tbuckley/cabot-search huggingface dataset:
A1 Adenosine Receptor Activation Inhibits Inflammation, Necrosis, and Apoptosis after Renal Ischemia-Reperfusion Injury in Mice
Authors: H Thomas Lee, George Gallos, Samih H Nasr, Charles W Emala
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. It was previously demonstrated that preischemic A<sub>1</sub> adenosine receptor (AR) activation protects renal function after ischemia-reperfusion (IR) injury in rats. The role of the A<sub>1</sub> AR in modulating inflammation, necrosis, and apoptosis in the kidney after IR renal injury was further characterized. C57BL/6 mice were subjected to 30 min of renal ischemia, with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine or 2- chlorocyclopentyladenosine (selective A<sub>1</sub> AR antagonist and agonist, respectively). Plasma creatinine levels and renal inflammation, necrosis, and apoptosis were compared 24 h after renal injury. C57BL/6 mice that had been pretreated with the A<sub>1</sub> AR agonist demonstrated significantly improved renal function and reduced expression of inflammatory markers, necrosis, and apoptosis 24 h after IR injury. In contrast, C57BL/6 mice that had been pretreated with the A<sub>1</sub> AR antagonist demonstrated significantly worsened renal function and increased expression of inflammatory markers, necrosis, and apoptosis. In conclusion, it was demonstrated that endogenous and exogenous preischemic activation of the A<sub>1</sub> AR protects against IR injury <i>in vivo</i>, through mechanisms that reduce inflammation, necrosis, and apoptosis. E-mail: tl128@columbia.edu
Skin-resident memory CD4+ T cells enhance protection against <i>Leishmania major</i> infection
Authors: Nelson D. Glennie, Venkata A. Yeramilli, Daniel P. Beiting, Susan W. Volk, Casey T. Weaver, Phillip Scott
Journal: The Journal of Experimental Medicine (2015)

Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection after disease resolution, effective immune protection has not yet been achieved by human vaccines. Although circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFN-γ and remain resident in the skin when transplanted by skin graft onto naive mice. They function to recruit circulating T cells to the skin in a CXCR3-dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells.
Frequency, Significance and Therapy of the Mallory–Weiss Syndrome in Patients With Portal Hypertension
Authors: Karl J. Paquet, Miguel Mercado-Diaz, Johann F. Kalk
Journal: Hepatology (1990)

The files of patients who underwent emergency endoscopy in a 2-yr period (January 1985 to January 1987) in the Heinz-Kalk Hospital were analyzed to establish the frequency, significance and therapy of the Mallory-Weiss syndrome associated with portal hypertension, an association observed in 55 of 339 patients (16.2%). Portal hypertension was caused by cirrhosis in 53 patients and by a prehepatic block in two patients. For 21 of these patients (37%) with portal hypertension, Mallory-Weiss syndrome was the first bleeding manifestation. They numbered 6.2% of the whole population. In the remaining 34 patients (63%) sclerotherapy treatment had been previously performed. No lesions that suggested peptic esophagitis were seen in these 55 patients, although in 25 of them (45.4%) a gastroesophageal reflux was observed. The frequency of bleeding from a Mallory-Weiss tear was significantly higher in patients with advanced liver disease, particularly with Child-Pugh classifications C and B. In patients with prehepatic block, a hemorrhage from a Mallory-Weiss tear may occur, but the frequency is significantly lower than it is in patients with cirrhosis. The bleeding tear was treated by transendoscopic esophageal and cardial wall sclerosis (paravariceal technique) and was, in all cases, successfully controlled. Mallory-Weiss syndrome is observed more frequently in patients with portal hypertension and cirrhosis. Gastroesophageal reflux apparently does not play a major role in the pathogenesis of this syndrome. It may simply be the manifestation of an abnormal gastroesophageal function. Mallory-Weiss syndrome can also be observed as a cause of rebleeding in patients treated with chronic sclerotherapy. Paravariceal endoscopic sclerotherapy is apparently the treatment of first choice to stop hemorrhage.
Sildenafil does not improve 6 min walk distance in advanced idiopathic pulmonary fibrosis
Authors: M. Lavender
Journal: Thorax (2010)

