tbuckley/cabot-search huggingface dataset:
Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells
Authors: Tomokazu Souma, Michiaki Abe, Takashi Moriguchi, Jun Takai, Noriko Yanagisawa-Miyazawa, Eisuke Shibata, Yasutoshi Akiyama, Takafumi Toyohara, Takehiro Suzuki, Masayuki Tanemoto, Takaaki Abe, Hiroshi Sato, Masayuki Yamamoto, Sadayoshi Ito
Journal: Journal of the American Society of Nephrology (2011)

A highly acidic environment surrounds proximal tubular cells as a result of their reabsorption of HCO3−. It is unclear whether this luminal acidity affects proteinuria-induced progression of tubular cell damage. Here, we investigated the contribution of luminal acidity to superoxide (O2·−) production induced by oleic acid–bound albumin (OA-Alb) in proximal tubular cells. Acidic media significantly enhanced OA-Alb–induced O2·− production in the HK-2 proximal tubular cell line. Simultaneous treatment with both OA-Alb and acidic media led to phosphorylation of the intracellular pH sensor Pyk2. Highly phosphorylated Pyk2 associated with activation of Rac1, an essential subcomponent of NAD(P)H oxidase. Furthermore, knockdown of Pyk2 with siRNA attenuated the O2·− production induced by cotreatment with OA-Alb and acid. To assess whether luminal alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO3 feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O2·−-induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease.
Robert David Alexander ("Sandy") Coxon William Erik Norman Cummings Nigel John Hunter James MacMaster Macfie Frank McDowell James Barr McWhinnie David Rice John Cornelius Blair Serjeant Joseph Taylor Maurice Lionel Walt Robert James Alan Webb John Frederick ("Jock") Wilkinson
Authors: J. Rawlinson, T M Richards, D. Stevens, J M Macfie, I. McDowell, P. D Macdougall, H. M Rice, J. Mason, G G Bisley, F. Walt, J. Rimington, E Tibbetts
Journal: BMJ (1998)
Sensory neuropeptides and hypoxic pulmonary vasoconstriction in the rat.
Authors: D G McCormack, R G Rees, D Crawley, P J Barnes, T W Evans
Journal: Thorax (1993)

Endogenous vasodilators such as endothelially derived relaxant factor have been shown to modulate hypoxic pulmonary vasoconstriction. Sensory peptides such as substance P (SP) and calcitonin gene related peptide (CGRP) are also potent pulmonary vasodilators in both animals and humans. Their possible role in the modulation of the normal hypoxic pressor response has been examined in an isolated, ventilated, and blood perfused rat lung preparation.Animals (n = 7) were pretreated with 50 mg/kg capsaicin administered subcutaneously to deplete nerve endings of sensory neuropeptides. A control group (n = 7) received a subcutaneous dose of capsaicin vehicle. One week later the rats were killed and the rise in pulmonary artery pressure was measured during four successive periods of hypoxic ventilation (FIO2 0.03), and after four injections of angiotensin II (1.0 microgram).A 60% depletion of SP levels was measured in the sciatic nerves of animals treated with capsaicin. The hypoxic pressor response was not significantly altered in capsaicin treated animals compared with controls, except during the fourth hypoxic episode when it was augmented. The angiotensin II pressor response was the same in both groups during each of the injections.The sensory neuropeptide SP (and possibly CGRP) does not have a major role in modulating the pulmonary vascular response to hypoxia.
Nitrosoureas Inhibit the Stathmin-Mediated Migration and Invasion of Malignant Glioma Cells
Authors: Xing-Jie Liang, Yong Choi, Dan L. Sackett, John K. Park
Journal: Cancer Research (2008)

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement-related processes. Scratch wound-healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 micromol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects.
820 CD81 EXPRESSION ON LYMPHOCYTE SUBTYPES FOR DISCRIMINATION BETWEEN SUSTAINED VIROLOGIC RESPONSE AND RELAPSE IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH PEG-INTERFERON-ALFA AND RIBAVIRIN
Authors: M. Welker, W.P. Hofmann, C. Lange, E. Herrmann, C. Sarrazin, S. Zeuzem, B. Kronenberger
Journal: Journal of Hepatology (2011)
Cardiovascular Actions of Incretin-Based Therapies
Authors: John R. Ussher, Daniel J. Drucker
Journal: Circulation Research (2014)

Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9-36), a cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9-36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9-36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease.
Getting to the Guts of HIV Pathogenesis
Authors: Ronald S. Veazey, Andrew A. Lackner
Journal: The Journal of Experimental Medicine (2004)

