tbuckley/cabot-search huggingface dataset:
Can Phase III Trial Results of Antidepressant Medications Be Generalized to Clinical Practice? A STAR*D Report
Authors: Stephen R. Wisniewski, A. John Rush, Andrew A. Nierenberg, Bradley N. Gaynes, Diane Warden, James F. Luther, Patrick J. McGrath, Philip W. Lavori, Michael E. Thase, Maurizio Fava, Madhukar H. Trivedi
Journal: American Journal of Psychiatry (2009)

Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project--which used broad inclusion and minimal exclusion criteria--to evaluate whether phase III clinical trials recruit representative depressed outpatients.Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment.The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences.Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events.
Primary osteoathrosis of the hip and Heberden's nodes.
Authors: J S Marks, I M Stewart, K Hardinge
Journal: Annals of the Rheumatic Diseases (1979)

One hundred patients with primary osteoarthrosis of the hip were examined for evidence of generalised arthrosis associated with Heberden's nodes, and in addition their hips were graded by the radiographic pattern of loss of joint space. Twenty-nine patients had bilateral concentric loss of joint space, and 18 in this group had Heberden's nodes. None of the 17 patients with bilateral upper pole changes had Heberden's nodes, and only 7 of the 31 patients with unilateral upper pole changes had Heberden's nodes. None of the 6 patients with medial loss of joint space had Heberden's nodes. This study has shown an association between Heberden's nodes had primary osteoarthrosis of the hip where this is characterised by concentric loss of joint space. The association is most marked where hip changes are bilateral, suggesting that hip involvement in generalised osteoarthrosis is part of a generalised disorder with possible genetic or biochemical abnormalities.
Pulmonary vascular lesions in the toxic oil syndrome in Spain.
Authors: P Fernandez-Segoviano, A Esteban, R Martinez-Cabruja
Journal: Thorax (1983)

A histological study was made of pulmonary arteries at the necropsies of nine patients who died after the ingestion of denatured rapeseed oil during the epidemic which occurred in Spain in May 1981. Lesions found in the elastic pulmonary arteries were characterised by pronounced intimal proliferation of an oedematous nature, accumulation of large vacuolated cells within the media, and loss of vascular smooth muscle. In muscular pulmonary arteries there was pronounced medial hypertrophy and intimal proliferation, which was so severe in one case that it completely occluded the arterial lumen. Foamy cells were found in the intima. Muscularisation was seen in the walls of pulmonary arterioles.
Microvascular Diabetes Complications in Wolfram Syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness [DIDMOAD])
Authors: Aline Cano, Laurent Molines, René Valéro, Gilbert Simonin, Véronique Paquis-Flucklinger, Bernard Vialettes
Journal: Diabetes Care (2007)

Some previous studies suggested that patients suffering from Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) might be relatively preserved from diabetic retinopathy and nephropathy. However, these data were not conclusive because either observations were only anecdotic or did not match with control type 1 diabetic populations.A group of 26 French diabetic patients with DIDMOAD was compared with a population of 52 patients with common type 1 diabetes matched for age at diabetes diagnosis (8.62 +/- 1.84 vs. 8.27 +/- 1.30 years; P = NS) and diabetes duration (12.88 +/- 1.58 vs. 12.87 +/- 1.13 years; P = NS) to study the quality of glycemic control and the incidence of microvascular complications.Glycemic control was significantly better in the DIDMOAD group than in the type 1 diabetic group (A1C: 7.72 +/- 0.21 vs. 8.99 +/- 0.25%, respectively; P = 0.002), with significant lower daily insulin requirements (0.71 +/- 0.07 vs. 0.88 +/- 0.04 UI x kg(-1) x day(-1), respectively; P = 0.0325). The prevalence of microvascular complications in the DIDMOAD group was half that observed in the type 1 diabetic group, but the difference was not significant.Diabetes in DIDMOAD patients is more easily controlled despite the presence of other handicaps. This better glycemic control could explain the trend to decreased microvascular diabetes complications observed in previous studies.
Combination of inhaled corticosteroids and long acting beta two agonists improve lung clearance index (LCI) in preschoolers with cystic fibrosis
Authors: Elpis Hatziagorou, Vasiliki Avramidou, Sophia Botskariova, Fotis Kirvassilis, John Tsanakas
Journal: European Respiratory Journal (2011)

Background: Lung function testing is a means of monitoring progression of lung disease in cystic fibrosis (CF). Studies investigating Multiple Breath Washout (MBW) measurements in children older than 2 years with CF have shown lung clearance index (LCI) to be significantly greater in CF than in a reference population. Bronchodilators are used in CF to facilitate airway clearance and provide protection against potential bronchoconstrictors, ie DNase, hypertonic saline and inhaled antibiotics.