It has been postulated that sildenafil, a phosphodiesterase-5 inhibitor and pulmonary artery vasodilator, may improve gas exchange in advanced idiopathic pulmonary fibrosis by preferentially increasing perfusion to well-ventilated areas of lung. This double-blind randomised placebo controlled study was designed to investigate the effect of sildenafil on 6 min walk distance (6MWD) in patients with advanced idiopathic …
The Long-Term Effects of Type 1 Diabetes Treatment and Complications on Health-Related Quality of Life
Authors: Alan M. Jacobson, Barbara H. Braffett, Patricia A. Cleary, Rose A. Gubitosi-Klug, Mary E. Larkin
Journal: Diabetes Care (2013)

OBJECTIVE To examine the long-term effects of type 1 diabetes treatment, metabolic control, and complications on health-related quality of life (HRQOL). RESEARCH DESIGN AND METHODS A total of 1,441 participants, initially 13–39 years of age, were followed for an average of 23.5 years as part of the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. The Diabetes Quality-of-Life questionnaire (DQOL) was administered annually during DCCT and every other year during EDIC. Biomedical data, including HbA1c levels, exposure to severe hypoglycemia, intercurrent psychiatric events, and development of diabetes complications were collected at regular intervals throughout the follow-up. RESULTS Mean total DQOL scores were not significantly different between the former DCCT intensive and conventional treatment groups (DCCT baseline, 78 ± 8 vs. 78 ± 9; EDIC year 17, 75 ± 11 vs. 74 ± 11). Over the course of the study, a drop of ≥5 points in DQOL score from DCCT baseline maintained on two successive visits occurred in 755 individuals and was associated with increased HbA1c, albumin excretion rate, mean blood pressure, BMI, and occurrence of hypoglycemic events requiring assistance. Lower DQOL scores after 23.5 years of follow-up were associated with prior development of retinopathy (P = 0.0196), nephropathy (P = 0.0019), and neuropathy (P &amp;lt; 0.0001) as well as self-reported chest pain (P = 0.0004), decreased vision in both eyes (P = 0.0005), painful paresthesias (P &amp;lt; 0.0001), recurrent urinary incontinence (P = 0.0001), erectile dysfunction (P &amp;lt; 0.0001), and history of psychiatric events (P &amp;lt; 0.0001). CONCLUSIONS Among DCCT/EDIC participants, worsening metabolic control, serious diabetes complications and their associated symptoms, and development of psychiatric conditions led to decreased HRQOL.
Carotid body oxygen sensing
Authors: J. López-Barneo, P. Ortega-Sáenz, R. Pardal, A. Pascual, J. I. Piruat
Journal: European Respiratory Journal (2008)

The carotid body (CB) is a neural crest-derived organ whose major function is to sense changes in arterial oxygen tension to elicit hyperventilation in hypoxia. The CB is composed of clusters of neuron-like glomus, or type-I, cells enveloped by glia-like sustentacular, or type-II, cells. Responsiveness of CB to acute hypoxia relies on the inhibition of O(2)-sensitive K(+) channels in glomus cells, which leads to cell depolarisation, Ca(2+) entry and release of transmitters that activate afferent nerve fibres. Although this model of O(2) sensing is generally accepted, the molecular mechanisms underlying K(+) channel modulation by O(2) tension are unknown. Among the putative hypoxia-sensing mechanisms there are: the production of oxygen radicals, either in mitochondria or reduced nicotinamide adenine dinucleotide phosphate oxidases; metabolic mitochondrial inhibition and decrease of intracellular ATP; disruption of the prolylhydroxylase/hypoxia inducible factor pathway; or decrease of carbon monoxide production by haemoxygenase-2. In chronic hypoxia, the CB grows with increasing glomus cell number. The current authors have identified, in the CB, neural stem cells, which can differentiate into glomus cells. Cell fate experiments suggest that the CB progenitors are the glia-like sustentacular cells. The CB appears to be involved in the pathophysiology of several prevalent human diseases.
A MOLECULAR PERSPECTIVE OF CTLA-4 FUNCTION
Authors: Wendy A. Teft, Mark G. Kirchhof, Joaquín Madrenas
Journal: Annual Review of Immunology (2005)

Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules' potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design immunotherapeutic agents that target CTLA-4.
Autophagy in Ischemic Heart Disease
Authors: Åsa B. Gustafsson, Roberta A. Gottlieb
Journal: Circulation Research (2009)

Autophagy is a major catabolic pathway by which mammalian cells degrade and recycle macromolecules and organelles. It plays a critical role in removing protein aggregates, as well as damaged or excess organelles, to maintain intracellular homeostasis and to keep the cell healthy. In the heart, autophagy occurs at low levels under normal conditions, and defects in this process cause cardiac dysfunction and heart failure. However, this pathway is rapidly upregulated under environmental stress conditions, including ATP depletion, reactive oxygen species, and mitochondrial permeability transition pore opening. Although autophagy is enhanced in various pathophysiological conditions, such as during ischemia and reperfusion, the functional role of increased autophagy is not clear and is currently under intense investigation. In this review, we discuss the evidence for autophagy in the heart in response to ischemia and reperfusion, identify factors that regulate autophagy, and analyze the potential roles autophagy might play in cardiac cells.
A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation
Authors: Morten Salling Olesen, Lena Refsgaard, Anders Gaarsdal Holst, Anders Peter Larsen, Søren Grubb, Stig Haunsø, Jesper Hastrup Svendsen, Søren-Peter Olesen, Nicole Schmitt, Kirstine Calloe
Journal: Cardiovascular Research (2013)

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 leading to an increase in the transient outward potassium current (Ito) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the auxiliary subunit K+ Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF. Two hundred and nine unrelated early-onset lone AF patients (<40 years) were recruited. The entire coding sequence of KCND3 and KCNIP2 was bidirectionally sequenced. One novel non-synonymous mutation A545P was found in KCND3 and was neither present in the control group (n = 432 alleles) nor in any publicly available database. The proband had onset of persistent AF at the age of 22, and no mutations in genes previously associated with AF were found. Electrophysiological analysis of KV4.3-A545P expressed in CHO-K1 cells, revealed that peak-current density was increased and the onset of inactivation was slower compared with WT, resulting in a significant gain-of-function both in the absence and the presence of KChIP2. Gain-of-function mutations in KV4.3 have previously been described in Brugada Syndrome, however, this is the first report of a KV4.3 gain-of-function mutation in early-onset lone AF. This association of KV4.3 gain-of-function and early-onset lone AF further supports the hypothesis that increased potassium current enhances AF susceptibility.
Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs
Authors: Arup Bhattacharya, Mukund Seshadri, Steven D. Oven, Károly Tóth, Mary M. Vaughan, Youcef M. Rustum
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and anticancer drugs could not be shown in vitro. Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery in the observed therapeutic synergy in vivo. Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d × 14 days orally). Changes in microvessel density (CD31), vascular maturation (CD31/α-smooth muscle actin), perfusion (Hoechst 33342/DiOC7), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin using high-performance liquid chromatography and fluorescence microscopy. Results: Double immunostaining of tumor sections revealed a marked reduction (∼40%) in microvessel density accompanying tumor growth inhibition following MSC treatment along with a concomitant increase in the vascular maturation index (∼30% &amp;gt; control) indicative of increased pericyte coverage of microvessels. Hoechst 33342/DiOC7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared with administration of doxorubicin alone. Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation in vivo, and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo.
<i>In Vivo</i>Fluorescence Lifetime Imaging for Monitoring the Efficacy of the Cancer Treatment
Authors: Yasaman Ardeshirpour, Victor Chernomordik, Moinuddin Hassan, Rafal Zielinski, Jacek Capala, Amir Gandjbakhche
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in vivo fluorescence lifetime imaging with HER2-targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors. Experimental Design: HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe injections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pretreatment size. Results: Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (∼0.13 ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment), the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03 ns. Conclusions: The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. Clin Cancer Res; 20(13); 3531–9. ©2014 AACR.
The Neuropharmacology of Attention-Deficit Hyperactivity Disorder
Authors: Alan J. Zametkin, Breck G. Borcherding
Journal: Annual Review of Medicine (1989)

