tbuckley/cabot-search huggingface dataset:
Endothelin A Receptor Blockade and Endothelin B Receptor Blockade Improve Hypokalemic Nephropathy by Different Mechanisms
Authors: Shin-ichi Suga, Naomi Yasui, Fumiki Yoshihara, Takeshi Horio, Yuhei Kawano, Kenji Kangawa, Richard J. Johnson
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Hypokalemia causes renal tubulointerstitial injury with an elevation in renal endothelin-1 (ET-1). It was hypothesized that hypokalemic tubulointerstitial injury is ameliorated by the blockade of ET-A receptors (ETA), whereas ET-B receptor (ETB) antagonism may exacerbate the injury, because ETB is thought to mediate vasodilation. Rats were fed a K+-deficient diet alone (LC) or with an ETA-selective antagonist ABT-627 (LA) or an ETB-selective antagonist A-192621 (LB) for 8 wk. Control rats were on a normal K+ diet alone or with the ETA-selective or ETB-selective antagonists. The severity of hypokalemia was not significantly different among LA, LB, and LC. LC developed tubulointerstitial injury with an elevation of renal preproET-1 mRNA level. There was an increase in tubular osteopontin expression, macrophage infiltration, collagen accumulation, and tubular cell hyperplasia. ETA blockade significantly ameliorated all parameters for renal injury in the cortex without suppressing local ET-1 and ETA expression. By contrast, ETB blockade significantly reduced local ET-1 and ETA expression and improved the injury to a similar extent in the cortex. In the medulla, ETA or ETB blockade only partially blocked renal injury. ETA blockade did not affect BP in normokalemic or hypokalemic rats. ETB blockade induced a BP elevation with a decrease in urinary Na+ excretion in normokalemic but not in hypokalemic rats. These results indicate that ET-1 can mediate hypokalemic renal injury in two different ways: by directly stimulating ETA and by locally promoting endogenous ET-1 production via ETB. Thus, ETA as well as ETB blockade may be renoprotective in hypokalemic nephropathy. E-mail: [email protected]
Minocycline induced arthritis associated with fever, livedo reticularis, and pANCA.
Authors: O Elkayam, M Yaron, D Caspi
Journal: Annals of the Rheumatic Diseases (1996)

OBJECTIVE: To describe a novel iatrogenic immunological reaction produced by minocycline. CASE REPORTS: The clinical course and laboratory results of three women who presented with similar rheumatological manifestations after a prolonged exposure to minocycline are described. All three presented a unique reaction manifested by fever, arthritis/arthralgia and livedo reticularis during treatment with minocycline for acne vulgaris. The clinical syndrome was associated with high titre of serum perinuclear anticytoplasmatic antibodies (p-ANCA) and antimyeloperoxidase antibody (anti-MPO). Symptoms resolved after stopping the drug and recurred promptly after rechallenge in all three patients. CONCLUSIONS: Minocycline, which is widely used in the treatment of acne, often without adequate supervision, may induce arthritis and livedo vasculitis associated with anti-MPO.
Reduced opsonisation of protein A containing Staphylococcus aureus in sera with cryoglobulins from patients with active systemic lupus erythematosus.
Authors: O Nived, C Linder, H Odeberg, B Svensson
Journal: Annals of the Rheumatic Diseases (1985)

Among a total of 41 patients with systemic lupus erythematosus (SLE) 11 of 14 patients with active disease had reduced capacity (p less than 0.05) to opsonify Staphylococcus aureus in undiluted sera, as compared with nine of 27 patients with inactive disease (p less than 0.02). The opsonic reduction in the active patients increased with the number of active organ systems (p less than 0.002). No correlation was found between reduced opsonisation and corticosteroid treatment, or serum concentrations of complement components (C) of the classical pathway, or bacteria-associated activated C3. When the cryoglobulin fraction of immune complexes (IC) was removed, normal opsonic capacity was restored, and the opsonic reduction could be transferred with the cryoglobulins to pooled serum. Increased IC values, as measured by C1q binding assay, were found in conjunction with reduced opsonic capacity (p less than 0.04). Since opsonisation in SLE sera of a protein A deficient strain of S. aureus was normal, reduced S. aureus phagocytosis in SLE sera may be explained by IC binding to staphylococcal protein A.
A central role of GPIb-IX in the procoagulant function of platelets that is independent of the 45-kDa GPIbα N-terminal extracellular domain
Authors: Catherine Ravanat, Catherine Strassel, Béatrice Hechler, Simone Schuhler, Gaëtan Chicanne, Bernard Payrastre, Christian Gachet, François Lanza
Journal: Blood (2010)
Systemic Arterial Vasodilation, Vasopressin, and Vasopressinase in Pregnancy
Authors: Robert W. Schrier
Journal: Journal of the American Society of Nephrology (2009)