Aim: 1). To compare LCI values among CF preschoolers, and healthy controls, 2). To compare LCI with atopy and 3). To assess the effect of the combination of inhaled steroids with long-acting beta two agonists (LABA), among CF preschoolers, by changes in LCI values.

Method: Twenty-eight children with CF, and recurrent cough and wheeze, aged 2 to 5 years and 27 healthy controls performed MBW measurements. Children with CF received prophylaxis with inhaled corticosteroids + LABA for six months. History of atopy was recorded and total serum IgE was measured. The primary endpoint was change of LCI values.

Results: Children with CF had significantly higher LCI compared to controls (mean difference [95% CI] 2.6 [1.8, 3.7], p<0.001). LCI values were not correlated with history of atopy (p=0.128), or total IgE (p= 0.318, R=0.247). Six months after treatment with combination of inhaled steroids + LABA, LCI was reduced significantly (mean difference [95% CI]: -1.19 [-3.6, -1.01], p: 0.038).

Conclusions: Combination of inhaled steroids + LABA seem to improve lung function among preschooler with CF, as measured by LCI.
Synchronous Tumor With Diffuse Large B-Cell Lymphoma and Ameboma
Authors: Mari Takashima, Tsunayuki Kakimoto, Hideaki Saito, Sayaka Misaki, Yoshiki Onishi, Tsutomu Kasugai, Keigo Akuta, Hidenori Kasahara, Kazutaka Yamamoto, Yukiko Doi, Hidetoshi Ujiie, Hiroyuki Sugahara, Yoshihiko Hoshida, Hiroto Sakoda
Journal: Journal of Clinical Oncology (2011)

A 73-year-old Japanese man was admitted to the hospital in June 2010.He complained of general fatigue, high fever, weight loss of 10 kg in 2 months, and right lower abdominal pain without diarrhea that had been ongoing for several months before admission.He denied alcohol abuse or risk factors for HIV.He had type 2 diabetes mellitus that was controlled by insulin, as well as hypertension, previous myocardial infarction, and current mild dementia.He had traveled extensively in developing countries about 30 years before.Tests for HIV and hepatitis B and C viruses were negative.The patient's WBC count was 11.0 ϫ 10 9 /L; 7% were eosinophils.No abnormal cells were seen.His hemoglobin level was 12.7 g/dL and the platelet count was 37.2 ϫ 10 9 /L.The serum C-reactive protein level was 5.34 mg/dL, lactate dehydrogenase was 756 IU/L, and the level of soluble interleukin-2 receptor in serum was 19,100 U/mL.The serum antibody titer of Epstein-Barr virus revealed a postinfection pattern.Other liver and renal function tests were close to normal.A computed tomography scan revealed enlargement of the left cervical lymph nodes, left pleural effusion, and multiple small lymphadenopathies in the mediastinum and abdomen, but there was no evidence of abscess or enlargement of the liver or spleen.Tumor formation was detected and found to be affecting the cecum and ascending colon, and a total colonoscopy was performed immediately; it revealed a large tumor that was accompanied by multiple ulcer lesions (Fig 1A, arrow; Fig 1B).Microscopically, the mass contained large CD20-positive abnormal lymphoid cells admixed with and/or adjacent to amebic trophozoites (Figs 2A and2B).The patient was diagnosed with diffuse large B-cell lymphoma (DL-BCL) superimposed on amebiasis.Subsequent testing for anti-Entamoeba histolytica (E.histolytica) antibody was positive, although
Binding of Myosin Binding Protein-C to Myosin Subfragment S2 Affects Contractility Independent of a Tether Mechanism
Authors: Samantha P. Harris, Elena Rostkova, Mathias Gautel, Richard L. Moss
Journal: Circulation Research (2004)

