tbuckley/cabot-search huggingface dataset:
Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia
Authors: Lon S. Schneider, Karen S. Dagerman, Philip Insel
Journal: JAMA (2005)

ContextAtypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use.ObjectiveTo assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia.Data SourcesMEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.Study SelectionPublished and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors.Data ExtractionTrials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer.Data SynthesisFifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.ConclusionsAtypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed.
Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial
Authors: Merit E Cudkowicz, Sarah Titus, Marianne Kearney, Hong Yu, Alexander Sherman, David Schoenfeld, Douglas Hayden, Amy Shui, Benjamin Brooks, Robin Conwit, Donna Felsenstein, David J Greenblatt, Myles Keroack, John T Kissel, Robert Miller, Jeffrey Rosenfeld, Jeffrey D Rothstein, Ericka Simpson, Nina Tolkoff-Rubin, Lorne Zinman, Jeremy M Shefner
Journal: The Lancet Neurology (2014)
Normalization of the IGF-IGFBP Axis by Sustained Nightly Insulinization in Type 1 Diabetes
Authors: Klas Ekström, Jenny Salemyr, Ingmar Zachrisson, Christine Carlsson-Skwirut, Eva Örtqvist, Peter Bang
Journal: Diabetes Care (2007)

OBJECTIVE—We sought to test the hypothesis that start of insulin glargine with sustained nightly insulin action results in changes in circulating concentrations of IGF-I and IGF binding proteins (IGFBPs) in adolescents with type 1 diabetes—changes that may support improvement of A1C. RESEARCH DESIGN AND METHODS—Twelve pubertal adolescents with type 1 diabetes and initially on NPH insulin were studied during 12 weeks of intensified treatment with glargine. RESULTS—Subnormal IGF-I SD scores on NPH (−1.8 ± 0.4) rapidly increased and remained 54 ± 9% elevated (P &amp;lt; 0.001) after 12 weeks on glargine. A1C decreased from 8.3 ± 0.6% to a nadir of 6.9 ± 0.3% (P = 0.002) at 6 weeks and correlated with changes in IGF-I (r = −0.64, P &amp;lt; 0.05). The increase in IGF-I did not suppress the mean overnight growth hormone (GH) secretion at 6 weeks. The mean overnight IGFBP-1 levels decreased (P = 0.035), supporting the hypothesis that the nightly hepatic insulin action was increased. Circulating IGF-I increased in the absence of changes in both GH secretion and GH receptor numbers (assessed by growth hormone binding protein), indicating that postreceptor mechanisms are involved. IGFBP-3 proteolysis was decreased. CONCLUSIONS—Increased hepatic insulin action after start of glargine was evident from a decrease in night time IGFBP-1 concentrations. This may improve GH postreceptor signaling, resulting in increased circulating IGF-I. We suggest that even in the absence of changes in GH, increased IGF-I and decreased IGFBP-1 support the improvement of metabolic control.
Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study
Authors: Krzysztof Selmaj, David KB Li, Hans-Peter Hartung, Bernhard Hemmer, Ludwig Kappos, Mark S Freedman, Olaf Stüve, Peter Rieckmann, Xavier Montalban, Tjalf Ziemssen, Lixin Zhang Auberson, Harald Pohlmann, Francois Mercier, Frank Dahlke, Erik Wallström
Journal: The Lancet Neurology (2013)
Churg-Strauss syndrome associated with montelukast therapy
Authors: J M Tuggey
Journal: Thorax (2000)

Churg-Strauss syndrome is a rare form of eosinophilic vasculitis associated with asthma. There have been several recent case reports of the condition in association with leukotriene antagonists and it has been speculated that the Churg-Strauss syndrome was unmasked when oral corticosteroids were withdrawn. We report a case of Churg-Strauss syndrome associated with montelukast therapy in an asthmatic patient in whom there had been no recent oral corticosteroid use. We believe that this is the first such reported case and would suggest that clinicians need to be vigilant in all patients who develop systemic symptoms when starting treatment with leukotriene antagonists.
A new look at international research ethics
Authors: S. R Benatar
Journal: BMJ (2000)

Editorial by Lansang 

The normal “standard of care” against which new interventions are tested in medical research has not been formally defined. It is usually taken to mean the “best proved treatment” for any condition under investigation in a trial. We reject the arbitrariness of this notion of the standard of care and offer a more comprehensive alternative. Use of this new standard invokes a new approach to international research ethics that focuses on reducing inequalities in global health.