Attention-deficit hyperactivity disorder, as described in the American Psychiatric Association's diagnostic manual DSM III-R (1), is a broadly defined syndrome of cognitive and behavioral problems that were originally found in children, but that have been increasingly identified in adults who had similar complaints in childhood (2). This paper briefly reviews the definition and treatment of this syndrome in children, evidence for specific neurochemical abnormalities, and effects of stimulants on neurochemistry. Finally, problems of diagnosis and treatment in adults are discussed.
Familial Aggregation of Pulmonary Function in a Rural Chinese Community
Authors: XIPING XU, JIANHUA YANG, CHANGZHONG CHEN, BINYAN WANG, YONTONG JIN, ZHIAN FANG, XIAOBIN WANG, SCOTT T. WEISS
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We investigated familial aggregation of pulmonary function among asthma index families and randomly selected nuclear families in a rural community in China. Measurements of pulmonary function and related risk factors were obtained from each family member. A generalized estimation equation model was used to explore the independent relation of pulmonary function among family members, with adjustment for sex, age, height, weight, education, smoking, and asthma status. There was a significant parent-child and sib-sib correlation of pulmonary function. The parent-child correlation of pulmonary function was similar for the first and second children. The correlation was greatest between sib-sibs, followed by mother-child, and less pronounced between father-child among asthma families. The rate of reduced pulmonary function in a subsequent sibling was lowest (4.0%) when both of the parents and the first sibling were in the high-pulmonary-function tertile (high-high group) and was highest (18.4%) when both the parents and the first sibling were in the low-pulmonary-function tertile (low-low group). The rates were intermediate if only the parents (7.0%, low-high group) or only the first sibling (11.5%, high-low group) was in the reduced-pulmonary-function tertile. Our data indicate a strong familial aggregation of pulmonary function in both asthma and random families in this population. Xu X, Yang J, Chen C, Wang B, Jin Y, Fang Z, Wang X, Weiss ST. Familial aggregation of pulmonary function in a rural Chinese community.
Developing and evaluating complex interventions: the new Medical Research Council guidance
Authors: Peter Craig, Paul Dieppe, Sally Macintyre, Susan Michie, Irwin Nazareth, Mark Petticrew
Journal: BMJ (2008)

<h3>Abstract</h3> DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 <i>cis</i> methylation QTLs (meQTLs)—i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs. <h3>Author Summary</h3> DNA methylation is an important epigenetic mark that contributes to many biological processes including the regulation of gene expression. Genetic variation has been associated with quantitative changes in DNA methylation (meQTLs). We identified thousands of meQTLs using an assay that allowed us to measure methylation levels at around 300 thousand cytosines. We found that meQTLs are enriched with loci that is also associated with quantitative changes in gene expression, DNase I hypersensitivity, PolII occupancy, and a number of histone marks. This suggests that many molecular events are likely regulated in concert. Finally, we found that changes in transcription factor binding as well as transcription factor abundance are associated with changes in DNA methylation near transcription factor binding sites. This work contributes to our understanding of the regulation of DNA methylation in the larger context of gene regulatory landscape.