Mutations in the cardiac myosin binding protein-C gene (cMyBP-C) are among the most prevalent causes of inherited hypertrophic cardiomyopathy. Although most cMyBP-C mutations cause reading frameshifts that are predicted to encode truncated peptides, it is not known if or how expression of these peptides causes disease. One possibility is that because the N-terminus contains a unique binding site for the S2 subfragment of myosin, shortened cMyBP-C peptides could directly affect myosin contraction by binding to S2. To test this hypothesis, we compared the effects of a C1C2 protein containing the myosin S2 binding site on contractile properties in permeablized myocytes from wild-type and cMyBP-C knockout mice. In wild-type myocytes, the C1C2 protein reversibly increased myofilament Ca 2+ sensitivity of tension, but had no effect on resting tension. Identical results were observed in cMyBP-C knockout myocytes where C1C2 increased Ca 2+ sensitivity of tension with the half-maximal response elicited at ≈5 μmol/L C1C2. Maximum force was not affected by C1C2. However, phosphorylation of C1C2 by cAMP-dependent protein kinase reduced its ability to increase Ca 2+ sensitivity. These results demonstrate that binding of the C1C2 peptide to S2 alone is sufficient to affect myosin contractile function and suggest that regulated binding of cMyBP-C to myosin S2 by phosphorylation directly influences myofilament Ca 2+ sensitivity.
Obesity and Overfeeding Affecting Both Tumor and Systemic Metabolism Activates the Progesterone Receptor to Contribute to Postmenopausal Breast Cancer
Authors: Erin D. Giles, Elizabeth A. Wellberg, David P. Astling, Steven M. Anderson, Ann D. Thor, Sonali Jindal, Aik-Choon Tan, Pepper S. Schedin, Paul S. MacLean
Journal: Cancer Research (2012)

Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight gain may provide a life cycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake, and proliferation markers. Treatment with the antidiabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast cancer.
Relation between income inequality and mortality: empirical demonstration Diminishing returns to aggregate level studies Two pathways, but how much do they diverge?
Authors: M. Wolfson, G. Kaplan, J. Lynch, N. Ross, E. Backlund, H. Gravelle, R. G Wilkinson
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective:</b> To assess the extent to which observed associations at population level between income inequality and mortality are statistical artefacts. <b>Design:</b> Indirect "what if" simulation by using observed risks of mortality at individual level as a function of income to construct hypothetical state level mortality specific for age and sex as if the statistical artefact argument were 100% correct. <b>Setting:</b> Data from the 1990 census for the 50 US states plus Washington, DC, were used for population distributions by age, sex, state, and income range; data disaggregated by age, sex, and state from the Centers for Disease Control and Prevention were used for mortality; and regressions from the national longitudinal mortality study were used for the individual level relation between income and risk of mortality. <b>Results:</b> Hypothetical mortality, while correlated with inequality (as implied by the logic of the statistical artefact argument), showed a weaker association with states9 levels of income inequality than the observed mortality. <b>Conclusions:</b> The observed associations in the United States at the state level between income inequality and mortality cannot be entirely or substantially explained as statistical artefacts of an underlying individual level relation between income and mortality. There remains an important association between income inequality and mortality at state level over and above anything that could be accounted for by any statistical artefact. This result reinforces the need to consider a broad range of factors, including the social milieu, as fundamental determinants of health. <h3>Key messages</h3> Evidence is accumulating that living in a society with higher inequality in income predisposes its members to higher mortality; at the same time, there is widespread evidence that, for individuals, higher income is protective This individual level relation could "explain" the former societal level relation The strength of observed levels of association between income inequality and mortality, however, may go well beyond what can be explained as a statistical artefact of an individual level relation between income and mortality The empirical analysis reported here, based on 1990 data for US states, suggests that the association between income inequality and mortality is considerably stronger than can be accounted for by any statistical artefact Research underpinning public health policy should therefore take a broad view of the importance of the social milieu as a fundamental determinant of health
Chronic itch development in sensory neurons requires BRAF signaling pathways
Authors: Zhong-Qiu Zhao, Fu-Quan Huo, Joseph Jeffry, Lori Hampton, Shadmehr Demehri, Seungil Kim, Xian-Yu Liu, Devin M. Barry, Li Wan, Zhong-Chun Liu, Hui Li, Ahu Turkoz, Kaijie Ma, Lynn A. Cornelius, Raphael Kopan, James F. Battey, Jian Zhong, Zhou-Feng Chen
Journal: Journal of Clinical Investigation (2013)

Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAFNav1.8 mice). We found that constitutive BRAF pathway activation in BRAFNav1.8 mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAFNav1.8 mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excitability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for maintaining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation.
Effect of cocoa supplementation on athlete's blood coagulation factors after an incremental exhaustive exercise
Authors: Mehdey Soleimani, Fariba Aghaei, Sirvan Atashak, Ayub Mehdivand
Journal: British Journal of Sports Medicine (2010)

