tbuckley/cabot-search huggingface dataset:
Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans
Authors: Bernhard Bielesz, Yasemin Sirin, Han Si, Thiruvur Niranjan, Antje Gruenwald, Seonho Ahn, Hideki Kato, James Pullman, Manfred Gessler, Volker H. Haase, Katalin Susztak
Journal: Journal of Clinical Investigation (2010)

Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.
Fluvastatin Ameliorates Podocyte Injury in Proteinuric Rats via Modulation of Excessive Rho Signaling
Authors: Shigeru Shibata, Miki Nagase, Toshiro Fujita
Journal: Journal of the American Society of Nephrology (2006)

Statins have been reported to confer renoprotection in several experimental models of renal disease through pleiotropic actions. The roles of statins in glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of fluvastatin on podocyte and tubulointerstitial injury in puromycin aminonucleoside (PAN)-induced nephrosis. PAN induced massive proteinuria and serum creatinine elevation on day 7, which were significantly suppressed by fluvastatin. Immunofluorescence studies of podocyte-associated proteins nephrin and podocin revealed diminished and discontinuous staining patterns in rats with PAN nephrosis, indicating severe podocyte injury. Fluvastatin treatment dramatically mitigated the abnormal staining profiles. Reduction of nephrin expression by PAN and its reversal by fluvastatin were confirmed by quantitative analyses. By electron microscopy, effacement of foot processes was ameliorated in fluvastatin-treated rats. Fluvastatin also mitigated tubulointerstitial damage in PAN nephrosis, with the repression of PAN-induced NF-kappaB and activator protein-1 activation in the kidneys. In addition, expression of activated membrane-bound small GTPase RhoA was markedly increased in the glomeruli of PAN nephrosis, which was inhibited by fluvastatin treatment. In cultured podocytes, fluvastatin suppressed PAN-evoked activation of RhoA and actin cytoskeletal reorganization. Furthermore, fasudil, a specific Rho-kinase inhibitor, successfully ameliorated PAN-induced podocyte damage and proteinuria. In summary, fluvastatin alleviated podocyte and tubulointerstitial injury in PAN nephrosis. The beneficial effects of fluvastatin on podocytes can be attributable to direct modulation of excessive RhoA activity. Our data suggest a therapeutic role for statins in clinical conditions that are relevant to podocyte injury.
Letter by O’Rourke Regarding Articles, “Prevalence of Long-QT Syndrome Gene Variants in Sudden Infant Death Syndrome,” “Cardiac Sodium Channel Dysfunction in Sudden Infant Death Syndrome,” and “Contribution of Long-QT Syndrome Genes to Sudden Infant Death Syndrome: Is It Time to Consider Newborn Electrocardiographic Screening?”
Authors: Michael F. O’Rourke
Journal: Circulation (2007)
Maternal smoking during pregnancy and adolescent depression at 18 years old: The Pelotas 1993 birth cohort, Brazil
Authors: Fernando C. Wehrmeister, Ana M.B. Menezes, Helen Gonçalves, Maria C. Assunção, Joseph Murray, Carolina B. Menezes, Luciana Anselmi, Pedro C. Hallal
Journal: European Respiratory Journal (2013)

