tbuckley/cabot-search huggingface dataset:
Augmented Protein Kinase C-α–Induced Myofilament Protein Phosphorylation Contributes to Myofilament Dysfunction in Experimental Congestive Heart Failure
Authors: Rashad J. Belin, Marius P. Sumandea, Edward J. Allen, Kelly Schoenfelt, Helen Wang, R. John Solaro, Pieter P. de Tombe
Journal: Circulation Research (2007)

It is becoming clear that upregulated protein kinase C (PKC) signaling plays a role in reduced ventricular myofilament contractility observed in congestive heart failure. However, data are scant regarding which PKC isozymes are involved. There is evidence that PKC-α may be of particular importance. Here, we examined PKC-α quantity, activity, and signaling to myofilaments in chronically remodeled myocytes obtained from rats in either early heart failure or end-stage congestive heart failure. Immunoblotting revealed that PKC-α expression and activation was unaltered in early heart failure but increased in end-stage congestive heart failure. Left ventricular myocytes were isolated by mechanical homogenization, Triton-skinned, and attached to micropipettes that projected from a force transducer and motor. Myofilament function was characterized by an active force–[Ca 2+ ] relation to obtain Ca 2+ -saturated maximal force (F max ) and myofilament Ca 2+ sensitivity (indexed by EC 50 ) before and after incubation with PKC-α, protein phosphatase type 1 (PP1), or PP2a. PKC-α treatment induced a 30% decline in F max and 55% increase in the EC 50 in control cells but had no impact on myofilament function in failing cells. PP1-mediated dephosphorylation increased F max (15%) and decreased EC 50 (≈20%) in failing myofilaments but had no effect in control cells. PP2a-dependent dephosphorylation had no effect on myofilament function in either group. Lastly, PP1 dephosphorylation restored myofilament function in control cells hyperphosphorylated with PKC-α. Collectively, our results suggest that in end-stage congestive heart failure, the myofilament proteins exist in a hyperphosphorylated state attributable, in part, to increased activity and signaling of PKC-α.
Quantification of intestinal microvascular growth during maturation: techniques and observations.
Authors: J L Unthank, H G Bohlen
Journal: Circulation Research (1987)

This study was undertaken to determine what changes occur in the intestinal microvasculature during the rapid growth associated with juvenile maturation. A technique was developed that permitted the comparison of the same microvessels in exactly the same intestinal region at two time periods of an animal's life. A region of the terminal ileum of 5-week-old rats was exposed and marked, and photographs and video recordings were made of the microvessels. Four weeks later, the marked intestinal region was located, and photography and videography of the microvessels were repeated. Comparison of indexes for body, intestinal, and microvascular growth for the treated rats and age- and colony-matched controls revealed no significant differences. The number and branching pattern of arterioles observed in the marked region remained remarkably constant during the 4 weeks between observation periods, even though body and bowel mass of the treated animals increased approximately 2.5 times. The lengths of the arterioles were increased (18%) by almost the same proportion as the axis of bowel (22%) in which they were oriented. The average distance between capillaries in the radial intestinal muscle layer was also increased by about the same percentage (24%) as that of tissue elongation (22%). The overall data are consistent with the hypothesis that during the growth spurt of juvenile life, the arterioles present at the weanling stage are elongated and new branches do not develop. The net effect of tissue growth with a minimal change in numbers of arterioles is a decreased ratio of number of arterioles to tissue mass as a normal consequence of maturation.
Essential role of membrane cholesterol in accelerated BCR internalization and uncoupling from NF-κB in B cell clonal anergy
Authors: Mathieu Bléry, Lina Tze, Lisa A. Miosge, Jesse E. Jun, Christopher C. Goodnow
Journal: The Journal of Experimental Medicine (2006)

