tbuckley/cabot-search huggingface dataset:
THE EFFECT OF DESOXYCORTICOSTERONE ACETATE ON BLOOD PRESSURE, RENAL FUNCTION, AND ELECTROLYTE PATTERN IN THE INTACT RAT
Authors: Sydney M. Friedman, John R. Polley, Constance L. Friedman
Journal: The Journal of Experimental Medicine (1948)

Small doses of DCA administered at intervals in pellet form are capable of raising the blood pressure, altering renal function, and changing the electrolyte pattern in the intact rat. The concomitant feeding of 1 per cent saline intensifies the process. The elevation in blood pressure occurs prior to demonstrable changes in renal excretory function. The alteration in renal function consists first of a reduction in C(PAH) with the maintenance of a normal filtration rate. Filtration fraction is elevated while there is no reduction in renal plasma flow per unit of tubular excretory tissue. Later, filtration is interfered with and renal ischemia occurs. The electrolyte change is characterized by a sustained fall in plasma K and Cl, a rise in plasma Na, an increase in the Na/Cl ratio, and finally an elevation of Na plus K. Plasma Ca is unaffected. These observations suggest the possible etiological significance of the adrenal cortex in some types of hypertension.
Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction
Authors: Kojiro Sato, Ayako Suematsu, Kazuo Okamoto, Akira Yamaguchi, Yasuyuki Morishita, Yuho Kadono, Sakae Tanaka, Tatsuhiko Kodama, Shizuo Akira, Yoichiro Iwakura, Daniel J. Cua, Hiroshi Takayanagi
Journal: The Journal of Experimental Medicine (2006)

In autoimmune arthritis, traditionally classified as a T helper (Th) type 1 disease, the activation of T cells results in bone destruction mediated by osteoclasts, but how T cells enhance osteoclastogenesis despite the anti-osteoclastogenic effect of interferon (IFN)-gamma remains to be elucidated. Here, we examine the effect of various Th cell subsets on osteoclastogenesis and identify Th17, a specialized inflammatory subset, as an osteoclastogenic Th cell subset that links T cell activation and bone resorption. The interleukin (IL)-23-IL-17 axis, rather than the IL-12-IFN-gamma axis, is critical not only for the onset phase, but also for the bone destruction phase of autoimmune arthritis. Thus, Th17 is a powerful therapeutic target for the bone destruction associated with T cell activation.
The TRIB3 R84 variant is associated with increased carotid intima–media thickness in vivo and with enhanced MAPK signalling in human endothelial cells
Authors: Gloria Formoso, Pamela Di Tomo, Francesco Andreozzi, Elena Succurro, Sara Di Silvestre, Sabrina Prudente, Francesco Perticone, Vincenzo Trischitta, Giorgio Sesti, Assunta Pandolfi, Agostino Consoli
Journal: Cardiovascular Research (2010)

AimsTRIB3, a mammalian tribbles homologue, affects insulin signalling and action by inhibiting Akt phosphorylation. A TRIB3 Q84R gain-of-function polymorphism has been associated with insulin resistance both in vitro and in vivo and with several atherosclerotic phenotypes, including increased carotid intima–media thickness (IMT). We wanted to replicate this latter association and, if so, to get deeper insights about the molecular mechanisms underlying the role of the TRIB3 Q84R polymorphism in atherosclerosis.
A new therapeutic approach to treat psoriasis by inhibition of fatty acid oxidation by Etomoxir
Authors: F. Caspary, G. Elliott, B.T. Nave, P. Verzaal, M. Rohrbach, P.K. Das, L. Nagelkerken, J.D. Nieland
Journal: British Journal of Dermatology (2005)