Two groups have shown that, as in macaques infected with simian immunodeficiency virus (SIV), intestinal CD4(+) T cells are selectively and rapidly depleted in the intestine of HIV-infected patients. Depletion of intestinal CD4(+) T cells occurred at all stages of infection regardless of highly active antiretroviral therapy (HAART). Here we discuss the important implications of these papers for our understanding of HIV pathogenesis, treatment, and vaccine design.
A DENSIMETRIC METHOD FOR ASSAY OF SMALL AMOUNTS OF ANTIDIURETIC HORMONE
Authors: Niels A. Thorn
Journal: The Journal of Experimental Medicine (1957)

A sensitive and reproducible method for assay of antidiuretic activity, described in this paper, yielded accurate measurements in the range 60 to 540 micropressor units of pitressin, corresponding to about 15 to 130 micropressor units of arginine-vasopressin. The method differs from previous techniques mainly in using urine density, rather than urinary flow rates, as the index of response.
Impact of Sex and Age at Onset of Diabetes on Mortality From Ischemic Heart Disease in Patients With Type 1 Diabetes
Authors: Valma Harjutsalo, Christine Maric-Bilkan, Carol Forsblom, Per-Henrik Groop
Journal: Diabetes Care (2013)

OBJECTIVE To study whether ischemic heart disease (IHD) mortality among patients with type 1 diabetes (T1D) depends on the age at onset of diabetes and whether this effect is sex specific. RESEARCH DESIGN AND METHODS The study examined long-term IHD-specific mortality in a Finnish population-based cohort of patients with early-onset (0-14 years) and late-onset (15-29 years) T1D (n = 17,306). RESULTS During 433,782 person-years of follow-up, 478 deaths from IHD were observed. Within the early-onset cohort, the average crude mortality rate in women was 33.3% lower than in men, whereas in the late-onset cohort, mortality was only one-half that in men. In contrast, the standardized mortality ratio (SMR) was higher in women than in men (21.6 [95% CI 17.2-27.0] vs. 5.8 [5.1-6.6]). The difference in SMR between sexes was more striking in the early-onset cohort (women 52.8 [36.3-74.5], men 12.1 [9.2-15.8]). The SMR was also greater in women in the late-onset cohort (15.8 [11.8-20.7]) compared with men (5.0 [4.3-5.8]). The relative risk of dying from IHD was greatest in women aged <40 years and 40-60 years in the early- and late-onset cohorts, respectively. CONCLUSIONS The risk of mortality from IHD is exceptionally high in women with early-onset T1D compared with women in the background population. These observations underscore the importance of identifying risk factors early in women and delivering more-aggressive treatment after diagnosis.
What might dynamical intentionality be, if not computation?
Authors: Ronald L. Chrisley
Journal: Behavioral and Brain Sciences (1998)

(1) Van Gelder's concession that the dynamical hypothesis is not in opposition to computation in general does not agree well with his anticomputational stance. (2) There are problems with the claim that dynamic systems allow for nonrepresentational aspects of computation in a way in which digital computation cannot. (3) There are two senses of the “cognition is computation” claim and van Gelder argues against only one of them. (4) Dynamical systems as characterized in the target article share problems of universal realizability with formal notions of computation, but differ in that there is no solution available for them. (5) The dynamical hypothesis cannot tell us what cognition is, because instantiating a particular dynamical system is neither necessary nor sufficient for being a cognitive agent.
Predicting risk of osteoporotic fracture in men and women in England and Wales: prospective derivation and validation of QFractureScores
Authors: J. Hippisley-Cox, C. Coupland
Journal: BMJ (2009)