Divergent hypotheses exist to explain how signaling by the B cell receptor (BCR) is initiated after antigen binding and how it is qualitatively altered in anergic B cells to selectively uncouple from nuclear factor κB and c-Jun N-terminal kinase pathways while continuing to activate extracellular signal–regulated kinase and calcium–nuclear factor of activated T cell pathways. Here we find that BCRs on anergic cells are endocytosed at a very enhanced rate upon binding antigen, resulting in a large steady-state pool of intracellularly sequestered receptors that appear to be continuously cycling between surface and intracellular compartments. This endocytic mechanism is exquisitely sensitive to the lowering of plasma membrane cholesterol by methyl-β-cyclodextrin, and, when blocked in this way, the sequestered BCRs return to the cell surface and RelA nuclear accumulation is stimulated. In contrast, when plasma membrane cholesterol is lowered and GM1 sphingolipid markers of membrane rafts are depleted in naive B cells, this does not diminish BCR signaling to calcium or RelA. These results provide a possible explanation for the signaling changes in clonal anergy and indicate that a chief function of membrane cholesterol in B cells is not to initiate BCR signaling, but instead to terminate a subset of signals by rapid receptor internalization.
Magnesium levels in plasma and erythrocytes before and after histamine challenge
Authors: E. Zervas, S. Loukides, G. Papatheodorou, K. Psathakis, K. Tsindiris, P Panagou, N Kalogeropoulos
Journal: European Respiratory Journal (2000)

Previous studies have assessed the protective effect of nebulized magnesium sulphate on bronchial hyperreactivity. This study investigated the effect of histamine challenge on intracellular (erythrocytes) and extracellular (plasma) levels of magnesium and the possible relationship between degree of bronchial hyperreactivity and levels of Mg in plasma and erythrocytes. The authors studied 42 mildly asthmatic patients (10 on inhaled steroids) and 20 healthy subjects. Histamine challenge was performed by the dosimeter method and provocative dose causing a 20% fall in forced expiratory volume in one second (PD20) (FEV1) was calculated. Mg levels were measured with a calmagite colourimetric assay, both at baseline and when FEV1 had fallen by 20%. The results showed that Mg levels in plasma did not significantly change after histamine challenge (from 2.06+/-0.02 mg x dL(-1) to 2.08+/-0.02 mg x dL(-1) respectively, p=0.14). Conversely there was a statistically significant decrease in Mg levels in erythrocytes between these two time points (from 1.84+/-0.02 fmmol x cell to 1.78+/-0.02 fmmol x cell p<0.0001). Similar results were observed when the subgroups were studied separately. There was no significant correlation between PD20, the difference in both magnesium concentrations (baseline-PD20 time) or the initial values of Mg levels in erythrocytes and plasma. To conclude, histamine challenge reduces magnesium levels in erythrocytes while plasma levels remain unchanged. This histamine-induced decrease in magnesium levels occurs regardless of the diagnosis of asthma, and it is not correlated with the degree of bronchial hyperreactivity.
Enhanced sensitivity of heart cells to adenosine and up-regulation of receptor number after treatment of guinea pigs with theophylline.
Authors: S N Wu, J Linden, S Visentin, M Boykin, L Belardinelli
Journal: Circulation Research (1989)

Experiments were carried out in hearts from guinea pigs that were fed either the adenosine receptor antagonist theophylline (0.6 mg/ml) or no drug. The A1 adenosine receptor radioligand [125I]aminobenzyladenosine bound to a single affinity class of receptors in heart cell membranes from control animals with Bmax and KD of 18.3 +/- 1.0 fmol/mg protein and 3.7 +/- 0.6 nM, respectively (n = 8). Heart cell membranes from animals fed theophylline for 2, 7, and 14 days bound the radioligand with about the same affinity, but the number of binding sites was significantly increased (p less than 0.01) to 30.6 +/- 1.7 (n = 3), 30.0 +/- 0.8 (n = 3), and 27.3 +/- 2.9 (n = 4), respectively. Nearly identical results were obtained with membranes prepared from enzymatically dispersed ventricular myocytes. Fourteen days of theophylline treatment also produced a small increase (12%, p less than 0.01) in the number of binding sites in membranes derived from cerebral cortexes. Isolated ventricular myocytes prepared from animals fed no drug or theophylline for 7 days were used to determine the effect of adenosine on 20 nM isoproterenol-stimulated calcium current (ICa) measured by the whole-cell patch-clamp technique. Adenosine reduced isoproterenol-stimulated ICa without affecting the activation or inactivation kinetics of the current; ICa density was reduced less by 5 microM adenosine in cells from control (25 +/- 3 to 21 +/- 3 microA/microF) than in cells from theophylline-fed animals (26 +/- 5 to 17 +/- 2 microA/microF). Although a high concentration (0.5 mM) of adenosine abolished isoproterenol-stimulated ICa in cells from control or theophylline-fed animals, the IC50 for adenosine was sixfold less in cells derived from theophylline-fed animals than in cells from control animals (4.6 +/- 0.6 microM and 28.3 +/- 1.4 microM, respectively, p less than 0.01). In contrast, the increase in ICa in response to isoproterenol alone and the potency of acetylcholine to antagonize this effect of isoproterenol were the same in both groups of cells. A maximally effective concentration of R-phenylisopropyladenosine (0.1 mM) inhibited isoproterenol-stimulated cyclic AMP accumulation less in cardiomyocytes from control than from theophylline-fed animals (28.7 +/- 1.8% vs. 42.0 +/- 4.2%, p less than 0.05). In summary, exposure of the myocardium to theophylline increases the number of adenosine receptors and the effects of receptor occupancy by agonists. These findings imply that the endogenous concentration of adenosine is high enough in the normoxic guinea pig heart to chronically maintain adenosine receptors in a partially down-regulated state.
A fundamental bimodal role for neuropeptide Y1 receptor in the immune system
Authors: Julie Wheway, Charles R. Mackay, Rebecca A. Newton, Amanda Sainsbury, Dana Boey, Herbert Herzog, Fabienne Mackay
Journal: The Journal of Experimental Medicine (2005)