The dogma in psoriasis is that due to pathogen-induced inflammatory responses, an autoreactive immune response is induced that leads to tissue destruction. However, this model might be too simplistic. Literature data suggest that the expression of enzymes crucial for fatty acid oxidation is upregulated in the skin of patients with psoriasis compared with healthy individuals.To examine the influence of fatty acid oxidation on psoriasis with regard to expression and activity of the key enzyme in fatty acid oxidation, carnitine palmitoyltransferase-1 (CPT-1) and the effect of the CPT-1 inhibitor, Etomoxir.Experiments were performed with homogenates of lesional and healthy skin, fibroblast cultures and a model of human psoriatic skin transplanted on immune-deficient BNX mice.CPT-1 was highly active in lesional skin. Etomoxir was able to block CPT-1 activity in skin, implying that this antagonist may have the potential to suppress psoriasis when administered topically. In the mouse model, Etomoxir had an antipsoriatic effect that was at least as good as that of betamethasone, as evidenced by reduction of epidermal thickness, keratinocyte proliferation and differentiation.We conclude that fatty acid metabolism and in particular CPT-1 may be an excellent target for treatment of psoriasis.
Effects of Sodium Pentobarbital on Electrical and Reflex Activation of the Cardiovascular System
Authors: CLARENCE N. PEISS, JOHN W. MANNING
Journal: Circulation Research (1964)

The effects of small doses of sodium pentobarbital (5 mg/kg) on the cardiovascular responses to stimulation of the medulla, hypothalamus, stellate ganglia and sciatic nerve, and to bilateral occlusion of the carotid arteries were studied. It was concluded that: 1) this drug depressed cardiovascular responses to all of these procedures except stimulation of the stellate ganglia; 2) the effects of the anesthetic in this dose are referable to some part(s) of the central nervous system; 3) cardiovascular responses to hypothalamic stimulation were depressed more than those elicited by stimulation of the dorsal medullary reticular formation.
An alternative view of apoptosis in heart development and disease
Authors: D. Sanchis, M. Llovera, M. Ballester, J. X. Comella
Journal: Cardiovascular Research (2007)

Although the involvement of caspases in cardiomyocyte death is widely accepted [reviewed in1], increasing experimental evidence suggests that caspase activation is not relevant for post-mitotic cardiomyocyte cell death.2–7 Controversy also exists as to the mechanisms conferring cardioprotection by caspase inhibitors, which could be unrelated to apoptosis or target non-myocardial cells.8–11 In addition, the genes controlling the caspase-dependent death pathway are silenced during early post-natal development.7,12 Finally, the major role of death receptors and the Bcl-2-related proteins in the myocardium is probably to control differentiation, adaptation to stress and mitochondrial integrity. In light of these findings, we propose here an alternative explanation of the role of canonical apoptosis regulators in the control of cardiomyocyte life and death.

Cell death implying apoptotic-like DNA damage occurs during embryonic heart development.13–15 Experiments using caspase inhibitors suggest that caspase-dependent cell death occurs in the cardiac regions submitted to important morphological changes, such as the ventriculoarterial connections, the atrioventricular cushions, and the conduction tissue.16–18 Therefore, caspase activation is likely assuring the proper formation of the cardiac cavities and the correct docking of the arteries to the ventricles during development. Later, the caspase-dependent death machinery is repressed during cardiomyocyte terminal differentiation,7,12 as it has been described in retinal neurons.19

Many reports have demonstrated that mitochondrial damage precedes post-mitotic cardiomyocyte cell death and have suggested the involvement of caspases20 yet the engagement of these proteases downstream of mitochondrial damage is still debated [e.g. 4 vs. 21]. The Bcl-2 family controls mitochondrial events leading to caspase activation by regulating outer mitochondrial membrane permeabilization. However, mitochondrial damage also hinders aerobic metabolism and alters cellular Ca2+ homeostasis. Thus, Bcl-2 and Bcl-XL-dependent cardioprotection could be achieved by maintaining …
Community Center–Based Resistance Training for the Maintenance of Glycemic Control in Adults With Type 2 Diabetes
Authors: David W. Dunstan, Elena Vulikh, Neville Owen, Damien Jolley, Jonathan Shaw, Paul Zimmet
Journal: Diabetes Care (2006)

