tbuckley/cabot-search huggingface dataset:
Amisulpride, an Unusual “Atypical” Antipsychotic: A Meta-Analysis of Randomized Controlled Trials
Authors: Stefan Leucht, Gabi Pitschel-Walz, Rolf R. Engel, Werner Kissling
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The "atypical" profile of the new antipsychotics clozapine, olanzapine, quetiapine, and risperidone has been linked to combined antagonism of serotonin 2 (5-HT2) and dopamine 2 (D2) receptors. Although amisulpride is a highly selective D3/D2 receptor antagonist, it is assumed to have atypical properties as well. The purpose of this article was to compare the atypical profile of amisulpride with that of the 5-HT2/D2 antagonists. METHOD: Randomized controlled trials that compared amisulpride with conventional antipsychotics or placebo for patients with schizophrenia were identified and included in a meta-analysis. The mean effect sizes found for amisulpride were compared with those of an updated meta-analysis of the 5-HT2/D2 antagonists. RESULTS: Eighteen randomized controlled trials of amisulpride (N=2,214) were found. In 11 studies of acutely ill patients it proved to be consistently more effective than conventional antipsychotics for global schizophrenic symptoms (measured with the Brief Psychiatric Rating Scale) and negative symptoms. Amisulpride is to date the only atypical antipsychotic for which several studies of patients suffering predominantly from negative symptoms have been published. In four such studies amisulpride was significantly more effective than placebo. Three small studies with conventional antipsychotics as comparators showed only a trend in favor of amisulpride in this regard. Amisulpride was associated with clearly lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics. CONCLUSIONS: These results cast some doubt on the notion that combined 5-HT2/D2 antagonism is the reason that the newer antipsychotic medications are effective for negative symptoms and have fewer extrapyramidal side effects.
Basic tastes and basic emotions: Basic problems and perspectives for a nonbasic solution
Authors: David Sander
Journal: Behavioral and Brain Sciences (2008)

Abstract Contemporary behavioral and brain scientists consider the existence of so-called basic emotions in a similar way to the one described by Erickson for so-called basic tastes. Commenting on this analogy, I argue that similar basic problems are encountered in both perspectives, and I suggest a potential nonbasic solution that is tested in emotion research (i.e., the appraisal model of emotion).
Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus
Authors: Binh An Diep, Steven R Gill, Richard F Chang, Tiffany HaiVan Phan, Jason H Chen, Matthew G Davidson, Felice Lin, Jessica Lin, Heather A Carleton, Emmanuel F Mongodin, George F Sensabaugh, Françoise Perdreau-Remington
Journal: The Lancet (2006)
Enhanced viability of fresh aortic homografts stored in nutrient medium
Authors: N. AL-JANABI, D. N. ROSS
Journal: Cardiovascular Research (1973)

A method of sterilization and preservation which protects structure and cell viability is described. Valves preserved in antibiotic balanced salt solution preserve viability and structure for a limited period of time. Replacement of the balanced salt solution by a nutrient medium has the effect of prolonging viability and increasing storage time.
STUDY OF EXPERIMENTAL PURPURA
Authors: E. M. Cowell
Journal: BMJ (1912)

This comparison is not satisfactory because of the uncertainty as to the true minimal lethal dose in any species.It will b seen that some of the more tolerant animals possess the power of destroying atropine, but that the rat is exceptional since it is very tolerant to atropine, but none of its tissues have any power to destroy the drug.Botlh Cloetta and Hefftershow that an animal may be tolerant to subcutaneous doses but show no tolerance to intravenous doses, this is only natural because, when given intravenously, the drug exerts its specific action before sufficient time has- elapsed for any appreciable destruction to occur.This rule probably holds good for most other drugs in which tolerance is observed, and with the development of intravenous therapy it may become of considerable practical importance.CONCLUSIONS.
Abnormal Glucuronidation of Zomepirac in Patients with Cirrhosis of the Liver
Authors: Felix Witassek, Johannes Bircher, Philipp Huguenin, Rudolf Preisig
Journal: Hepatology (1983)