Systemic arterial vasodilation in early pregnancy is accompanied by a compensatory rise in cardiac output and a decline in BP. This relative arterial underfilling in early pregnancy is coupled to stimulation of the renin-angiotensin-aldosterone system and hypotonicity. Arterial underfilling induces the nonosmotic stimulation of arginine vasopressin and upregulation of aquaporin 2 followed by trafficking of this water channel to the apical membrane of principal cells along the collecting ducts. In middle and late pregnancy, there also is a four-fold increase in vasopressinase, a cystine aminopeptidase produced by placental trophoblasts, which enhances the metabolic clearance of vasopressin. In the setting of preeclampsia, twins or triplets, or subclinical central diabetes insipidus, a transient diabetes insipidus may ensue from this vasopressinase-mediated degradation of N-terminal amino acids from the vasopressin molecule. Because desmopressin is already deaminated at the N-terminal, it is resistant to the effect of vasopressinase and therefore is the treatment of choice for transient diabetes insipidus of pregnancy.
Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance
Authors: David Martino, Yuk Jin Loke, Lavinia Gordon, Miina Ollikainen, Mark N Cruickshank, Richard Saffery, Jeffrey M Craig
Journal: Genome biology (2013)

Abstract Background The extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy. Results In a pilot, genome-scale study of DNA from buccal epithelium, a relatively homogeneous tissue, we show that one-third of the CpGs assayed show dynamic methylation between birth and 18 months. Although all classes of annotated genomic regions assessed show an increase in DNA methylation over time, probes located in intragenic regions, enhancers and low-density CpG promoters are significantly over-represented, while CpG islands and high-CpG density promoters are depleted among the most dynamic probes. Comparison of co-twins demonstrated that within-pair drift in DNA methylation in our cohort is specific to a subset of pairs, who show more differences at 18 months. The rest of the pairs show either minimal change in methylation discordance, or more similar, converging methylation profiles at 18 months. As with age-associated regions, sites that change in their level of within-pair discordance between birth and 18 months are enriched in genes involved in development, but the average magnitude of change is smaller than for longitudinal change. Conclusions Our findings suggest that DNA methylation in buccal epithelium is influenced by non-shared stochastic and environmental factors that could reflect a degree of epigenetic plasticity within an otherwise constrained developmental program.
Gamma heavy chain disease simulating alpha chain disease.
Authors: S W Bender, F Danon, J L Preud'homme, H G Posselt, P Roettger, M Seligmann
Journal: Gut (1978)

A young Turkish girl presented with all the clinicopathological features of a digestive form of alpha chain disease. A gamma heavy chain disease protein, however, was found in her serum and also in the cells invading the intestinal mucosa and mesenteric lymph nodes.
Docetaxel in Combination With Doxorubicin and Cyclophosphamide As Adjuvant Treatment for Early Node-Positive Breast Cancer: A Cost-Effectiveness and Cost-Utility Analysis
Authors: Sorrel E. Wolowacz, David A. Cameron, Helen C. Tate, Adrian Bagust
Journal: Journal of Clinical Oncology (2008)

To estimate the cost effectiveness of TAC (docetaxel, doxorubicin, and cyclophosphamide) compared with FAC (fluorouracil, doxorubicin, and cyclophosphamide) when administered as adjuvant therapy to women with node-positive early breast cancer in the United Kingdom (UK), both with and without primary prophylaxis with granulocyte colony-stimulating factor (G-CSF).A standard health economic Markov model estimated the cost and outcome for node-positive early breast cancer patients, from initiation of adjuvant chemotherapy to death. Patient-level data were used from the Breast Cancer International Research Group (BCIRG) 001 trial for estimates of the effect of chemotherapy on toxicity and outcome, and an observational data set collected from a UK university hospital provided estimates of resource use and outcome for patients with relapsed disease.Over a 10-year analysis timeframe, the incremental cost per life-year saved associated with the use of TAC rather than FAC was estimated as pound 15,418 (95% CI, pound 13,734 to pound 17,997) and the incremental cost per quality-adjusted life-year gained (IC/QALY) was pound 18,188 (95% CI, pound 14,161 to pound 32,422). The addition of primary G-CSF (lenograstim or filgrastim) to the TAC regimen resulted in an IC/QALY of pound 20,432. The results were most sensitive to the quality-of-life (QOL) score for patients in remission postchemotherapy. However, even if QOL was assumed to be as poor as for patients with metastatic disease, the IC/QALY estimate rose only to pound 32,430.The use of adjuvant TAC rather than FAC for node-positive early breast cancer patients is cost effective, despite the increased drug and toxicity treatment costs, and when primary G-CSF prophylaxis is given to all patients.
Mutation in<i>TET2</i>in Myeloid Cancers
Authors: François Delhommeau, Sabrina Dupont, Véronique Della Valle, Chloé James, Severine Trannoy, Aline Massé, Olivier Kosmider, Jean-Pierre Le Couedic, Fabienne Robert, Antonio Alberdi, Yann Lécluse, Isabelle Plo, François J. Dreyfus, Christophe Marzac, Nicole Casadevall, Catherine Lacombe, Serge P. Romana, Philippe Dessen, Jean Soulier, Franck Viguié, Michaela Fontenay, William Vainchenker, Olivier A. Bernard
Journal: New England Journal of Medicine (2009)