The debate on what constitutes a fair and reasonable standard of care for subjects in developing countries who participate in clinical trials has been rekindled by critics of studies on the transmission of HIV.1-3 They argued that placebo controlled trials of new regimens to prevent the vertical transmission of HIV were unethical because they included a placebo arm rather than “the best proven treatment” available in developed countries. Some commentators considered the criticisms to be unfounded4-6 and associated with imperialistic attitudes.7

The debate made it clear that the high standards of research aspired to have not been adequately defined. It was also marred by simplistic notions of ethics. Although there was justified concern that pressure from the US Food and Drug Administration could “dilute” the Declaration of Helsinki, critics also presumed that whether a trial was ethical could simply be deduced from the text of a declaration. But declarations—such as the Declaration of Helsinki, governing international research ethics—are like constitutions, needing interpretation. Determining what is ethical goes beyond merely following prescriptions and requires moral reasoning: consideration of all relevant aspects of the case in its context, weighing and balancing competing moral requirements, and developing justifiable conclusions.

Although more mature insight is gradually emerging into the complexity associated with the ethics of research in developing countries, the debate remains …
Nutritional rehabilitation: from pulmonary cachexia to sarcoPD
Authors: A. M. W. J. Schols
Journal: European Respiratory Journal (2009)

Evidence is accumulating that disease burden in chronic obstructive pulmonary disease (COPD) is determined by not only pulmonary impairment but the fact that skeletal muscle pathology and cardiovascular disease also contribute to decreased physical performance and increased mortality. An integrated view of the decline in function of multiple organs as a disturbed homeostatic network resulting from smoking, suboptimal diet, inactivity and disease susceptibility has not yet been conceptualised in COPD management but could lead to a shift in clinical medicine and public health towards personalised lifestyle.

Research into the pathogenesis and treatment of skeletal muscle pathology in pulmonary cachexia to alleviate progressive disability has been the subject of intensive research during the past decade. While the anabolic and metabolic potential of multimodal nutritional rehabilitation strategies, including exercise, protein-calorie supplementation, polyunsaturated fatty acids and/or anabolic agents, has been demonstrated in the short-term 1–3, efficacy in pulmonary cachexia is limited by the absence of long-term strategies to maintain physical fitness in advanced disease and by adverse effects of persistent inflammation on …
Smoking and Colorectal Cancer: a 20-Year Follow-up Study of Swedish Construction Workers
Authors: O. Nyren, R. Bergstrom, L. Nystrom, G. Engholm, A. Ekbom, H.-O. Adami, A. Knutsson, N. Stjernberg
Journal: JNCI Journal of the National Cancer Institute (1996)

Although cigarette smoking has consistently been shown to be positively related to the risk of adenomatous polyp development (benign neoplastic growth of epithelial tissue in the colon), most studies of cigarette smoking and the risk of colorectal cancer have been negative. However, in two large prospective studies in women and men, a statistically significant association between cigarette smoking and an increased risk of colorectal cancer was found, but only after more than 35 years of smoking. To shed further light on the alleged relationship between long-term smoking and colorectal cancer risk, we performed a retrospective cohort study among Swedish construction workers, with many long-term smokers, complete long-term follow-up, and a large number of observed cases. We analyzed the association of smoking with colon cancer and with rectal cancer, using data on a cohort of approximately 135 000 male construction workers. High-quality exposure information was collected with the use of a comprehensive questionnaire filled out at the time of enrollment in the cohort, from 1971 through 1975. Complete follow-up was achieved through 1991 and the subjects were observed for an average of 17.6 years, thereby contributing approximately 2 375 000 person-years of follow-up. We calculated age-adjusted rate ratios (RRs) with the use of Poisson-based multiplicative multivariate models followed by further multivariate modeling that adjusted for other variables. A total of 713 incident colon cancers and 505 rectal cancers were observed. There was no statistically significant association between current smoking status, number of cigarettes smoked or number of years smoking, and risk of colorectal cancer. The age-adjusted RRs were 0.98 (95% confidence interval [CI] = 0.82–1.17) and 1.16 (95% CI = 0.94–1.44) for colon and rectal cancers, respectively, among current smokers, and 1.07 (95% CI = 0.63–1.82) and 1.08 (95% CI = 0.58–2.03) among smokers of 25 or more cigarettes per day, relative to nonsmokers. Among smokers for more than 30 years at the start of follow-up, the age-adjusted RRs were 1.03 (95% CI = 0.85–1.25) and 1.21 (95% CI = 0.96–1.53) for colon and rectal cancers, respectively, relative to nonsmokers. Heavy smokers of cigars and pipes had a statistically nonsignificant tendency toward excess risk for colon cancer, but there was no clear dose-risk trend. Our large cohort study did not indicate any excess risk of colon cancer in males who were long-term heavy smokers and provided only weak support for an association with rectal cancer. Our data are thus consistent with the majority of previous reports. The reasons for the discrepancies in comparison with recent U.S. data have yet to be identified. [J Natl Cancer Inst 1996; 88: 1302–7]
Recent skin self-examination and doctor visits in relation to melanoma risk and tumour depth
Authors: L.J. Titus, K. Clough-Gorr, T.A. Mackenzie, A. Perry, S.K. Spencer, J. Weiss, S. Abrahams-Gessel, M.S. Ernstoff
Journal: British Journal of Dermatology (2012)