The disposition of zomepirac was investigated in 18 patients with various liver diseases and in 10 healthy normal subjects in order to further test the hypothesis that glucuronidation of drugs may be spared in liver disease. Severity of the liver disease was assessed by the galactose elimination capacity. Following oral administration of zomepirac (200 mg), plasma and urinary drug concentrations were measured by high-pressure liquid chromatography. Urine was assayed before and after alkaline hydrolysis. The apparent oral clearance of zomepirac was 3.7 ± S.D. 1.2, 3.0 ± 0.8, and 1.8 ± 0.6 mlmin _1 kg _1 in normal subjects, patients with mild liver disease, and cases with cirrhosis, respectively. In patients with liver disease, the reduction in zomepirac clearance was significantly correlated with the abnormalities in galactose elimination capacity (r = 0.83, n = 18), suggesting that the functioning liver cell mass was the major determinant of the rate of zomepirac disposition. These results are not consistent with the original hypothesis but suggest that-in contrast to ether-glucuronidation-ester-glucuronidation may be abnormal in liver disease. Dosage adjustments may, therefore, be necessary in patients with cirrhosis of the liver.
Role of the X Chromosome in Cancer
Authors: C. J. Brown
Journal: JNCI Journal of the National Cancer Institute (1996)

NK-mediated cytolysis of blood-borne tumor cells.In addition, Giovarelli et al. (7) previously performed depletion experiments that implicated NK cells, CD8 + cells, and neutrophils in IL-10mediated tumor rejection.Thus, multiple antitumor and antimetastatic mechanisms are most likely involved in the IL-10-mediated suppression of tumor growth and metastasis.Although the studies discussed above were performed with animal tumor models, and it is likely that additional problems will be forthcoming in the translation of these results to clinical settings, the use of recombinant IL-10, a less toxic systemic bioregulator than many of the cytokines currently in clinical use, may bring about the development of an exciting new approach to the treatment of highly metastatic tumors.Since IL-10 appears to act at multiple steps of the malignant process, it might be a useful new tool in suppressing primary tumor growth as well as in inhibiting metastasis formation and the growth of micrometastatic disease.
Graft-<b><i>versus</i></b>-Tax Response in Adult T-Cell Leukemia Patients after Hematopoietic Stem Cell Transplantation
Authors: Nanae Harashima, Kiyoshi Kurihara, Atae Utsunomiya, Ryuji Tanosaki, Shino Hanabuchi, Masato Masuda, Takashi Ohashi, Fumiyo Fukui, Atsuhiko Hasegawa, Takao Masuda, Yoichi Takaue, Jun Okamura, Mari Kannagi
Journal: Cancer Research (2004)

Abstract Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) is characterized by poor prognosis after chemotherapy. Recent clinical trials have indicated, however, that allogeneic but not autologous hematopoietic stem cell transplantation (HSCT) for ATL can yield better clinical outcomes. In the present study, we investigated cellular immune responses of ATL patients who obtained complete remission after nonmyeloablative allogeneic peripheral blood HSCT from HLA-identical sibling donors. In the culture of peripheral blood mononuclear cells (PBMCs) from a post-HSCT but not pre-HSCT ATL patient, CD8+ CTLs proliferated vigorously in response to stimulation with autologous HTLV-I-infected T cells that had been established before HSCT in vitro. These CTLs contained a large number of monospecific CTL population directed to a HLA-A2-restricted HTLV-I Tax 11-19 epitope. The frequency of Tax 11-19-specific CD8+ CTLs in this patient markedly increased also in vivo after HSCT, as determined by staining with HLA-A2/Tax 11-19 tetramers. Similar clonal expansion of HTLV-I Tax-specific CTLs exclusively directed to a HLA-A24-restricted Tax 301-309 epitope was observed in the PBMCs from another ATL patient after HSCT from a HTLV-I-negative donor. Among four post-HSCT ATL patients tested, HTLV-I-specific CTLs were induced in the PBMC culture from three patients but not from the remaining one who had later recurrence of ATL. These observations suggested that reconstituted immunity against antigen presentation in ATL patients after HSCT resulted in strong and selective graft-versus-HTLV-I response, which might contribute to graft-versus-leukemia effects.
Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats
Authors: Tiebing Liang, Mark W Kimpel, Jeanette N McClintick, Ashley R Skillman, Kevin McCall, Howard J Edenberg, Lucinda G Carr
Journal: Genome biology (2010)

Selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ greatly in alcohol preference, in part due to a highly significant quantitative trait locus (QTL) on chromosome 4. Alcohol consumption scores of reciprocal chromosome 4 congenic strains NP.P and P.NP correlated with the introgressed interval. The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in five brain regions of alcohol-naïve inbred alcohol-preferring and P.NP congenic rats: amygdala, nucleus accumbens, hippocampus, caudate putamen, and frontal cortex.Within the QTL region, 104 cis-regulated probe sets were differentially expressed in more than one region, and an additional 53 were differentially expressed in a single region. Fewer trans-regulated probe sets were detected, and most differed in only one region. Analysis of the average expression values across the 5 brain regions yielded 141 differentially expressed cis-regulated probe sets and 206 trans-regulated probe sets. Comparing the present results from inbred alcohol-preferring vs. congenic P.NP rats to earlier results from the reciprocal congenic NP.P vs. inbred alcohol-nonpreferring rats demonstrated that 74 cis-regulated probe sets were differentially expressed in the same direction and with a consistent magnitude of difference in at least one brain region.Cis-regulated candidate genes for alcohol consumption that lie within the chromosome 4 QTL were identified and confirmed by consistent results in two independent experiments with reciprocal congenic rats. These genes are strong candidates for affecting alcohol preference in the inbred alcohol-preferring and inbred alcohol-nonpreferring rats.
Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition
Authors: T Fujisawa, H Endo, A Tomimoto, M Sugiyama, H Takahashi, S Saito, M Inamori, N Nakajima, M Watanabe, N Kubota, T Yamauchi, T Kadowaki, K Wada, H Nakagama, A Nakajima
Journal: Gut (2008)

<h3>Background and aims:</h3> The effect of adiponectin on colorectal carcinogenesis has been proposed but not fully investigated. We investigated the effect of adiponectin deficiency on the development of colorectal cancer. <h3>Methods:</h3> We generated three types of gene-deficient mice (adiponectin-deficient, adiponectin receptor 1-deficient, and adiponectin receptor 2-deficient) and investigated chemical-induced colon polyp formation and cell proliferation in colon epithelium. Western blot analysis was performed to elucidate the mechanism which affected colorectal carcinogenesis by adiponectin deficiency. <h3>Results:</h3> The numbers of colon polyps were significantly increased in adiponectin-deficient mice compared with wild-type mice fed a high-fat diet. However, no difference was observed between wild-type and adiponectin-deficient mice fed a basal diet. A significant increase in cell proliferative activity was also observed in the colonic epithelium of the adiponectin-deficient mice when compared with wild-type mice fed a high-fat diet; however, no difference was observed between wild-type and adiponectin-deficient mice fed a basal diet. Similarly, an increase in epithelial cell proliferation was observed in adiponectin receptor 1-deficient mice, but not in adiponectin receptor 2-deficient mice. Western blot analysis revealed activation of mammalian target of rapamycin, p70 S6 kinase, S6 protein and inactivation of AMP-activated protein kinase in the colon epithelium of adiponectin-deficient mice fed with high-fat diet. <h3>Conclusions:</h3> Adiponectin suppresses colonic epithelial proliferation via inhibition of the mammalian target of the rapamycin pathway under a high-fat diet, but not under a basal diet. These studies indicate a novel mechanism of suppression of colorectal carcinogenesis induced by a Western-style high-fat diet.
Forty Years of Work on End-of-Life Care — From Patients' Rights to Systemic Reform
Authors: Susan M. Wolf, Nancy Berlinger, Bruce Jennings
Journal: New England Journal of Medicine (2015)

Nearly 40 years of work to improve end-of-life care has revealed the difficulty of aligning care with patients' needs and preferences to ease the dying process. The problem must be attacked at all levels, from individual rights to relationships to systemic reform.
The First Positive: Computing Positive Predictive Value at the Extremes
Authors: James E. Smith, Robert L. Winkler, Dennis G. Fryback
Journal: Annals of Internal Medicine (2000)