The purpose of this study was to determine whether beneficial effects on glycemic control of an initial laboratory-supervised resistance training program could be sustained through a community center-based maintenance program.We studied 57 overweight (BMI >or=27 kg/m2) sedentary men and women aged 40-80 years with established (>6 months) type 2 diabetes. Initially, all participants attended a twice-weekly 2-month supervised resistance training program conducted in the exercise laboratory. Thereafter, participants undertook a resistance training maintenance program (2 times/week) for 12 months and were randomly assigned to carry this out either in a community fitness and recreation center (center) or in their domestic environment (home). Glycemic control (HbA1c [A1C]) was assessed at 0, 2, and 14 months.Pooling data from the two groups for the 2-month supervised resistance training program showed that compared with baseline, mean A1C fell by -0.4% [95% CI -0.6 to -0.2]. Within-group comparisons showed that A1C remained lower than baseline values at 14 months in the center group (-0.4% [-0.7 to -0.03]) but not in the home group (-0.1% [-0.4 to 0.3]). However, no between-group differences were observed at each time point. Changes in A1C during the maintenance period were positively associated with exercise adherence in the center group only.Center-based but not home-based resistance training was associated with the maintenance of modestly improved glycemic control from baseline, which was proportional to program adherence. Our findings emphasize the need to develop and test behavioral methods to promote healthy lifestyles including increased physical activity in adults with type 2 diabetes.
H2AX Is Required for Recombination Between Immunoglobulin Switch Regions but Not for Intra-Switch Region Recombination or Somatic Hypermutation
Authors: Bernardo Reina-San-Martin, Simone Difilippantonio, Leif Hanitsch, Revati F. Masilamani, André Nussenzweig, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2003)

Changes in chromatin structure induced by posttranslational modifications of histones are important regulators of genomic function. Phosphorylation of histone H2AX promotes DNA repair and helps maintain genomic stability. Although B cells lacking H2AX show impaired class switch recombination (CSR), the precise role of H2AX in CSR and somatic hypermutation (SHM) has not been defined. We show that H2AX is not required for SHM, suggesting that the processing of DNA lesions leading to SHM is fundamentally different from CSR. Impaired CSR in H2AX−/− B cells is not due to alterations in switch region transcription, accessibility, or aberrant joining. In the absence of H2AX, short-range intra-switch region recombination proceeds normally while long-range inter-switch region recombination is impaired. Our results suggest a role for H2AX in regulating the higher order chromatin remodeling that facilitates switch region synapsis.
Intact serotonin signaling is not required for the development of severe angioproliferative pulmonary hypertension in rats
Authors: Michiel Alexander De Raaf, Yvet Kroeze, Anthonieke Middelman, Frances de Man, Nico Westerhof, Anton Vonk Noordegraaf, Chris De Korte, Judith Homberg, Harm Jan Bogaard
Journal: European Respiratory Journal (2014)

Introduction: The Serotonin pathway regulates vessel tone and induces smooth muscle cell proliferation. Serotonin levels are increased in Pulmonary Arterial Hypertension (PAH) patients, pharmacological interventions in this pathway may provoke PAH and SERotonin Transporter (SERT) knock-out (KO) mice are less sensitive to hypoxic PH. We hypothesized that intact serotonin signaling is required for the development of severe angioproliferative pulmonary hypertension in rats.  Methods: Wild type (WT) and SERT-KO rats, lacking SERT as well circulating serotonin, were exposed to hypoxia alone or combined exposure of hypoxia with SU5416 (SuHx) to induce smooth muscle cell hypertrophy and intima proliferation.  Results: Hypoxia only: after 3 weeks of hypoxia, the SERT KO showed, as expected, fewer signs of RV pressure overload. SuHx: after 3 weeks of hypoxia and 4 weeks of normoxia, no differences were noted between SERT WT and KO rats with respect to echocardiographic parameters (cardiac output, tricuspid annular plane systolic excursion, total pulmonary resistance, right ventricular wall thickness and end diastolic diameter), hemodynamic parameters (right ventricular systolic pressure, end systolic pressure volume relationship, arterial elastance) or lung histology.  Conclusion: Serotonin does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats.
Penetration of moxifloxacin in bronchial secretions in hospitalized patients with acute exacerbation of COPD
Authors: Maria Sionidou, Georgia Pitsiou, Katerina Manika, Kalliopi Chatzika, Paschalina Kontou, Konstantinos Zarogoulidis, Ioannis Kioumis
Journal: European Respiratory Journal (2013)