Little is known about the potential benefit of skin self-examination for melanoma prevention and early detection.
Population screening for lung cancer using computed tomography, is there evidence of clinical effectiveness? A systematic review of the literature
Authors: C. Black, R. de Verteuil, S. Walker, J. Ayres, A. Boland, A. Bagust, N. Waugh
Journal: Thorax (2007)

Lung cancer is the leading cause of death among all cancer types in the UK, killing approximately 34 000 people per year. By the time symptoms develop, the tumour is often at an advanced stage and the prognosis is bleak. Treatment at a less advanced stage of disease by surgical resection has been shown to substantially reduce mortality. Screening would be attractive if it could detect presymptomatic lung cancer at a stage when surgical intervention is feasible but has been the subject of scientific debate for the past three decades. The aim of this review was to examine the current evidence on the clinical effectiveness of screening for lung cancer using computed tomography. A systematic literature review searching 15 electronic databases and Internet resources from 1994 until December 2004/January 2005 was carried out. Information was summarised narratively. A total of 12 studies of computed tomography screening for lung cancer were identified including two RCTs and 10 studies of screening without comparator groups. The two RCTs were of short duration (1 year). None examined the effect of screening on mortality compared with no screening. The proportion of people with abnormal computed tomography findings varied widely between studies (5–51%). The prevalence of lung cancer detected was between 0.4% and 3.2% (number needed to screen to detect one lung cancer = 31 to 249). Incidence rates of lung cancer were lower (0.1–1%). Among the detected tumours, a high proportion were stage I or resectable tumours, 100% in some studies. Currently, there is insufficient evidence that computed tomography screening is clinically effective in reducing mortality from lung cancer.
BLOOD PLASMA PROTEIN REGENERATION CONTROLLED BY DIET
Authors: W. T. Pommerenke, H. B. Slavin, D. H. Kariher, G. H. Whipple
Journal: The Journal of Experimental Medicine (1935)

When blood plasma proteins are depleted by bleeding, with return of washed red cells (plasmapheresis) it is possible to bring the dog to a steady state of low plasma protein and uniform plasma protein production on a basal diet. Such dogs are excellent test subjects by which the potency of various diet factors for plasma protein regeneration can be measured. To regenerate plasma proteins in any significant amount the depleted dog requires food protein. Some proteins are very potent for new plasma protein production and others are utilized poorly. Beef serum is very potent and its proteins (2.6 gm.) will produce 1 gm. of new plasma protein in the depleted dog-a potency ratio of 2.6. Kidney protein stands at the bottom of our list and the dog needs 21 gm. of kidney protein to regenerate 1 gm. of plasma protein-a potency ratio of 21.0. Some grain proteins approximate the potency of beef serum and may show potency ratios of 2.7 to 4.6. Some of these grain proteins appear to favor the production of globulin more than albumin in the plasma. Skeletal muscle, gizzard (smooth muscle), lactalbumin and egg white fall into a favorable group with a potency ratio of 5.3 to 6.0. Whole liver, liver fractions, casein, and beef heart are a little less potent and present potency ratios of 6.5 to 8.0. Many of these food substances favor the production of albumin more than globulin. Pancreas and salmon muscle show less favorable potency ratios of 19.0 and 15.0 respectively. Fasting periods indicate that these depleted dogs can produce little if any new plasma protein. Iron feeding in some unexplained manner will influence body metabolism so that an excess of plasma protein will be produced. These observations have a bearing on clinical conditions associated with hypoproteinemia and give suggestions for diet aid or control in some of these abnormal states. The make-up of the diet is obviously of great interest and it is possible that protein combinations may be more potent than a single protein or that food potency ratios may differ in health and disease.
Relationship between histopathological features and the course of idiopathic pulmonary fibrosis/usual interstitial pneumonia
Authors: L Tiitto, R Bloigu, U Heiskanen, P Paakko, V L Kinnula, R Kaarteenaho-Wiik
Journal: Thorax (2006)