The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined.We conducted a combination of molecular, cytogenetic, comparative-genomic-hybridization, and single-nucleotide-polymorphism analyses to identify a candidate tumor-suppressor gene common to patients with myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia (AML). The coding sequence of this gene, TET2, was determined in 320 patients. We analyzed the consequences of deletions or mutations in TET2 with the use of in vitro clonal assays and transplantation of human tumor cells into mice.We initially identified deletions or mutations in TET2 in three patients with myelodysplastic syndromes, in three of five patients with myeloproliferative disorders, in two patients with primary AML, and in one patient with secondary AML. We selected the six patients with myelodysplastic syndromes or AML because they carried acquired rearrangements on chromosome 4q24; we selected the five patients with myeloproliferative disorders because they carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the Janus kinase 2 (JAK2) gene. TET2 defects were observed in 15 of 81 patients with myelodysplastic syndromes (19%), in 24 of 198 patients with myeloproliferative disorders (12%) (with or without the JAK2 V617F mutation), in 5 of 21 patients with secondary AML (24%), and in 2 of 9 patients with chronic myelomonocytic leukemia (22%). TET2 defects were present in hematopoietic stem cells and preceded the JAK2 V617F mutation in the five samples from patients with myeloproliferative disorders that we analyzed.Somatic mutations in TET2 occur in about 15% of patients with various myeloid cancers.
Oxygen-Derived Free Radicals in Postischemic Tissue Injury
Authors: Franklin H. Epstein, Joe M. McCord
Journal: New England Journal of Medicine (1985)

ISCHEMIA-induced pathologic processes are responsible for the single greatest cause of death in this country — heart disease; cerebral ischemia also makes a major contribution to our nation's morbidity and mortality. A relatively subtle indicator of ischemic injury to a tissue is enhanced capillary permeability, which results in edema formation. More pronounced damage may be manifested as leakage of cytosolic enzymes into the circulation or as microscopic or gross morphologic changes and tissue destruction. Recent evidence suggests that oxygen-derived free radicals may be abundantly produced in ischemic tissues, accounting for at least part of the damage that results.What exactly . . .
Hemodynamic Effects of Catecholamine Stimulation in Constrictive Pericarditis
Authors: FRED K. NAKHJAVAN, HARRY GOLDBERG
Journal: Circulation (1970)

Cardiac hemodynamic studies during control resting state and isoproterenol infusion were performed on five patients with constrictive pericarditis. During isoproterenol infusion, stroke volume increased by 60%, while there was no significant change in pulmonary wedge and right atrial mean pressures. The relatively fixed filling pressure is the indirect evidence of fixed diastolic size of the heart. However, the fixed cardiac size in diastole per se does not necessarily indicate hindrance to filling of the heart unless the limits of diastolic size of the heart are reached. It is concluded that during the supine resting state, when the influence of catecholamines is minimal, systolic emptying of ventricles is hindered. The systolic hindrance is, however, overcome by strong positive inotropic stimulation.
The Physiology, Signaling, and Pharmacology of Dopamine Receptors
Authors: Jean-Martin Beaulieu, Raul R. Gainetdinov
Journal: Pharmacological Reviews (2011)

G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson9s disease, schizophrenia, bipolar disorder, Huntington9s disease, attention deficit hyperactivity disorder (ADHD<sup>1</sup>), and Tourette9s syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.
Long-Term Consequences of Kidney Donation
Authors: Hassan N. Ibrahim, Robert Foley, LiPing Tan, Tyson Rogers, Robert F. Bailey, Hongfei Guo, Cynthia R. Gross, Arthur J. Matas
Journal: New England Journal of Medicine (2009)