Moxifloxacin (MXF) is recommended for the treatment of acute COPD exacerbation in hospitalized patients. However, pharmacokinetics of the drug in “real life” patients has not been investigated thoroughly.  Aim: To determine the pharmacokinetic profile of MXF in COPD exacerbations, penetration of MXF into bronchial secretions and pharmacodynamic parameters for common pathogens.  Methods: 16 hospitalized patients with COPD exacerbation (aged 69.3±9.2) were included (5 ICU, 11 ward). Patients received 400mg intravenous MXF o.d. Serial blood and bronchial secretions samples were taken in steady state for a 24hour interval. MXF concentrations in plasma and secretions were determined by high-performance liquid chromatography. Areas under the curve (AUC’s) were calculated and penetration in secretions was expressed as AUCsecretions/AUCplasma ratio. Pharmacodynamic target attainment was estimated for the MICs of common pathogens: AUC24/MIC>30 for Gram positive and >125 for Gram negative.  Results:  MXF penetration in secretions is particularly sufficient (85%). Pharmocodynamic target for gram positive and negative pathogens is adequately attained.  Conclusion: MXF, in the common applied i.v. dose for hospitalized COPD exacerbations, penetrates well in bronchial secretions with sufficient concentrations against respiratory pathogens.
Rapid A1c Availability Improves Clinical Decision-Making in an Urban Primary Care Clinic
Authors: Christopher D. Miller, Catherine S. Barnes, Lawrence S. Phillips, David C. Ziemer, Daniel L. Gallina, Curtiss B. Cook, Sandra D. Maryman, Imad M. El-Kebbi
Journal: Diabetes Care (2003)

Failure to meet goals for glycemic control in primary care settings may be due in part to lack of information critical to guide intensification of therapy. Our objective is to determine whether rapid-turnaround A1c availability would improve intensification of diabetes therapy and reduce A1c levels in patients with type 2 diabetes.In this prospective controlled trial, A1c was determined on capillary glucose samples and made available to providers, either during ("rapid") or after ("routine") the patient visit. Frequency of intensification of pharmacological diabetes therapy in inadequately controlled patients and A1c levels were assessed at baseline and after follow-up.We recruited 597 subjects. Patients were 79% female and 96% African American, with average age of 61 years, duration of diabetes 10 years, BMI 33 kg/m(2), and A1c 8.5%. The rapid and routine groups had similar clinical demographics. Rapid A1c availability resulted in more frequent intensification of therapy when A1c was >/=7.0% at the baseline visit (51 vs. 32% of patients, P = 0.01), particularly when A1c was >8.0% and/or random glucose was in the 8.4-14.4 mmol/l range (151-250 mg/dl). In 275 patients with two follow-up visits, A1c fell significantly in the rapid group (from 8.4 to 8.1%, P = 0.04) but not in the routine group (from 8.1 to 8.0%, P = 0.31).Availability of rapid A1c measurements increased the frequency of intensification of therapy and lowered A1c levels in patients with type 2 diabetes in an urban neighborhood health center.
γ Synuclein, a Novel Heat-Shock Protein-Associated Chaperone, Stimulates Ligand-Dependent Estrogen Receptor α Signaling and Mammary Tumorigenesis
Authors: Yangfu Jiang, Yiliang Ellie Liu, Itzhak D. Goldberg, Y. Eric Shi
Journal: Cancer Research (2004)

