik seems to imagine it will), then it seems to be clearly illicit, given that liberty has already been weighed in the balance against the other goods at the stage of working out which policies are proportional and necessary. Liberty is an important value, but it is not so important that it ought to be counted multiple times.
A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice
Authors: Thomas J. Hund, Olha M. Koval, Jingdong Li, Patrick J. Wright, Lan Qian, Jedidiah S. Snyder, Hjalti Gudmundsson, Crystal F. Kline, Nathan P. Davidson, Natalia Cardona, Matthew N. Rasband, Mark E. Anderson, Peter J. Mohler
Journal: Journal of Clinical Investigation (2010)

Ion channel function is fundamental to the existence of life. In metazoans, the coordinate activities of voltage-gated Na(+) channels underlie cellular excitability and control neuronal communication, cardiac excitation-contraction coupling, and skeletal muscle function. However, despite decades of research and linkage of Na(+) channel dysfunction with arrhythmia, epilepsy, and myotonia, little progress has been made toward understanding the fundamental processes that regulate this family of proteins. Here, we have identified β(IV)-spectrin as a multifunctional regulatory platform for Na(+) channels in mice. We found that β(IV)-spectrin targeted critical structural and regulatory proteins to excitable membranes in the heart and brain. Animal models harboring mutant β(IV)-spectrin alleles displayed aberrant cellular excitability and whole animal physiology. Moreover, we identified a regulatory mechanism for Na(+) channels, via direct phosphorylation by β(IV)-spectrin-targeted calcium/calmodulin-dependent kinase II (CaMKII). Collectively, our data define an unexpected but indispensable molecular platform that determines membrane excitability in the mouse heart and brain.
THE BLOOD-CEREBROSPINAL FLUID BARRIER IN MENTAL DISORDERS
Authors: D. Rothschild, C. N. Hamberg
Journal: American Journal of Psychiatry (1935)

The distribution of calcium between blood and cerebrospinal fluid was investigated in 400 cases of mental disorder. Five hundred and twenty-three determinations of the ratio of blood to spinal fluid calcium were made. In addition, 480 determinations of the distribution ratio of bromide and 347 determinations of the protein content of the cerebrospinal fluid were performed on parts of the same specimens that were used for the calcium determinations. In the schizophrenic group 29 per cent of the calcium ratios were above 2.2 and 3 per cent were below 1.8. In neurosyphilis 8 per cent of the calcium ratios were above 2.2 and 12.5 per cent were below 1.8. Low ratios occurred with greatest frequency in untreated patients with general paresis. The other groups showed a smaller proportion of abnormal results without any striking preponderance of increased or decreased values. The results were suggestive of a tendency towards decreased permeability of the blood-cerebrospinal fluid barrier in schizophrenia and increased permeability in untreated patients with general paresis. There was a general correlation between the distribution ratios of calcium and bromide in schizophrenia, affective psychoses and untreated neurosyphilis. In the individual cases this correlation was frequently lacking. Low calcium ratios tended to occur in cases presenting increased amounts of protein in the cerebrospinal fluid and high ratios in cases showing decreased amounts of protein, but this relationship was not consistent. A scrutiny of our data clearly indicated that the variations in the distribution ratio of calcium could not be accounted for by alterations in the protein content of the cerebrospinal fluid.
6-minute walk distance is an independent predictor of mortality in patients with idiopathic pulmonary fibrosis
Authors: Roland M. du Bois, Carlo Albera, Williamson Z. Bradford, Ulrich Costabel, Jonathan A. Leff, Paul W. Noble, Steven A. Sahn, Dominique Valeyre, Derek Weycker, Talmadge E. King
Journal: European Respiratory Journal (2013)

6-min walk distance (6MWD) has recently been shown to be associated with the risk of mortality in patients with idiopathic pulmonary fibrosis (IPF); however, the independent contribution of 6MWD to the prediction of mortality risk has not been evaluated in a large, well-defined population of patients with IPF. A Cox proportional hazards model was used to characterise the relationship between risk factors of interest and all-cause mortality in IPF patients who completed a week 24 study visit in a clinical trial evaluating interferon γ-1b (n=748). Risk factors of interest included the independent predictors of mortality in the previously published clinical prediction model together with 6MWD and 24-week change in 6MWD. Baseline 6MWD &lt;250 m was associated with a two-fold increase in the risk of mortality (hazard ratio 2.12, 95% CI 1.15–3.92) and a 24-week decline in 6MWD &gt;50 m was associated with a nearly three-fold increase in mortality risk (hazard ratio 2.73; 95% CI 1.60–4.66). Inclusion of 6MWD data improved model discrimination compared with the original model (C-statistic 0.80 (95% CI 0.76–0.85) versus 0.75 (0.71–0.79)). Both 6MWD and change in 6MWD are independent predictors of mortality in patients with IPF. The addition of 6MWD to the clinical prediction model improves model discrimination compared with the original model.
Hedgehog-Producing Cancer Cells Respond to and Require Autocrine Hedgehog Activity
Authors: Samer Singh, Zhiqiang Wang, Dennis Liang Fei, Kendall E. Black, John A. Goetz, Robert Tokhunts, Camilla Giambelli, Jezabel Rodriguez-Blanco, Jun Long, Ethan Lee, Karoline J. Briegel, Pablo A. Bejarano, Ethan Dmitrovsky, Anthony J. Capobianco, David J. Robbins
Journal: Cancer Research (2011)

A number of Smoothened (SMO) pathway antagonists are currently undergoing clinical trials as anticancer agents. These drugs are proposed to attenuate tumor growth solely through inhibition of Hedgehog (HH), which is produced in tumor cells but acts on tumor stromal cells. The pivotal argument underlying this model is that the growth-inhibitory properties of SMO antagonists on HH-producing cancer cells are due to their off-target effects. Here, we show that the tumorigenic properties of such lung cancer cells depend on their intrinsic level of HH activity. Notably, reducing HH signaling in these tumor cells decreases HH target gene expression. Taken together, these results question the dogma that autocrine HH signaling plays no role in HH-dependent cancers, and does so without using SMO antagonists.