tbuckley/cabot-search huggingface dataset:
Effect Size of Symptom Status in Withdrawal of Typical Antipsychotics and Subsequent Clozapine Treatment in Patients With Treatment-Resistant Schizophrenia
Authors: David Pickar, John J. Bartko
Journal: American Journal of Psychiatry (2003)

In light of the efficacy of newer antipsychotic agents and the possibility that drug withdrawal may negatively affect subsequent drug response, concern has arisen that the use of placebo in schizophrenia research may be unethical. This study examines the effect size of symptom exacerbation during drug washout with placebo and the effects of drug washout on the efficacy of subsequent drug treatment.Fifty patients with treatment-resistant schizophrenia hospitalized on a research unit participated in a double-blind longitudinal study of the effects of drug washout after chronic treatment with a typical antipsychotic and before prospective treatment with clozapine. Brief Psychiatric Rating Scale (BPRS) scores were analyzed to examine drug effects and effect sizes for baseline treatment with a typical antipsychotic (>6 months treatment), drug washout with placebo (mean=34 days), early treatment with clozapine (mean=42 days, mean dose=345.0 mg/day), and optimal clozapine treatment (mean=83 days, mean dose=450.5 mg/day).Patients' BPRS total, positive, and negative symptom scores significantly increased during placebo washout, compared with baseline treatment, and significantly decreased with administration of clozapine, compared with placebo washout and baseline treatment. However, 30% of patients showed some symptom improvement during placebo washout. The effect sizes for the BPRS total score were 0.63 for baseline treatment versus placebo washout, 1.10 for optimal clozapine treatment versus placebo washout, and 0.82 for optimal clozapine treatment versus baseline treatment.Symptom exacerbation induced by drug withdrawal in patients with treatment-resistant schizophrenia did not impede subsequent responsiveness to clozapine. The effect size for clozapine, compared with typical antipsychotics, suggests that the drug-washout longitudinal design is useful for establishing a drug-free baseline and for investigating drug response, while requiring relatively few subjects.
The Faeces of Children and Adults
Authors: A. M O'Donnell
Journal: BMJ (2009)

Though Alfred Kinsey is best known for his works on sexual behaviour, the late Stephen Jay Gould admired him most for his earlier work, a definitive study of gall forming wasps of the genus Cynips . Gould argued that Kinsey’s rigorous methods and scrupulous attention to detail lent him impeccable scholastic credentials. Harvard University’s only copy of Kinsey’s great wasp monograph contains this graffito: “Why don’t you write about something more interesting, Al?” As an undergraduate I was disappointed to find that Kinsey wrote about sexuality with every bit as much academic detachment as he had no doubt applied to his wasps.

Kinsey was not alone in devoting an enormous amount of scholarly …
Evaluation of pulsed dose oxygen delivery during exercise in patients with severe chronic obstructive pulmonary disease
Authors: R Garrod, J C Bestall, E Paul, J A Wedzicha
Journal: Thorax (1999)

Oxygen conserving devices may lead to substantial increases in the duration of oxygen provided. A study was undertaken to compare the performance of a pulsed dose oxygen delivery (PDOD) system with continuous flow oxygen or air during a maximal walking test.Fourteen patients with chronic obstructive pulmonary disease (COPD) and arterial oxygen desaturation on exercise (mean (SD) forced expiratory volume in one second (FEV1) 0.83 (0.28) 1, arterial oxygen pressure (PaO2) 8.38 (1.24) kPa, arterial carbon dioxide pressure (PaCO2) 5.95 (0.86) kPa) were randomised to perform a walking test using air administered via a cylinder or continuous flow oxygen at 2 l/min or by a PDOD system.There was no significant difference in the mean arterial oxygen saturation (SaO2) using the PDOD system or with continuous flow oxygen (p = 0.33). Patients showed greatest desaturation whilst walking with the air cylinder (SaO2 79.2 (8.59)%) which was significantly different from the desaturation with both continuous flow oxygen (87.6 (5.85)%, p = 0.001) and PDOD (85.6 (7.36)%, p = 0.004). There was no significant difference between the distance walked using oxygen delivered at 2 l/min by continuous flow or via the PDOD (p = 0.72; CI 0.34 to 1.08). The mean (SD) distance walked on continuous flow oxygen (203.6 (106.1) m) and PDOD (207.9 (109.8) m) was significantly greater than the distance walked with the air cylinder (188.6 (110.02) m); (1.12 fold increase in distance, CI 1.01 to 1.23, p = 0.02, and 1.14 fold increase in distance, CI 1.01 to 1.28, p = 0.03, respectively).These findings suggest that the pulsed dose oxygen conserving device was as effective as continuous flow oxygen in maintaining arterial oxygen saturation and that the use of this device was associated with similar improvements in exercise tolerance to patients taking continuous flow oxygen therapy.
Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality
Authors: Jason H.Y. Wu, Rozenn N. Lemaitre, Irena B. King, Xiaoling Song, Bruce M. Psaty, David S. Siscovick, Dariush Mozaffarian
Journal: Circulation (2014)