Computing the positive predictive value (PPV) of a well-known test for a relatively common disease is a straightforward exercise. However, in the case of a new test for a rare disorder, the extreme numbers involved—the very low prevalence of the disorder and the lack of previous false-positive results—make it difficult to compute the PPV. As new genetic tests become available in the next decade, more and more clinicians will have to answer questions about PPVs in cases with extreme prevalence, sensitivity, and specificity. This paper presents some tools for thinking about these calculations. First, a standard PPV calculation with rough estimates of the prevalence, sensitivity, and specificity is reviewed. The "zero numerator" problem posed by not having seen any false-positive results is then discussed, and a Bayesian approach to this problem is described. The Bayesian approach requires specification of a prior distribution that describes the initial uncertainty about the false-positive rate. This prior distribution is updated as new evidence is obtained, and the updated expected false-positive rate is used to calculate PPVs. The Bayesian approach provides appropriate and defensible PPVs and can be used to estimate failure rates for other rare events as well.
Only a tenth of pregnant smokers are prescribed nicotine replacement therapy
Authors: A. O'Dowd
Journal: BMJ (2014)

Only a tenth of pregnant women who smoke are prescribed nicotine replacement therapy (NRT) and many opportunities for smoking cessation are lost, says a study published in the British Journal of General Practice on 1 September.

Researchers from the University of Nottingham set out to see how often NRT was recommended to expectant mothers. NRT became available on NHS prescription in 2001, and UK licensing arrangements were changed in December 2005 to allow its prescription to pregnant smokers. Previously, only two small …
Cost and Cost-effectiveness of an Early Invasive vs Conservative Strategy for the Treatment of Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction
Authors: Elizabeth M. Mahoney, Claudine T. Jurkovitz, Haitao Chu, Edmund R. Becker, Steven Culler, Andrzej S. Kosinski, Debbie H. Robertson, Charles Alexander, Soma Nag, John R. Cook, Laura A. Demopoulos, Peter M. DiBattiste, Christopher P. Cannon, William S. Weintraub
Journal: JAMA (2002)

ContextIn the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)–Thrombolysis in Myocardial Infarction (TIMI) 18 trial, patients with either unstable angina or non–ST-segment elevation myocardial infarction (UA/NSTEMI) treated with the platelet glycoprotein (Gp IIb/IIIa) inhibitor tirofiban had a significantly reduced rate of major cardiac events at 6 months with an early invasive vs a conservative strategy.ObjectiveTo examine total 6-month costs and long-term cost-effectiveness of an invasive vs a conservative strategy.DesignRandomized controlled trial including a priori economic end points.SettingHospitalization for UA/NSTEMI with 6-month follow-up period.PatientsA total of 2220 patients with UA/NSTEMI; economic data from 1722 patients at US–non-VA hospitals.InterventionEarly invasive strategy with routine catheterization and revascularization as appropriate vs a conservative strategy with catheterization performed only for recurrent ischemia or a positive stress test.Main Outcome MeasureTotal 6-month costs and incremental cost-effectiveness ratio.ResultsThe average initial hospitalization costs among those in the invasive strategy group were $15714 vs $14047 among those in the conservative stategy group, a difference of $1667 (95% confidence interval [CI], $387-3091). The in-hospital costs were offset significantly at the 6-month follow-up, with an average cost in the invasive group of $6098 vs $7180 in the conservative group, a difference of $1082 (95% CI, −$2051 to $76). The average total costs at 6 months, including productivity costs, for the invasive group was $21 813 vs $21 227 for the conservative group, a $586 difference (95% CI, −$1087 to $2486). The average 6-month costs excluding productivity costs in the invasive group was $19 780 vs $19 111 in the conservative group, a difference of $670, 95% CI; (−$1035 to $2321). Estimated cost per year of life gained for the invasive strategy, based on projected life expectancy, was $12739 for the base case, and ranged from $8371 to $25769, based on model assumptions.ConclusionsIn patients with UA/NSTEMI treated with the Gp IIb/IIIa inhibitor tirofiban, the clinical benefit of an early invasive strategy was achieved with a small increase in cost, yielding favorable projected estimates of cost per year of life gained. These results support the broader use of an early invasive strategy in these patients.
PWE-043 Polyp Detection Rate And Association With Midazolam Dose: Abstract PWE-043 Table 1
Authors: J Boyd, C Harper, L Lee, T Chapman, S Lanzon-Miller
Journal: Gut (2014)