<b>Background:</b> Fibroblastic focus (FF) is the typical histopathological feature of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). A study was undertaken to analyse FF at diagnosis, to analyse the histopathological findings at necropsy, and to examine their association with the course of the disease. <b>Methods:</b> A retrospective study was made of 76 UIP cases collected over a period of 30 years from one university hospital; 64 had idiopathic IPF. The surface area of one slide of each lung biopsy specimen was defined by image analysis and the total number of FF was quantified. The histological features of necroscopic lung samples were re-analysed in 11 cases. Clinical follow up information was obtained from the registers. <b>Results:</b> Patients with ⩽50 FF/cm<sup>2</sup> (n = 34) in the lung biopsy specimen had a median survival of 89 months (95% CI 38 to 140) compared with 49 months (95% CI 36 to 62) in those with &gt;50 FF/cm<sup>2</sup> (n = 42, p = 0.0358). Diffuse alveolar damage (DAD) was detected in 10 necropsy samples and almost prevented the histopathological confirmation of UIP in six cases. Accumulation of neutrophils occurred in nine cases. There was no association between FF at diagnosis and DAD at necropsy, or between FF and exacerbation of the disease before death. <b>Conclusions:</b> The number of FF in lung samples before death is associated with poor survival but not with DAD, which is a common feature in necropsy specimens of patients with UIP. FF cannot predict an acute exacerbation of IPF.
Predictors of aneurysmal formation after surgical correction of aortic coarctation
Authors: Yskert von Kodolitsch, Muhammet A Aydin, Dietmar H Koschyk, Roger Loose, Ilka Schalwat, Matthias Karck, Jochen Cremer, Axel Haverich, Jürgen Berger, Thomas Meinertz, Christoph A Nienaber
Journal: Journal of the American College of Cardiology (2002)
Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1polymorphisms
Authors: Suzanne E Wahrle, Aarti R Shah, Anne M Fagan, Scott Smemo, John SK Kauwe, Andrew Grupe, Anthony Hinrichs, Kevin Mayo, Hong Jiang, Leon J Thal, Alison M Goate, David M Holtzman
Journal: Molecular Neurodegeneration (2007)

Animal studies suggest that brain apolipoprotein E (apoE) levels influence amyloid-beta (Abeta) deposition and thus risk for Alzheimer's disease (AD). We have previously demonstrated that deletion of the ATP-binding cassette A1 transporter (ABCA1) in mice causes dramatic reductions in brain and cerebrospinal fluid (CSF) apoE levels and lipidation. To examine whether polymorphisms in ABCA1 affect CSF apoE levels in humans, we measured apoE in CSF taken from 168 subjects who were 43 to 91 years old and were either cognitively normal or who had mild AD. We then genotyped the subjects for ten previously identified ABCA1 single nucleotide polymorphisms (SNPs).In all subjects, the mean CSF apoE level was 9.09 microg/ml with a standard deviation of 2.70 microg/ml. Levels of apoE in CSF samples taken from the same individual two weeks apart were strongly correlated (r2 = 0.93, p < 0.01). In contrast, CSF apoE levels in different individuals varied widely (coefficient of variation = 46%). CSF apoE levels did not vary according to AD status, APOE genotype, gender or race. Average apoE levels increased with age by approximately 0.5 microg/ml per 10 years (r2 = 0.05, p = 0.003). We found no significant associations between CSF apoE levels and the ten ABCA1 SNPs we genotyped. Moreover, in a separate sample of 1225 AD cases and 1431 controls, we found no association between the ABCA1 SNP rs2230806 and AD as has been previously reported.We found that CSF apoE levels vary widely between individuals, but are stable within individuals over a two-week interval. AD status, APOE genotype, gender and race do not affect CSF apoE levels, but average CSF apoE levels increase with age. Given the lack of association between CSF apoE levels and genotypes for the ABCA1 SNPs we examined, either these SNPs do not affect ABCA1 function or if they do, they do not have strong effects in the CNS. Finally, we find no evidence for an association between the ABCA1 SNP rs2230806 and AD in a large sample set.
A 68-kD GTP-binding protein associated with the T cell receptor complex.
Authors: T Ohmura, A Sakata, K Onoue
Journal: The Journal of Experimental Medicine (1992)

The identity of the guanine nucleotide-binding protein (G protein) involved in T cell activation pathways remains unclear. We identified a 68-kD GTP-binding protein associated with the T cell receptor (TCR)/CD3 complex using immunoprecipitation and GTP-affinity labeling techniques. Proteins coimmunoprecipitated with the TCR/CD3 complex in digitonin lysate of a human leukemic T cell line, MOLT 16, were incubated with alpha-[32P]GTP and irradiated with ultraviolet rays to covalently link the labeled GTP to GTP-binding proteins. They were then analyzed by electrophoresis. The 68-kD protein exhibited nucleotide specificity for GTP-binding and was insensitive to cholera and pertussis toxins. The 68-kD GTP-binding protein could be coimmunoprecipitated with the TCR/CD3 complex but not with other surface molecules such as major histocompatibility complex class I and lymphocyte function associated-1, which do not cause rapid Ca2+ mobilization. These suggest that the 68-kD GTP-binding protein is specifically associated with the TCR/CD3 complex.