Background— Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort. Methods and Results— Among 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992–2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 ( P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32–0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70–1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality ( P =0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both. Conclusions— High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.
Liver stiffness after meal intake at different stages of fibrotic evolution
Authors: Ingmar Mederacke, Matthias J. Bahr
Journal: Hepatology (2013)

With great interest, we read the study by Arena et al.1 showing an increase in liver stiffness 15 to 45 minutes after the intake of a standardized liquid meal lowering the accuracy of fibrosis assessment by transient elastography (TE). These results are in line with another study using liquid meals2 and our previous findings obtained under "real-life" conditions using standardized solid meals.3 Similarly, liver stiffness as assessed by acoustic radiation force impulse (ARFI) elastography is influenced by food intake.4 In patients with cirrhosis, Berzigotti et al.2 showed that increased hepatic arterial but not portal blood flow is responsible for the increase of liver stiffness after food intake. Unfortunately, the initial studies on liver stiffness determination using TE did not explicitly pay regard to currently known confounding factors (Table 1). TE appeared to be reasonably accurate to distinguish cirrhosis from precirrhotic stages, and severe fibrosis from early fibrosis.5 However, early fibrosis stages exhibited considerable overlap in liver stiffness measurement. Final assessment was hampered by the limitations of liver biopsy as the reference method.6 Although knowledge of confounding factors of TE might raise speculations that "optimized" TE could even outperform histology, we should not forget that liver stiffness indicates hepatic collagen content rather than a histological picture and that there is significant overlap of hepatic collagen content in the different stages of fibrosis.7, 8 Thus, taking hepatic collagen content instead of histologically defined stages might improve revelation of the full performance of TE if measurement is performed under standardized conditions with accepted reliability criteria.9 However, the ultimate test will be the prediction of clinically relevant endpoints. Ingmar Mederacke, M.D.1 Matthias J. Bahr, M.D.2 1Hannover Medical School Gastroenterology, Hepatology and Endocrinology Hannover, Germany 2Sana Kliniken Luebeck Luebeck, Germany
A Population-Based Validation of the American Joint Committee on Cancer Melanoma Staging System
Authors: Phyllis A. Gimotty, Jeffrey Botbyl, Seng-jaw Soong, DuPont Guerry
Journal: Journal of Clinical Oncology (2005)

Purpose A major revision of the American Joint Committee on Cancer (AJCC) stages for melanoma was implemented in 2002 after its validation in multinational cohorts including patients from cancer centers and cooperative groups. This staging system has not been validated in a US population-based cohort. Patients and Methods We used 41,417 patients with primary invasive cutaneous melanoma diagnosed between 1988 and 2001 from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registry to validate the revised AJCC staging system. Survival rates computed from stage-specific Kaplan-Meier curves (time to melanoma-specific death) were compared with the survival rates from 17,600 patients in the original AJCC validation study. Results In the SEER cohort, 65% of reported melanomas were ≤ 1.00 mm in thickness and 8.7% were more than 4.00 mm compared with 39% and 10% in the AJCC cohort (P &lt; .001), respectively. AJCC stages were able to discriminate among SEER patient groups with different prognosis. However, SEER survival rates were significantly higher than those in the AJCC study and notably so in patients with T1a lesions (≤ 1 mm without ulceration). This population-specific effect remained significant after controlling for lesion thickness in all substages except stage IIA. Conclusion Although this national population-based study validates the most recent revision of AJCC stages for melanoma, it emphasizes that survival rates are population specific and found them to be generally higher for SEER compared with AJCC patients. Population-specific survival rates should be used in study designs and decisions about patient-specific interventions.
Unicellular Ca2+ Signaling 'Toolkit' at the Origin of Metazoa
Authors: X. Cai
Journal: Molecular Biology and Evolution (2008)