Psychological conditions, including stress, compromise immune defenses. Although this concept is not novel, the molecular mechanism behind it remains unclear. Neuropeptide Y (NPY) in the central nervous system is a major regulator of numerous physiological functions, including stress. Postganglionic sympathetic nerves innervating lymphoid organs release NPY, which together with other peptides activate five Y receptors (Y1, Y2, Y4, Y5, and y6). Using Y1-deficient (Y1−/−) mice, we showed that Y1−/− T cells are hyperresponsive to activation and trigger severe colitis after transfer into lymphopenic mice. Thus, signaling through Y1 receptor on T cells inhibits T cell activation and controls the magnitude of T cell responses. Paradoxically, Y1−/− mice were resistant to T helper type 1 (Th1) cell–mediated inflammatory responses and showed reduced levels of the Th1 cell–promoting cytokine interleukin 12 and reduced interferon γ production. This defect was due to functionally impaired antigen-presenting cells (APCs), and consequently, Y1−/− mice had reduced numbers of effector T cells. These results demonstrate a fundamental bimodal role for the Y1 receptor in the immune system, serving as a strong negative regulator on T cells as well as a key activator of APC function. Our findings uncover a sophisticated molecular mechanism regulating immune cell functions that can lead to stress-induced immunosuppression.
PTEN overexpression suppresses proliferation and differentiation and enhances apoptosis of the mouse mammary epithelium
Authors: Joëlle Dupont, Jean Pierre Renou, Moshe Shani, Lothar Hennighausen, Derek LeRoith
Journal: Journal of Clinical Investigation (2002)

The phosphatase PTEN regulates growth, adhesion, and apoptosis, among many other cell processes. To investigate its role during mouse mammary gland development, we generated MK-PTEN, a transgenic mouse model in which human PTEN is overexpressed in ductal and alveolar mammary epithelium during puberty, pregnancy, lactation, and involution. No obvious phenotype was observed in mammary tissue of pubescent virgin mice. However, MK-PTEN females could not lactate normally, and ∼30% of pups died, with survivors exhibiting growth retardation. Transgenic offspring nursed by wild-type foster mothers, conversely, developed normally. This phenotype is consistent with a reduced number of alveolar epithelial cells due to a decrease in cell proliferation and an increase in apoptosis. Using mammary-enriched cDNA microarrays, we identified several genes that were preferentially expressed in MK-PTEN mammary tissue, including the IGF-binding protein-5 (Igfbp5) gene, and others whose expression was reduced, including the genes for c-Jun amino-terminal kinase. Secretory epithelial cell differentiation was impaired, as measured by the expression of specific milk protein genes. MK-PTEN mice also exhibited a 50% decrease in the phosphorylation state of Akt. Taken together, these results suggest that PTEN controls mammary gland development and, consequently, lactation.
On Catgut Sutures in the Operation for Ruptured Perineum
Authors: G. E. Herman
Journal: BMJ (1888)