Cardiovascular disease (CVD) is the main indicator of cardiac arrests and mortality (Willoughby and Holmes 2002).Disruption of the normal rheological properties of blood is considered an independent risk factor for CVD (Douglas and Hein 1998). Platelets play an important role in the pathophysiology of CVD and its associated risk factors (El-sayed 2005). In addition, current evidence implicates fibrinogen (Fib) in the pathogenesis of atherosclerotic vascular diseases and as an independent cardiovascular risk factor (Lars 2003). Also, haemoglobin (Hb) and haematocrit (Htc) factors have the key and important role in whole blood viscosity (El-sayed 2005). Habitual, regular physical activity has been postulated to reduce the incidence of CVD (Johansson and Sundquist 1999). However, high intensity exercise may precipitate acute cardiac events and sudden cardiac death through an occlusive platelet-rich thrombus (Bartsch 1999). However, it has been shown that flavanol-rich foods, such as cocoa promote health and attenuate, or delay the onset of CVD (Murphy 2003). The present study designed to evaluate if cocoa attenuate the effect of an incremental exhaustive exercise on platelet count (Plt), Fib, Hb and Htc. Twenty athlete (football player) male (mean age: 22±1.3 years; body mass: 71.1±4.5 kg; BF%: 22.5±1.2; VO 2 max: 54.6±2.4 ml/kg/min) provided written informed consent. Bruce exercise test was performed as an incremental exhaustive protocol on two occasions, 1 week apart. In a double-blind design, each participant received either a volume of cocoa solution or flavoured solution based on his body mass before exercise trial. Venous blood samples were collected 2-h prior to exercise (baseline), pre-, post- and 1-h after completion of each trial. Differences were examined using a two-factor analysis of variance with repeated measures as appropriate. Platelet counts, Fib, Hb and Htc decreased significantly (p&lt;0.001) after exercise compared with before exercise in cocoa trials (Plt: from 280.30±31.20 to 206.00±21.13; Fib: from 231±2.20 to 200±1.13; Hb: from 16.80±0.58 to 14.36±1.22; Htc: from 49.60±1.97 to 44.36±2.42). Fib were unaffected by condition and did not differ at any time after exercise protocol (p&gt;0.05). This study showed that increased platelet activity in response to an incremental exercise could be decreased with oral supplementation of cocoa that is line with Murphy et al (2003) and Rein et al (2000). In addition, very little is known about cocoa and it's effecting on Fib, Hb and Htc levels. However, the findings showed that cocoa supplementation decreased Fib, Hb and Htc levels. In conclusion, short-term cocoa supplementation decreased blood coagulation in response to an incremental exhaustive exercise.
Restricted helper function of F1 hybrid T cells positively selected to heterologous erythrocytes in irradiated parental strain mice. II. Evidence for restrictions affecting helper cell induction and T-B collaboration, both mapping to the K-end of the H-2 complex.
Authors: J Sprent
Journal: The Journal of Experimental Medicine (1978)

Studies with H-2-congenic and recombinant strains showed that when F1 hybrid T cells were activated to sheep erythrocytes in irradiated mice of parental strain or related strain, a population of helper cells was generated which collaborated only with B cells sharing the K-end of the H-2 complex with the strain used for activation. No evidence was found that the restriction in helper function (a) reflected a deficiency of appropriate macrophages during T-B collaboration, or (b) was influenced by the Ig allotype of the B cells. It was concluded that the results signified restrictions acting at both the level of helper cell induction (presumed to be a reflection of T-macrophage interactions in the irradiated intermediate hosts) and during T-B collaboration. With (CBA X C57BL/6)F1 cells, the restrictions at each level mapped to the same region i.e. to the left of the I-B subregion. Consequently, one gene (or set of genes) might control restriction at both levels. If so, T-cell recognition of major histocompatibility complex-associated antigen on macrophages and on specific B cells would be either identical or very similar. The fact that genes mapping to the K-end of the H-2 complex also control the restrictive interactions of homozygous T cells implies that F1 T cells behave functionally as a mixture of T cells derived from the two parental strains. Positive selection to antigen in parental strain mice appears simply to alter the ratio of these two populations.
Menstrual cycle and timing of breast surgery in premenopausal node-positive breast cancer: Results of the International Breast Cancer Study Group (IBCSG) Trial VI
Authors: A. Goldhirsch, M. Castiglione, R.D. Gelber, A. O'Neill, K. Price, D. Crivellari, E. Simoncini, J. Collins, C.-M. Rudenstam, J. Lindtner, J. Forbes, A. Coates, M.F. Fey, H.-J. Senn, B. Thürlimann, F. Cavalli, O. Pagani
Journal: Annals of Oncology (1997)
Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1
Authors: M Trevisani, D Smart, M J. Gunthorpe, M Tognetto, M Barbieri, B Campi, S Amadesi, J Gray, J C. Jerman, S J. Brough, D Owen, G D. Smith, A D. Randall, S Harrison, A Bianchi, J B. Davis, P Geppetti
Journal: Nature Neuroscience (2002)