Ca2+ signaling pathways control many physiological processes in almost all types of animal cells such as fertilization, muscle contraction, hormone release, and learning and memory. Each animal cell type expresses a unique group of molecules from the Ca2+ signaling 'toolkit' to control spatiotemporal patterns of Ca2+ signaling. It is generally believed that the complex Ca2+ signaling 'toolkit' has arisen from the ancestral multicellular organisms to fit unique physiological roles of specialized cell types. Here, we demonstrate for the first time the presence of an extensive Ca2+ signaling 'toolkit' in the unicellular choanoflagellate Monosiga brevicollis. Choanoflagellates possess homologues of various types of animal plasma membrane Ca2+ channels including the store-operated channel, ligand-operated channels, voltage-operated channels, second messenger-operated channels, and 5 out of 6 animal transient receptor potential channel families. Choanoflagellates also contain homologues of inositol 1,4,5-trisphosphate receptors. Furthermore, choanoflagellates master a complete set of Ca2+ removal systems including plasma membrane and sarco/endoplasmic reticulum Ca2+ ATPases and homologues of 3 animal cation/Ca2+ exchanger families. Therefore, a complex Ca2+ signaling 'toolkit' might have evolved before the emergence of multicellular animals.
Generation of functional human hepatic endoderm from human induced pluripotent stem cells
Authors: Gareth J. Sullivan, David C. Hay, In-Hyun Park, Judy Fletcher, Zara Hannoun, Catherine M. Payne, Donna Dalgetty, James R. Black, James A. Ross, Kay Samuel, Gang Wang, George Q. Daley, Je-Hyuk Lee, George M. Church, Stuart J. Forbes, John P. Iredale, Ian Wilmut
Journal: Hepatology (2009)

With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled with direct differentiation to a defined lineage, such as hepatic endoderm (HE), iPSCs would revolutionize the way we study human liver biology and generate efficient “off the shelf” models of human liver disease. Here, we show the “proof of concept” that iPSC lines representing both male and female sexes and two ethnic origins can be differentiated to HE at efficiencies of between 70%–90%, using a method mimicking physiological relevant condition. The iPSC-derived HE exhibited hepatic morphology and expressed the hepatic markers albumin and E-cadherin, as assessed by immunohistochemistry. They also expressed alpha-fetoprotein, hepatocyte nuclear factor-4a, and a metabolic marker, cytochrome P450 7A1 (Cyp7A1), demonstrating a definitive endodermal lineage differentiation. Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin, and alpha-fetoprotein, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and CYP3A4 metabolism, which is essential for drug and toxicology testing. Conclusion: This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSCs that exhibits key attributes of hepatocytes, and the potential application of iPSC-derived HE in studying human liver biology. In particular, iPSCs from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionize predictive drug toxicology assays and allow the creation of in vitro hepatic disease models. (Hepatology 2009.)
IMMUNOLOGICAL AND CHEMICAL INVESTIGATIONS OF VACCINE VIRUS
Authors: Robert F. Parker, Thomas M. Rivers
Journal: The Journal of Experimental Medicine (1937)

A method has been described by which a stable, serologically active substance has been isolated in a relatively pure state from tissues infected with vaccine virus. It has the characteristics of an alcohol-soluble protein which is not precipitated by boiling in a neutral aqueous solution. In a dilution of 1:640,000 it gives a precipitate when mixed with a serum containing antibodies against Craigie's S antigen of vaccine virus, but no visible reaction occurs when it is mixed with serum depleted of S antibodies by means of absorption.
Prognostic Impact of Aortic Stiffness in High-Risk Type 2 Diabetic Patients
Authors: Claudia R.L. Cardoso, Marcel T. Ferreira, Nathalie C. Leite, Gil F. Salles
Journal: Diabetes Care (2013)

The prognostic importance of carotid-femoral pulse wave velocity (PWV), the gold standard measure of aortic stiffness, has been scarcely investigated in type 2 diabetes and never after full adjustment for potential confounders. The aim was to evaluate the prognostic impact of carotid-femoral PWV for cardiovascular morbidity and all-cause mortality in a cohort of 565 high-risk type 2 diabetic patients.Clinical, laboratory, ambulatory blood pressure (BP) monitoring, and carotid-femoral PWV data were obtained at baseline. The primary end points were a composite of fatal and nonfatal cardiovascular events and all-cause mortality. Multiple Cox survival analysis was used to assess the associations between carotid-femoral PWV, as a continuous variable and categorized at 10 m/s, and the end points.After a median follow-up of 5.75 years, 88 total cardiovascular events and 72 all-cause deaths occurred. After adjustments for potential cardiovascular risk factors, including micro- and macrovascular complications, ambulatory BP, and metabolic control, carotid-femoral PWV was predictive of the composite end point but not of all-cause mortality both as a continuous variable (hazard ratio 1.13 [95% CI 1.03-1.23], P = 0.009 for increments of 1 m/s) and as categorized at 10 m/s (1.92 [1.16-3.18], P = 0.012). On sensitivity analysis, carotid-femoral PWV was a better predictor of cardiovascular events in younger patients (<65 years), in those with microvascular complications, and in those with poorer glycemic control (HbA1c ≥7.5% [58.5 mmol/mol]).Carotid-femoral PWV provides cardiovascular risk prediction independent of standard risk factors, glycemic control, and ambulatory BPs and improves cardiovascular risk stratification in high-risk type 2 diabetes.
Efficacy of systemic administration of SDF-1 in a model of vascular insufficiency: Support for an endothelium-dependent mechanism
Authors: A CARR, B HOWARD, H YANG, E EBYWILKENS, P LOOS, A VARBANOV, A QU, J DEMUTH, M DAVIS, A PROIA
Journal: Cardiovascular Research (2006)