Background: maternal smoking during pregnancy has been related to behavior disorders and psychiatric problems in adolescence. Aim: evaluate the association between maternal smoking during pregnancy and offspring depression at age 18 years old in a cohort in a middle income country (Brazil). Methods: the original cohort comprised 5,249 children born in the calendar year 1993. In 2011-12, all cohort members were sought to be evaluated. Maternal smoking during pregnancy was self-reported for the full gestational period and analyzed as the mean cigarettes smoked per day. Offspring depression at age 18 was assessed by the Mini International Neuropsychiatric Interview (MINI). We performed crude and adjusted logistic regression analyses (for confounders and mediators) to obtain odds ratios (OR). Results: In the 2011-12 visit the follow-up rate was 81.4% (n = 4106 + occurred deaths). The prevalence of depression among adolescents at age 18 was 6.8% (95% CI 6.1 – 7.6). Around 1/3 of the mothers smoked during pregnancy. Adolescents whose mothers had smoked during pregnancy had a higher risk (OR = 1.36; 95% CI 1.04 – 1.79) of depression at age 18, even after adjusting for confounders and mediators. A dose-response relationship for the association was also observed (<20 cigarettes/day [OR = 1.27; 95% CI 0.95 – 1.71] and 20 or more cigarettes/day [OR = 1.89; 95% CI 1.16 – 3.08]; p=0.008). Conclusions: maternal smoking during pregnancy was associated with a higher risk of depression among 18-year-old adolescents, suggesting that this harmful maternal behavior during pregnancy may significantly impair offspring mental health in late adolescence.
Dyslipidaemia, statins and rheumatoid arthritis
Authors: Michael T Nurmohamed, Ben A C Dijkmans
Journal: Annals of the Rheumatic Diseases (2009)

Cardiovascular morbidity and mortality are enhanced in rheumatoid arthritis (RA) and there is increasing evidence that this is due to the inflammatory process as well as to an increased prevalence of traditional cardiovascular risk factors, such as dyslipidaemia.
(2) Cockayne's syndrome
Authors: G.M. Murphy, P.G. Norris, J.L.M. Hawk
Journal: British Journal of Dermatology (1988)

Journal Article (2) Cockayne's syndrome Get access G.M. Murphy, G.M. Murphy St John's Hospital for Diseases of the Skin, London Search for other works by this author on: Oxford Academic Google Scholar P.G. Norris, P.G. Norris St John's Hospital for Diseases of the Skin, London Search for other works by this author on: Oxford Academic Google Scholar J.L.M. Hawk J.L.M. Hawk St John's Hospital for Diseases of the Skin, London Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 119, Issue s33, 1 July 1988, Page 62, https://doi.org/10.1111/j.1365-2133.1988.tb05405.x Published: 01 July 1988
High Calorie Intake Is Associated With Worsening Insulin Resistance and β-Cell Function in Hispanic Women After Gestational Diabetes Mellitus
Authors: Zhanghua Chen, Richard M. Watanabe, Daniel O. Stram, Thomas A. Buchanan, Anny H. Xiang
Journal: Diabetes Care (2014)

OBJECTIVE To assess associations between dietary intake and rates of change in insulin resistance and β-cell function in Hispanic women with prior gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS Sixty-two nondiabetic Hispanic women with pregnancies complicated by GDM completed oral and intravenous glucose tolerance tests and bioelectrical impedance measurements of body fat every 12–15 months postpartum for up to 12 years. Self-reported dietary intake was collected at all visits by structured food frequency questionnaires developed for Hispanics. Mixed-effects models were used to assess the relationship between dietary intake and rates of change in metabolic outcomes during follow-up. RESULTS The median length of follow-up from the first postpartum evaluation was 8.0 years (interquartile range 4.5–10.8 years). At baseline, women were 32 ± 5.7 years old and had a median calorie intake of 2,091 kcal/day. Over the course of follow-up, dietary intake did not change significantly. Higher baseline calorie intake was associated with a faster decline in insulin sensitivity, measured by the insulin sensitivity index (SI) (P = 0.029), and β-cell compensation, measured by the disposition index (DI) (P = 0.027), over time. These associations remained after adjustment for baseline characteristics; changes in BMI, calorie intake, levels of physical activity; and additional pregnancies during the follow-up period. The median rates were −0.06 vs. −0.02 units/year for SI and −810 vs. −692 units/year for DI for women with baseline calorie intake above versus below the cohort median. CONCLUSIONS High calorie intake is associated with a faster decline in insulin sensitivity and β-cell compensation in Hispanic women who are at high risk for type 2 diabetes, independent of adiposity.
Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
Authors: Sonny O. Ang, Hua Chen, Kiichi Hirota, Victor R. Gordeuk, Jaroslav Jelinek, Yongli Guan, Enli Liu, Adelina I. Sergueeva, Galina Y. Miasnikova, David Mole, Patrick H. Maxwell, David W. Stockton, Gregg L. Semenza, Josef T. Prchal
Journal: Nature Genetics (2002)
Asthma, airways responsiveness and air pollution in two contrasting districts of northern England.
Authors: G. Devereux, T. Ayatollahi, R. Ward, C. Bromly, S. J. Bourke, S. C. Stenton, D. J. Hendrick
Journal: Thorax (1996)