<b>Objective</b> To develop and validate two new fracture risk algorithms (QFractureScores) for estimating the individual risk of osteoporotic fracture or hip fracture over 10 years. <b>Design</b> Prospective open cohort study with routinely collected data from 357 general practices to develop the scores and from 178 practices to validate the scores. <b>Setting</b> General practices in England and Wales. <b>Participants</b> 1 183 663 women and 1 174 232 men aged 30-85 in the derivation cohort, who contributed 7 898 208 and 8 049 306 person years of observation, respectively. There were 24 350 incident diagnoses of osteoporotic fracture in women and 7934 in men, and 9302 incident diagnoses of hip fracture in women and 5424 in men. <b>Main outcome measures</b> First (incident) diagnosis of osteoporotic fracture (vertebral, distal radius, or hip) and incident hip fracture recorded in general practice records. <b>Results</b> Use of hormone replacement therapy (HRT), age, body mass index (BMI), smoking status, recorded alcohol use, parental history of osteoporosis, rheumatoid arthritis, cardiovascular disease, type 2 diabetes, asthma, tricyclic antidepressants, corticosteroids, history of falls, menopausal symptoms, chronic liver disease, gastrointestinal malabsorption, and other endocrine disorders were significantly and independently associated with risk of osteoporotic fracture in women. Some variables were significantly associated with risk of osteoporotic fracture but not with risk of hip fracture. The predictors for men for osteoporotic and hip fracture were age, BMI, smoking status, recorded alcohol use, rheumatoid arthritis, cardiovascular disease, type 2 diabetes, asthma, tricyclic antidepressants, corticosteroids, history of falls, and liver disease. The hip fracture algorithm had the best performance among men and women. It explained 63.94% of the variation in women and 63.19% of the variation in men. The D statistic values for discrimination were highest for hip fracture in women (2.73) and men (2.68) and were over twice the magnitude of the corresponding values for osteoporotic fracture. The ROC statistics for hip fracture were also high: 0.89 in women and 0.86 for men versus 0.79 and 0.69, respectively, for the osteoporotic fracture outcome. The algorithms were well calibrated with predicted risks closely matching observed risks. The QFractureScore for hip fracture also had good performance for discrimination and calibration compared with the FRAX (fracture risk assessment) algorithm. <b>Conclusions</b> These new algorithms can predict risk of fracture in primary care populations in the UK without laboratory measurements and are therefore suitable for use in both clinical settings and for self assessment (www.qfracture.org). QFractureScores could be used to identify patients at high risk of fracture who might benefit from interventions to reduce their risk.
Racial Disparity in Breast Cancer and Functional Germ Line Mutation in Galectin-3 (rs4644): A Pilot Study
Authors: Vitaly Balan, Pratima Nangia-Makker, Ann G. Schwartz, Young Suk Jung, Larry Tait, Victor Hogan, Tirza Raz, Yi Wang, Zeng Quan Yang, Gen Sheng Wu, Yongjun Guo, Huixiang Li, Judith Abrams, Fergus J. Couch, Wilma L. Lingle, Ricardo V. Lloyd, Stephen P. Ethier, Michael A. Tainsky, Avraham Raz
Journal: Cancer Research (2008)

Abstract For reasons largely unknown, Caucasian women are at a significantly higher risk of developing breast cancer than Asian women. Over a decade ago, mutations in BRCA1/2 were identified as genetic risk factors; however, the discovery of additional breast cancer genes and genes contributing to racial disparities are lacking. We report a functional germline mutation (polymorphism) in the galectin-3 gene at position 191 (rs4644) substituting proline with histidine (P64H), which results in susceptibility to matrix metalloproteinase cleavage and acquisition of resistance to drug-induced apoptosis. This substitution correlates with incidence of breast cancer and racial disparity. Genotype analysis of 338 Caucasian (194 disease free and 144 breast cancer patients) and 140 Asian (79 disease free and 61 breast cancer patients) women showed that the allele homozygous for H64 exists in disease free Caucasian and Asian women at a frequency of 12% and 5%, respectively, versus 37% and 82% in breast cancer patients. The data indicate that H/H allele is associated with increased breast cancer risk in both races. The data implicate galectin-3 H64 in breast cancer and explain, in part, the noted racial disparity, thus providing a novel target for diagnosis and treatment. [Cancer Res 2008;68(24):10045–50]
Frequency of Blood Glucose Monitoring in Relation to Glycemic Control in Patients With Type 2 Diabetes
Authors: Maureen I. Harris
Journal: Diabetes Care (2001)

OBJECTIVE—The aim of the study was to investigate the relationship between blood glucose level, measured as HbA1c, and frequency of self-monitoring in patients with type 2 diabetes. Daily self-monitoring is believed to be important for patients treated with insulin or oral agents to detect asymptomatic hypoglycemia and to guide patient and provider behavior toward reaching blood glucose goals. RESEARCH DESIGN AND METHODS—A national sample of patients with type 2 diabetes was studied in the third National Health and Nutrition Examination Survey. Data on therapy for diabetes, frequency of self-monitoring of blood glucose, and HbA1c values were obtained by structured questionnaires and by clinical and laboratory assessments. RESULTS—According to the data, 29% of patients treated with insulin, 65% treated with oral agents, and 80% treated with diet alone had never monitored their blood glucose or monitored it less than once per month. Self-monitoring at least once per day was practiced by 39% of those taking insulin and 5–6% of those treated with oral agents or diet alone. For all patients combined, the proportion of patients who tested their blood glucose increased with an increasing HbA1c value. However, when examined by diabetes therapy category, there was little relationship between HbA1c value and the proportion testing at least once per day or the proportion testing at least once per week. CONCLUSIONS—In this cross-sectional study of patients with type 2 diabetes, the increase in frequency of self-monitoring of blood glucose with increasing HbA1c value was associated with the higher proportion of insulin-treated patients in higher HbA1c categories. Within diabetes therapy categories, the frequency of self-monitoring was not related to glycemic control, as measured by HbA1c level.
Effects of inhaled saline and oxygen on noninvasive markers of airway and lung function
Authors: Myriam Ehret, Stefan Karrasch, Angelika Kronseder, Stefan Peters, Dennis Nowak, Rudolf A. Jörres, Uta Ochmann
Journal: European Respiratory Journal (2012)