JOUIRNAL 1217 aged 26, who had received a blow on the left breast five years before.A tumour the size of a small orange had formed in the substance of the gland midway between the nipple and the axillary periphery, taking about six months for its development.It varied in size under excitement and menstruation, but was never smaller than as described above.It gave rise to severe sponta- neous pain and was extremely sensitive to pressure.Wlth its removal all these symptoms disappeared.Ilistologically it was a tubular adenoma withl no cyst formation.
Associations of Serum Concentrations of Organochlorine Pesticides with Breast Cancer and Prostate Cancer in U.S. Adults
Authors: Xiaohui Xu, Amy B. Dailey, Evelyn O. Talbott, Vito A. Ilacqua, Greg Kearney, Nabih R. Asal
Journal: Environmental Health Perspectives (2009)

Organochlorine (OC) pesticides are a group of environmental endocrine disruptors that may be associated with an increased risk for hormone-related cancers including cancers of the breast and prostate. However, epidemiologic evidence is limited and inconsistent.We used 1999-2004 National Health and Nutrition Examination Survey data to examine associations between serum concentrations of OC pesticides and prostate and breast cancers.After adjustment for other covariates, serum concentrations of beta-hexachlorocyclohexane (HCH) (p for trend = 0.02), trans-nonachlor (p for trend = 0.002), and dieldrin (p for trend = 0.04) were significantly associated with the risk of prevalent prostate cancer. Adjusted odds ratios for the second and third tertiles of detectable values were 1.46 [95% confidence interval (CI), 0.52-4.13] and 3.36 (95% CI, 1.24-9.10) for beta-HCH; 5.84 (95% CI, 1.06-32.2) and 14.1 (95% CI, 2.55-77.9) for trans-nonachlor; and 1.06 (95% CI, 0.30-3.73) and 2.74 (95% CI, 1.01-7.49) for dieldrin compared with concentrations in the lowest tertile or below the limit of detection. However, there was no positive association between serum concentrations of OC pesticides and breast cancer prevalence.Although further study is necessary to confirm these findings, these results suggest that OC pesticide exposures may have a significant effect on cancer risk. Efforts to reduce worldwide OC use are warranted.
Immunology and immunopathology of the male genital tract: Experimental models to investigate the pathology of antisperm antibodies: approaches and problems
Authors: R. Clayton
Journal: Human Reproduction Update (2001)

Antisperm antibodies (ASA) can interfere with sperm function and fertilization. But we still know relatively little about the specific mechanisms that elicit an auto-immune response and we have a poor appreciation of the profile of ASA that lead to antibody-mediated infertility in the male. This brief review explores some of the experimental models, the current approaches and the problems associated with investigations of ASA.
The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. Relationship between macrophages, Langerhans cells, reticular cells, and dendritic cells in lymphoid and hematopoietic organs.
Authors: D A Hume, A P Robinson, G G MacPherson, S Gordon
Journal: The Journal of Experimental Medicine (1983)

The macrophage-specific antigen F4/80 has been localized in mouse lymphoid and hematopoietic tissue and skin using immunoperoxidase staining. The antigen permits identification of early mononuclear phagocyte precursors in the bone marrow, and is present also on larger cells forming the center of hematopoietic islands and lining vascular sinuses. In thymus F4/80+ cells are numerous in both cortex and medulla and are particularly concentrated around the corticomedullary region. In spleen, lymph node, and gut-associated lymphoid areas the major F4/80+ populations are in the red pulp, the medulla and subcapsular sinus, and the adjacent lamina propria, respectively. F4/80+ cells are rarely seen in T-dependent areas of lymph nodes, spleen, or Peyer's patch, but are present in large numbers in these areas during bacillus Calmette-Guerin (BCG)-induced inflammation. Macrophage infiltration occurs also in lymph nodes from athymic nu/nu mice and is therefore T cell independent. The interdigitating cell of T-dependent areas is F4/80-, but the Langerhans cell of the epidermis of the skin, which bears some ultrastructural resemblance to the interdigitating cell, is F4/80+. We conclude that the two cell types are probably not related.
Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction
Authors: Rainer H. Böger, Stefanie M. Bode-Böger, Andrzej Szuba, Philip S. Tsao, Jason R. Chan, Oranee Tangphao, Terrence F. Blaschke, John P. Cooke
Journal: Circulation (1998)