The long-term renal consequences of kidney donation by a living donor are attracting increased appropriate interest. The overall evidence suggests that living kidney donors have survival similar to that of nondonors and that their risk of end-stage renal disease (ESRD) is not increased. Previous studies have included relatively small numbers of donors and a brief follow-up period.We ascertained the vital status and lifetime risk of ESRD in 3698 kidney donors who donated kidneys during the period from 1963 through 2007; from 2003 through 2007, we also measured the glomerular filtration rate (GFR) and urinary albumin excretion and assessed the prevalence of hypertension, general health status, and quality of life in 255 donors.The survival of kidney donors was similar to that of controls who were matched for age, sex, and race or ethnic group. ESRD developed in 11 donors, a rate of 180 cases per million persons per year, as compared with a rate of 268 per million per year in the general population. At a mean (+/-SD) of 12.2+/-9.2 years after donation, 85.5% of the subgroup of 255 donors had a GFR of 60 ml per minute per 1.73 m(2) of body-surface area or higher, 32.1% had hypertension, and 12.7% had albuminuria. Older age and higher body-mass index, but not a longer time since donation, were associated with both a GFR that was lower than 60 ml per minute per 1.73 m(2) and hypertension. A longer time since donation, however, was independently associated with albuminuria. Most donors had quality-of-life scores that were better than population norms, and the prevalence of coexisting conditions was similar to that among controls from the National Health and Nutrition Examination Survey (NHANES) who were matched for age, sex, race or ethnic group, and body-mass index.Survival and the risk of ESRD in carefully screened kidney donors appear to be similar to those in the general population. Most donors who were studied had a preserved GFR, normal albumin excretion, and an excellent quality of life.
Cytotoxicity of Dimethylacetamide and Pharmacokinetics in Children Receiving Intravenous Busulfan
Authors: Georg Hempel, Doris Oechtering, Claudia Lanvers-Kaminsky, Thomas Klingebiel, Josef Vormoor, Bernd Gruhn, Joachim Boos
Journal: Journal of Clinical Oncology (2007)

To assess the cytotoxicity and the exposure of N,N-dimethylacetamide (DMA) in children during high-dose therapy with an intravenous (IV) formulation of busulfan containing the potentially hepatotoxic and neurotoxic DMA as a solvent.Eighteen children aged 0.9 to 17.3 years (median age, 4.0 years) received IV busulfan in 15 doses of 0.7 to 1.0 mg/kg busulfan containing overall DMA amounts of between 5 mmol (437 mg) and 70.5 mmol (6,142 mg) per dose. Plasma concentrations of DMA and busulfan were quantified and analyzed using nonlinear mixed-effects modeling. Four different leukemic cell lines were incubated with DMA, and cytotoxicity was assessed in comparison with busulfan as well as in a combination reflecting the ratio in the formulation.Maximal plasma concentrations of DMA up to 3.09 mmol/L were observed. No accumulation of the solvent occurred. Instead, the trough levels decreased over the 4 treatment days. The population pharmacokinetic analysis revealed a clearance of 86.9 mL h(-1) kg(-1) +/- 27% that increased to 298 mL h(-1) kg(-1) on the fourth day and a volume of distribution of 469 mL kg +/- 22% (population mean +/- interindividual variability). DMA volume of distribution correlated with the volume of distribution of busulfan. The cytotoxicity of DMA in vitro was 3 orders of magnitude lower than that of busulfan. No synergism was observed.The lack of accumulation of DMA confirms that there is no safety concern related to the DMA content in this IV busulfan formulation. The contribution of DMA to the antileukemic effect of the formulation seems to be limited.
Decline in FEV1 and airflow limitation related to occupational exposures in men of an urban community
Authors: S Humerfelt, A Gulsvik, R Skjaerven, S Nilssen, G Kvåle, O Sulheim, E Ramm, E Eilertsen, S B Humerfelt
Journal: European Respiratory Journal (1993)

The purpose of this survey was to evaluate the effects of smoking and occupational exposures on the decline in forced expiratory volume in one second (FEV1), and the presence of airflow limitation (FEV1 x100/forced vital capacity (FVC) being < 65) at follow-up. A random sample of 1,933 men aged 22-54 years in Bergen, Norway, were invited into the survey. Smoking habits and measurements of FEV1 were recorded at the initial survey in 1965-1970 (n = 1,591) and at follow-up in 1988-1990 (n = 951). Past or present self-reported occupational exposures to eleven airborne agents (dusts, gases, vapours and fumes) and measurements of FVC were recorded at follow-up only. The decline in FEV1 was associated (p < 0.001) with age, body height and smoking. Smoking cessation reduced the decline to the level of lifetime nonsmokers. Accelerated decline in FEV1 was observed in subjects exposed to sulphur dioxide gas and to metal fumes. The adjusted decline in FEV1 increased progressively in subjects exposed to increasing numbers of occupational agents (test for trend: p < 0.01). Airflow limitation was observed in 9.5% at follow-up, and increased with age and cigarette consumption. In this community follow-up survey in men, smoking and occupational exposures to sulphur dioxide gas, metal fumes and the numbers of specific agents were found to be important predictors for accelerated decline in FEV1.