To assess the possible magnitude of differences between normal populations an epidemiological investigation of asthma was conducted in two strongly contrasting districts of northern England--rural West Cumbria on the west coast and urban Newcastle upon Tyne on the east coast.A cross sectional survey of randomly identified men aged 20-44 years was conducted in two phases: phase 1, a postal survey of respiratory symptoms and asthma medication in 3000 men from each district; and phase 2, a clinical assessment of 300 men from each district comprising investigator administered questionnaires, skin prick tests, spirometry, and methacholine challenge tests.The phase 1 (but not phase 2) study showed a small excess of "ever wheezed" in Newcastle (44% versus 40%), but neither phase showed differences between the two districts for recent wheeze or for other symptoms characteristic of asthma. There were also no differences with regard to diagnosed asthma, current asthma medication, spirometric parameters, or airways responsiveness. The prevalence of quantifiable airways responsiveness (PD20 < or = 6400 micrograms) was 27.7% in West Cumbria and 28.2% in Newcastle. Regression analyses showed that PD20 was negatively associated with atopy and positively with forced expiratory volume in one second (FEV1); that an association between PD20 and current smoking could be explained by diminished FEV1; and that PD20 was not related to geographical site of residence.Neither airways responsiveness nor the other parameters of diagnostic relevance to asthma varied much between the two study populations, despite the apparent environmental differences. The most obvious of these were the levels of outdoor air pollution attributable to vehicle exhaust emissions, the ambient levels of which were 2-10 fold greater in Newcastle. Our findings consequently shed some doubt over the role of such pollution in perceived recent increases in asthma prevalence. It is possible, however, that an air pollution effect in Newcastle has been balanced by asthmagenic effects of other agents in West Cumbria.
Renal bicarbonate reabsorption in the rat. III. Distal tubule perfusion study of load dependence and bicarbonate permeability.
Authors: Y L Chan, G Malnic, G Giebisch
Journal: Journal of Clinical Investigation (1989)

Using continuous microperfusion techniques, we studied the load dependence of bicarbonate reabsorption along cortical distal tubules of the rat kidney and their bicarbonate permeability. Net bicarbonate transport was evaluated from changes in tracer inulin concentrations and total CO2 measurements by microcalorimetry. Bicarbonate permeability was estimated from the flux of total CO2 along known electrochemical gradients into bicarbonate-and chloride-free perfusion solution containing 10(-4) M acetazolamide. Transepithelial potential differences were measured with conventional glass microelectrodes. Significant net bicarbonate reabsorption occurred at luminal bicarbonate levels from 5 to 25 mM, and at perfusion rates from 5 to 30 nl/min. Bicarbonate reabsorption increased in a load-dependent manner, both during increments in luminal bicarbonate concentration or perfusion rate, reaching saturation at a load of 250 pmol/min with a maximal reabsorption rate of approximately 75 pmol/min.mm. Rate of bicarbonate reabsorption was flow dependent at luminal concentrations of 10 but not at 25 mM. During chronic metabolic alkalosis, maximal rates of reabsorption were significantly reduced to 33 pmol/min.mm. The bicarbonate permeability was 2.32 +/- 0.13 x 10(-5) cm/s in control rats, and 2.65 +/- 0.26 x 10(-5) cm/s in volume-expanded rats. Our data indicate that at physiological bicarbonate concentrations in the distal tubule passive bicarbonate fluxes account for only 16-21% of net fluxes. At high luminal bicarbonate concentrations, passive bicarbonate reabsorption contributes moderately to net reabsorption of this anion.
Residual Plaque Burden, Delivered Dose, and Tissue Composition Predict 6-Month Outcome After Balloon Angioplasty and β-Radiation Therapy
Authors: Manel Sabaté, Johannes P. A. Marijnissen, Stéphane G. Carlier, I. Patrick Kay, Willem J. van der Giessen, Veronique L. M. A. Coen, Jurgen M. R. Ligthart, Eric Boersma, Marco A. Costa, Peter C. Levendag, Patrick W. Serruys
Journal: Circulation (2000)