Introduction Midazolam is a short acting benzodiazepine that is commonly used for sedation during colonoscopy. There is no standard dose of midazolam, however, British Society of Gastroenterology guidelines suggest a maximum of 5 mg with lower doses for elderly patients. Bowel preparation and endoscopist are factors that have been clearly associated with improved polyp detection during colonoscopy. Anecdotally, colonoscopy in patients who are extremely agitated limits views and leads to a more difficult procedure. Data exploring the relationship between midazolam dose and ability to detect colonic polyps is limited. Methods A retrospective cohort study of all patients who had undergone colonoscopy at Milton Keynes General hospital between January 2010 and December 2012. Patients were identified from the Endoscopy Unit database and their records were reviewed. Patient details, midazolam dose and diagnosis on colonoscopy were extracted into a standardised form. Results 6200 patients were included for analysis. The median age was 62 years and 49.4% were male. The mean midazolam dose was 1.9 mg. 16.2% of patients had a low dose of midazolam (<2 mg of midazolam), 74.5% a standard dose of midazolam (2 mg), and 9.3% a high dose (>2 mg). In the low dose cohort, the polyp detection rate (PDR) was 20.8%, in the standard dose, PDR was 26.9% and in the high dose PDR was 16.4%. Rates of agitation were significantly higher in patients who received higher doses of midazolam. When patients with poor bowel preparation were removed from the cohort (n = 5534), PDR was 21.4% in the low dose cohort vs. 27.1% in the standard dose. View this table: Abstract PWE-043 Table 1 Conclusion Adequate sedation of patients during endoscopy is important for patient comfort. In this study we demonstrate that a standard dose of midazolam is associated with a higher polyp detection rate than lower doses. Midazolam has been previously demonstrated to inhibit peristalsis in animal studies by preventing release of 5-HT and this is a probable mechanism for our findings. Limitations arise from the retrospective nature of this study, however, even following stratification of patients by adequacy of bowel prep, PDR remained lower in the low dose midazolam group. Appropriate patient selection for standard dose midazolam is important to avoid respiratory and cardiovascular compromise. Further confirmatory prospective studies are warranted. Disclosure of Interest None Declared.
Evolutionary History of the Third Chromosome Gene Arrangements of Drosophila pseudoobscura Inferred from Inversion Breakpoints
Authors: A. G. Wallace, D. Detweiler, S. W. Schaeffer
Journal: Molecular Biology and Evolution (2011)

The third chromosome of Drosophila pseudoobscura is polymorphic for numerous gene arrangements that form classical clines in North America. The polytene salivary chromosomes isolated from natural populations revealed changes in gene order that allowed the different gene arrangements to be linked together by paracentric inversions representing one of the first cases where genetic data were used to construct a phylogeny. Although the inversion phylogeny can be used to determine the relationships among the gene arrangements, the cytogenetic data are unable to infer the ancestral arrangement or the age of the different chromosome types. These are both important properties if one is to infer the evolutionary forces responsible for the spread and maintenance of the chromosomes. Here, we employ the nucleotide sequences of 18 regions distributed across the third chromosome in 80–100 D. pseudoobscura strains to test whether five gene arrangements are of unique or multiple origin, what the ancestral arrangement was, and what are the ages of the different arrangements. Each strain carried one of six commonly found gene arrangements and the sequences were used to infer their evolutionary relationships. Breakpoint regions in the center of the chromosome supported monophyly of the gene arrangements, whereas regions at the ends of the chromosome gave phylogenies that provided less support for monophyly of the chromosomes either because the individual markers did not have enough phylogenetically informative sites or genetic exchange scrambled information among the gene arrangements. A data set where the genetic markers were concatenated strongly supported a unique origin of the different gene arrangements. The inversion polymorphism of D. pseudoobscura is estimated to be about a million years old. We have also shown that the generated phylogeny is consistent with the cytological phylogeny of this species. In addition, the data presented here support hypothetical as the ancestral arrangement. One of the youngest arrangements, Arrowhead, has one of the highest population frequencies suggesting that selection has been responsible for its rapid increase.