Introduction:  Inhalation challenges have been shown to induce pulmonary effects, e.g. an increase in 8-isoprostane levels in exhaled breath condensate (EBC) by hyperoxic air. The current study examined the sensitivity of noninvasive measures such as bronchial (FeNO) and alveolar (NOalv) nitric oxide, diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO), and hydrogen peroxide (H 2 O 2 ) in EBC to detect alterations induced by oxidative or osmotic inhalative stress.   Methods:  20 healthy nonsmoking subjects aged 19-50y inhaled nebulised 3% hypertonic saline solution (HSS) over 20 min and 100% O 2  at a flow of 5l/min over 30 min on two days. Before and after inhalation spirometry, multiflow exhaled NO, DLCO and DLNO were measured and EBC was collected and analysed for H 2 O 2  using an optimised procedure with inhalation filter.   Results:  HSS inhalation induced a median decrease in FEV 1  of 3% (P 2 O 2 . Results for NOalv were ambiguous in both inhalation groups. Hyperoxic air did not cause significant changes in any other parameter.   Conclusion:  These results suggest that HSS inhalation not only causes slight airway obstruction but also induces alterations of fluid balance in the lung periphery that can be detected via DLNO but not DLCO. DLNO could thus be of clinical value in the diagnosis of mild pulmonary edema, e.g. related to cardiac dysfunction.  Supported by German Statutory accident insurance (DGUV), Berlin.
Conformational differences in major histocompatibility complex-peptide complexes can result in alloreactivity.
Authors: S Chattopadhyay, M Theobald, J Biggs, L A Sherman
Journal: The Journal of Experimental Medicine (1994)

Mutations within the class I major histocompatibility complex (MHC) molecule that affect a peptide binding can result in strong allogeneic responses. It is believed this reflects, in part, binding of a different set of endogenous peptides by each MHC molecule. We have examined the representation of allopeptides recognized by Kb-specific cytotoxic T lymphocytes (CTL) clones among targets that express either the Kb or the Kbm8 mutant. These class I molecules mutationally differ by several residues at the base of the peptide binding groove resulting in lack of recognition of bm8 targets by most Kb-specific CTL, and in strong mutual alloreactivity. Since these differences involve pockets in the base of the peptide binding groove that are presumed to contribute to the affinity of peptide binding, and there is evidence for differences in peptide binding by the mutant and wild type molecule, it was considered most likely that alloreactivity was due to binding of different sets of peptides by each of these molecules. Surprisingly, the allopeptides recognized by Kb-specific clones from a variety of responders, including bm8, are often found associated with both the wild type and mutant class I molecules. Although for some allopeptides the amount of peptide normally found associated with bm8 is less than that associated with Kb, reactivity could not be restored by increasing the amount of the relevant peptide. Thus, the basis for much of the alloreactivity observed in this particular mutant and wild type combination is not the presence or absence of the relevant allopeptide but rather the different conformation adapted by the peptide-MHC complex. These results allow us to conclude that strong alloreactive responses can result from T cell recognition of conformational differences between the stimulation and responder MHC molecules.
Coronary Artery Anomalies
Authors: Paolo Angelini
Journal: Circulation (2007)

Coronary artery anomalies (CAAs) are a diverse group of congenital disorders whose manifestations and pathophysiological mechanisms are highly variable. The subject of CAAs is undergoing profound evolutionary changes related to the definition, morphogenesis, clinical presentation, diagnostic workup, prognosis, and treatment of these anomalies. To understand the clinical impact of CAAs, the fundamental challenge is the firm establishment, for a particular type of CAA, of a mechanism capable of interference with the coronary artery’s function, which is to provide adequate blood flow to the dependent myocardium. The present review focuses on anomalous origination of a coronary artery from the opposite sinus—the subgroup of CAAs that has the most potential for clinical repercussions, specifically sudden death in the young. For this subgroup, solid diagnostic screening protocols should be established, especially for athletes and other young individuals subjected to extreme exertion. Intravascular ultrasonography is the preferred means to evaluate the mechanisms responsible for ischemia in anomalous origination of a coronary artery from the opposite sinus and other potentially significant CAAs. Patients symptomatic of anomalous origination of a coronary artery from the opposite sinus may undergo medical treatment/observation, coronary angioplasty with stent deployment, or surgical repair. To be competent to advise CAA carriers, especially in the context of sporting or military activities, cardiologists should undergo specific training in these disorders. Only multicenter collaboration on protocols dedicated to CAAs can give rise to the large-scale studies needed to define the prognosis and optimal treatment of these disorders.