Background —Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with β-radiation after BA. Methods and Results —Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a β-emitting 90 Sr/ 90 Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D v90 Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments ( P &lt;0.0001). D v90 Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components ( r =0.71; P =0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D v90 Adv, and type of plaque. Conclusions —Residual plaque burden, delivered dose, and tissue composition play a fundamental role in the volumetric outcome at 6-month follow-up after β-radiation therapy and BA.
Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas
Authors: Miriam J Smith, James O'Sullivan, Sanjeev S Bhaskar, Kristen D Hadfield, Gemma Poke, John Caird, Saba Sharif, Diana Eccles, David Fitzpatrick, Daniel Rawluk, Daniel du Plessis, William G Newman, D Gareth Evans
Journal: Nature Genetics (2013)
INDUCTION OF IMMUNITY AND TOLERANCE IN VITRO BY HAPTEN PROTEIN CONJUGATES
Authors: Marc Feldmann
Journal: The Journal of Experimental Medicine (1972)

Of many dinitrophenylated (DNP) protein conjugates tested, only DNP conjugated to polymerized flagellin (DNP-POL) (or the structurally related bacterial flagella) elicited a primary anti-DNP response in vitro. Other DNP proteins, such as DNP-monomeric flagellin (DNP-MON), were capable of inducing secondary responses in vitro. The capacity of DNP-POL to immunize spleen cell suspensions devoid of thymus-derived cells was the reason for the greater immunogenicity of DNP-POL, since even large numbers of flagellin-reactive activated thymus cells did not increase the anti-DNP response of normal spleen cells immunized with DNP-POL, whereas the thymus-dependent response to DNP-MON was markedly increased. The capacity of various batches of DNP-POL to immunize normal spleen cells in vitro varied markedly, depending on the number of DNP groups conjugated. DNP-POL with few DNP groups conjugated was immunogenic, but even at very high concentrations did not induce tolerance. In contrast, highly conjugated DNP-POL did not immunize, but readily induced tolerance. DNP-POL with intermediate degrees of conjugation were, like unconjugated polymeric flagellin, capable of inducing both immunity and tolerance. Since DNP-POL immunizes bone marrow-derived lymphocytes (B cells) directly the reduced response was not due to a masking of carrier determinants, necessary for cell collaboration. By using mixed DNP-5-(dimethylamino)-1-naphthalyl (dansyl)-POL conjugates, it was found that the inhibitory effect of a high degree of hapten conjugated was hapten specific. Depolymerization of DNP-POL to DNP-MON, which does not induce primary anti-DNP responses, was excluded by centrifugation analysis and electron microscopy. The relationship of the degree of hapten conjugation on DNP-POL to the capacity to induce tolerance and immunity in B cells has clarified the mechanism of immunological triggering of these cells. A model of the mechanism of "signal" discrimination between immunity and tolerance in B cells, based on these findings, is proposed.
Control of Brain Volume During Hyperosmolar and Hypoosmolar Conditions
Authors: S R Gullans, J G Verbalis
Journal: Annual Review of Medicine (1993)