Abstract Synucleins are emerging as central players in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. γ synuclein (SNCG), previously identified as a breast cancer-specific gene (BCSG1), is also highly associated with breast or ovarian cancer progression. However, the molecular targets of SNCG aberrant expression in breast cancer have not been identified. Here, we demonstrated a chaperone activity of SNCG in the heat-shock protein (Hsp)-based multiprotein chaperone complex for stimulation of estrogen receptor (ER)-α signaling. As an ER-α-associated chaperone, SNCG participated in Hsp-ER-α complex, enhanced the high-affinity ligand-binding capacity of ER-α, and stimulated ligand-dependent activation of ER-α. The SNCG-mediated stimulation of ER-α transcriptional activity is consistent with its stimulation of mammary tumorigenesis in response to estrogen. These data indicate that SNCG is a new chaperone protein in the Hsp-based multiprotein chaperone complex for stimulation of ligand-dependent ER-α signaling and thus stimulates hormone-responsive mammary tumorigenesis.
Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation
Authors: Laura E. Briggs, Aimee L. Phelps, Elizabeth Brown, Jayant Kakarla, Robert H. Anderson, Maurice J.B. van den Hoff, Andy Wessels
Journal: Circulation Research (2013)

Rationale: The dorsal mesenchymal protrusion (DMP) is a prong of mesenchyme derived from the second heart field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular (AV) septal defect. Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated. Objective: To determine the role of BMP signaling in DMP development. Methods and Results: Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AV septal defects. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/transforming growth factor β signaling were not significantly altered in the AV cushions of SHF-Alk3 mutants. Conclusions: BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.
New Atypical Antipsychotic
Authors: Rebecca Voelker
Journal: JAMA (2015)

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Pesticides in household dust and soil: exposure pathways for children of agricultural families.
Authors: N J Simcox, R A Fenske, S A Wolz, I C Lee, D A Kalman
Journal: Environmental Health Perspectives (1995)

Child of agriculture families are likely to be exposed to agricultural chemicals, even if they are not involved in farm activities. This study was designed to determine whether such children are exposed to higher levels of pesticides than children whose parents are not involved in agriculture and whose homes are not close to farms. Household dust and soil samples were collected in children's play areas from 59 residences in eastern Washington State (26 farming, 22 farmworker, and 11 nonfarming families). The majority of the farm families lived within 200 feet of an operating apple or pear orchard, whereas all reference homes were located at least a quarter of a mile from an orchard. Four organophosphorous (OP) insecticides commonly used on tree fruit were targeted for analysis: azinphosmethyl, chlorpyrifos, parathion, and phosmet. Samples were extracted and analyzed by gas chromatography/mass selective detection. Pesticide concentrations in household dust were significantly higher than in soil for all groups. OP levels for farmer/farm-worker families ranged from nondetectable to 930 ng/g in soil (0.93 ppm) and from nondetectable to 17,000 ng/g in dust (17 ppm); all four OP compounds were found in 62% of household dust samples, and two-thirds of the farm homes contained at least one OP above 1000 ng/g. Residues were found less frequently in reference homes and all levels were below 1000 ng/g. Household dust concentrations for all four target compounds were significantly lower in reference homes when compared to farmer/farmworker homes (Mann Whitney, U test; p < 0.05). These results demonstrate that children of agricultural families have a higher potential for exposure to OP pesticides than children of nonfarm families in this region. Measurable residues of a toxicity, I compound registered exclusively for agricultural use, azcnphosmettyl were found in household dust samples from all study homes, suggesting that low level exposure to such chemicals occurs throughout the region. Children's total and cumulative exposure to this pesticide class from household dust, soil, and other sources warrants further investigation.