Studies have reported that administration of stromal cell-derived factor-1 (SDF-1), the ligand for the G-protein coupled receptor CXCR4, increased collateral blood flow in a mouse model of vascular insufficiency via recruitment of endothelial precursor cells (EPC). The present study investigated the contribution of mature endothelial cells in the actions of SDF-1.The regulation of SDF-1 and CXCR4 was examined in the rat cornea cauterization (CC) and aortic ring (AR) model. The functional significance of the SDF-1/CXCR4 pathway was explored in cultured endothelial cells, the AR model, and on collateral blood flow in a rat model of vascular insufficiency.In the present study, the CXCR4 transcript was dramatically upregulated in the rat CC and AR explants, systems containing and lacking bone marrow-derived EPCs, respectively. Addition of AMD3100, a selective CXCR4 antagonist, had no effect on vessel growth in the AR alone, but completely inhibited SDF-1 mediated increases in vascular sprouting. In cultured endothelial cells, SDF-1 alone or in combination with vascular endothelial growth factor (VEGF) significantly enhanced cell survival and migration. Finally, systemic administration of SDF-1 in a rat model of arterial insufficiency enhanced collateral blood flow above vehicle control and equal to that of VEGF after 2 weeks of treatment.These studies support activation of the SDF-1/CXCR4 axis as a means to promote blood vessel growth and enhance collateral blood flow, at least in part, via direct effects on vascular endothelial cells.
Comparative Meta-analysis of Prognostic Gene Signatures for Late-Stage Ovarian Cancer
Authors: Levi Waldron, Benjamin Haibe-Kains, Aedín C. Culhane, Markus Riester, Jie Ding, Xin Victoria Wang, Mahnaz Ahmadifar, Svitlana Tyekucheva, Christoph Bernau, Thomas Risch, Benjamin Frederick Ganzfried, Curtis Huttenhower, Michael Birrer, Giovanni Parmigiani
Journal: JNCI Journal of the National Cancer Institute (2014)

Ovarian cancer is the fifth most common cause of cancer deaths in women in the United States. Numerous gene signatures of patient prognosis have been proposed, but diverse data and methods make these difficult to compare or use in a clinically meaningful way. We sought to identify successful published prognostic gene signatures through systematic validation using public data.A systematic review identified 14 prognostic models for late-stage ovarian cancer. For each, we evaluated its 1) reimplementation as described by the original study, 2) performance for prognosis of overall survival in independent data, and 3) performance compared with random gene signatures. We compared and ranked models by validation in 10 published datasets comprising 1251 primarily high-grade, late-stage serous ovarian cancer patients. All tests of statistical significance were two-sided.Twelve published models had 95% confidence intervals of the C-index that did not include the null value of 0.5; eight outperformed 97.5% of signatures including the same number of randomly selected genes and trained on the same data. The four top-ranked models achieved overall validation C-indices of 0.56 to 0.60 and shared anticorrelation with expression of immune response pathways. Most models demonstrated lower accuracy in new datasets than in validation sets presented in their publication.This analysis provides definitive support for a handful of prognostic models but also confirms that these require improvement to be of clinical value. This work addresses outstanding controversies in the ovarian cancer literature and provides a reproducible framework for meta-analytic evaluation of gene signatures.
PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis
Authors: Aleksandar Dakic, Donald Metcalf, Ladina Di Rago, Sandra Mifsud, Li Wu, Stephen L. Nutt
Journal: The Journal of Experimental Medicine (2005)

Although the transcription factor PU.1 is essential for fetal lymphomyelopoiesis, we unexpectedly found that elimination of the gene in adult mice allowed disturbed hematopoiesis, dominated by granulocyte production. Impaired production of lymphocytes was evident in PU.1-deficient bone marrow (BM), but myelocytes and clonogenic granulocytic progenitors that are responsive to granulocyte colony-stimulating factor or interleukin-3 increased dramatically. No identifiable common lymphoid or myeloid progenitor populations were discernable by flow cytometry; however, clonogenic assays suggested an overall increased frequency of blast colony-forming cells and BM chimeras revealed existence of long-term self-renewing PU.1-deficient cells that required PU.1 for lymphoid, but not granulocyte, generation. PU.1 deletion in granulocyte-macrophage progenitors, but not in common myeloid progenitors, resulted in excess granulocyte production; this suggested specific roles of PU.1 at different stages of myeloid development. These findings emphasize the distinct nature of adult hematopoiesis and reveal that PU.1 regulates the specification of the multipotent lymphoid and myeloid compartments and restrains, rather than promotes, granulopoiesis.