The brain is particularly vulnerable to disturbances of body fluid osmolality. Studies in animals indicate that brain adaptation to osmotic stresses is a very complex process involving transient changes in water content and sustained changes in electrolyte and organic osmolyte contents. Appreciation of the nature of the adaptation process enables a better understanding of the marked variations in neurological sequelae that characterize hyper- and hypoosmolar states and provides a basis for more rational therapy.
Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells.
Authors: N Kume, M A Gimbrone
Journal: Journal of Clinical Investigation (1994)

Lysophosphatidylcholine (lyso-PC) is a major phospholipid component of atherogenic lipoproteins (e.g., oxidized LDL and beta-VLDL) and also can be generated through the action of leukocyte-secreted phospholipase A2 at sites of inflammation. We have previously reported that lyso-PC can activate cultured endothelia, resulting in the selective upregulation of adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. In this study, we have found that lyso-PC increased steady state mRNA levels for two smooth muscle/fibroblast-directed growth factors, the A and B chains of PDGF and heparin-binding EGF-like protein (HB-EGF), in cultured human endothelial cells. Lyso-PC did not upregulate the expression of certain other inducible endothelial genes, including E-selectin, IL-8, or monocyte chemoattractant protein-1 in the same cells, in contrast to the coordinate pattern of activation typically observed with other stimuli, such as TNF alpha, bacterial endotoxin, or PMA. Nuclear runoff assays documented an increased transcriptional rate for the HB-EGF gene in lyso-PC-treated cells. Northern blot analyses, after actinomycin D treatment, further indicated that the increased amounts of mRNA for HB-EGF, PDGF A and B chains, and intercellular adhesion molecule-1 were not dependent upon message stabilization. We conclude that lyso-PC can induce growth factor gene expression in cultured endothelial cells and thus may contribute to the migration and proliferation of smooth muscle cells and fibroblasts in various response-to-injury settings in vivo.
Association of elevated anti-sarcolemma, anti-idiotype antibody levels with the clinical and pathologic expression of chronic Chagas myocarditis.
Authors: M Sadigursky, B F von Kreuter, P Y Ling, C A Santos-Buch
Journal: Circulation (1989)

Antibody F(ab')2 fragments derived from the sera of four patients with histology-proven chronic Chagas myocarditis [cF(ab')2]-complexed antibody F(ab')2 fragments of children with acute Trypanosoma cruzi infection [aF(ab')2] in significantly higher molar ratios than those measured with F(ab')2 antibody fragments of normal subjects [nF(ab')2] from nonendemic areas (p less than 0.05). Anti-idiotype [cF(ab')2 X aF(ab')2] immune-complex formation was significantly blunted by preabsorption of cF(ab')2 with porcine heart atria sarcolemma (PAMs) immobilized on sepharose beads (inhibition, mean, 78.1 +/- 2.4%, n = 4). cF(ab')2 X nF(ab')2] immune-complex formation was also inhibited by pretreatment of cF(ab')2 with PAMs (inhibition, mean, 48.7 +/- 7.5%, n = 4). The sera of three groups of subjects from a geographic zone endemic for T. cruzi infection in the northeast of Brazil were assayed for free and immune-complexed IgG anti-acute T. cruzi infection F(ab')2. The indexed levels of free IgG anti-idiotype antibody activity and levels of IgG anti-idiotype immune complexes (IC') were markedly elevated in hospitalized patients with severe, decompensated chronic Chagas myocarditis (n = 23), and their IC' indexes were significantly higher than those measured in asymptomatic seropositive subjects from a nearby endemic village of the northeast of Brazil (Moniz Ferreira, n = 92, p less than 0.001) and in healthy seronegative villagers (n = 84, p less than 0.001). There exists a strong correlation between elevated IgG anti-sarcolemma, anti-idiotype activity levels and the clinical and pathologic expression of chronic Chagas myocarditis.