Background —Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous l -arginine. Methods and Results —We measured plasma levels of l -arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of l -arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by &gt;100% (2.17±0.15 versus 1.03±0.09 μmol/L; P &lt;0.05) in HC subjects compared with NC adults. l -Arginine levels were similar, resulting in a significantly decreased l -arginine/ADMA ratio in HC subjects (27.7±2.4 versus 55.7±5.4; P &lt;0.05). In 8 HC subjects, intravenous infusion of l -arginine significantly increased the l -arginine/ADMA ratio and normalized endothelium-dependent vasodilation and urinary nitrate excretion. ADMA levels were inversely correlated with endothelium-mediated vasodilation ( R =0.762, P &lt;0.01) and urinary nitrate excretion rates ( R =0.534, P &lt;0.01). Conclusions —We find that ADMA is elevated in young HC individuals. Elevation of ADMA is associated with impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion. This abnormality is reversed by administration of l -arginine. ADMA may be a novel risk factor for endothelial dysfunction in humans.
Hypersensitivity to pyrazolones
Authors: M. Levy
Journal: Thorax (2000)

To the allergologist, hypersensitivity to drugs means immunological drug reactions as classified in the Gell and Coombs system. To others, it may also include non-dose related adverse drug reactions including the non-immune mediated idiosyncratic drug reactions (type B). In the following discussion the broad definition of idiosyncrasy including all type B reactions and a clinical approach rather than a mechanistic one will be used.

Pyrazolones are veteran drugs. Antipyrine was synthesised for clinical use in 1883. The methylated nitrogen derivative aminopyrine was introduced in 1897 and taken off the market in the 1970s because of its propensity to form nitrosamines. Dipyrone has been in clinical use since 1922. In some countries it was banned because of the risk of agranulocytosis. In others it is the leading analgesic/antipyretic drug. Annual sales figures of pyrazolones amount to kilotons, mainly dipyrone and propyphenazone.

Unlike the acidic non-steroidal anti-inflammatory drugs (NSAIDs) which are known to act on inflamed tissue by the inhibition of prostaglandin synthesis, pyrazolones produce analgesic/antipyretic effects associated with a much less potent anti-inflammatory effect on peripheral tissues. As shown in several animal species and also in humans, dipyrone acts on the central nervous system by the inhibition of prostanoids.1 2 Dipyrone has more than 20 known metabolites.3 A central hypothesis of immune mediated (hypersensitivity) drug reactions has been that drugs are metabolised to a reactive metabolite which can act as an hapten.4There are limited reports concerning the immunogenic potential of pyrazolone and pyrazolidine metabolites.5 6 Genetic heterogeneity could also predispose patients to adverse drug reactions by the formation or inability to detoxify a reactive metabolite.

In 1977 Szczeklik et al 7 put forward the hypothesis that, in sensitive patients, induction of asthmatic attacks by aspirin-like drugs is due to inhibition of tissue prostaglandin biosynthesis. In about …
Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis
Authors: S. Suri, S. E Gill, S. Massena de Camin, D. F McWilliams, D. Wilson, D. A Walsh
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Background</h3> Although certain types of sedentary behaviour have been linked to metabolic risk, prospective studies describing the links between sitting with incident diabetes are scarce and often do not account for baseline adiposity. We investigate the associations between context-specific sitting and incident diabetes in a cohort of mid-aged to older British civil servants. <h3>Methods</h3> Using data from the Whitehall II study (n=4811), Cox proportional hazards models (adjusted for age, sex, ethnicity, employment grade, smoking, alcohol intake, fruit and vegetable consumption, self-rated health, physical functioning, walking and moderate-to-vigorous physical activity, and body mass index (BMI)) were fitted to examine associations between total sitting and context–specific sitting time (work, television (TV), non-TV leisure time sitting at home) at phase 5 (1997–1999) and fasting glucose-defined incident diabetes up to 2011. <h3>Results</h3> Total sitting (HR of the top compared with the bottom group: 1.26; 95% CI 1.00 to 1.62; p=0.01) and TV sitting (1.33; 95% CI 1.03 to 1.88; p=0.05) showed associations with incident diabetes; once BMI was included in the model these associations were attenuated for both total sitting (1.19; 95% CI 0.92 to 1.55; p=0.22) and TV sitting (1.31; 95% CI 0.96 to 1.76; p=0.14). <h3>Conclusion</h3> We found limited evidence linking sitting and incident diabetes over 13 years in this occupational cohort of civil servants.