tbuckley/cabot-search huggingface dataset:
Tolvaptan, a Selective Oral Vasopressin V<sub>2</sub>-Receptor Antagonist, for Hyponatremia
Authors: Robert W. Schrier, Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank S. Czerwiec, Cesare Orlandi
Journal: New England Journal of Medicine (2006)

Hyponatremia (serum sodium concentration, <135 mmol per liter) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V(2)-receptor antagonist that promotes aquaresis--excretion of electrolyte-free water--might be of benefit in hyponatremia.In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15 mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30.Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey.In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. (ClinicalTrials.gov numbers, NCT00072683 [ClinicalTrials.gov] [SALT-1] and NCT00201994 [ClinicalTrials.gov] [SALT-2].).
Role of lymphotoxin- in cigarette smoke-induced inflammation and lymphoid neogenesis
Authors: T. Demoor, K. R. Bracke, T. Maes, B. Vandooren, D. Elewaut, C. Pilette, G. F. Joos, G. G. Brusselle
Journal: European Respiratory Journal (2009)

In chronic obstructive pulmonary disease (COPD), chronic inflammation is accompanied by peribronchial lymphoid aggregates. Lymphotoxin (LT)-α, crucial in secondary lymphoid organogenesis, may be involved in lymphoid neogenesis. We examined cigarette smoke (CS)-induced pulmonary lymphoid neogenesis and inflammation <i>in vivo</i> in LTα knockout (LTα<sup>-/-</sup>) and wild-type (WT) mice and studied the expression of lymphoid chemokines by lung fibroblasts <i>in vitro</i>. T-cell numbers (in bronchoalveolar lavage fluid (BALF) and lungs) and lymphoid aggregate numbers were significantly higher in air-exposed LTα<sup>-/-</sup> mice than in WT animals, and increased upon chronic CS exposure in both genotypes. In contrast, local immunoglobulin A responses upon chronic CS exposure were attenuated in LTα<sup>-/-</sup> mice. CXC chemokine ligand (CXCL) 13 and CC chemokine ligand (CCL) 19 mRNA in total lung and CXCL13 protein level in BALF increased upon CS exposure in WT, but not in LTα<sup>-/-</sup> mice. <i>In vitro</i> lymphotoxin-β receptor (LTβR) stimulation induced CXCL13 and CCL19 mRNA in WT lung fibroblasts. Furthermore, <i>in vitro</i> exposure to CS extract upregulated CXCL13 mRNA expression in WT, but not in LTβR<sup>-/-</sup>, lung fibroblasts. In this murine model of COPD, CS induces pulmonary expression of lymphoid chemokines CXCL13 and CCL19 in a LTαβ–LTβR-dependent fashion. However, LTα is not required for CS-induced pulmonary lymphocyte accumulation and neogenesis of lymphoid aggregates.
Prognostic Factors in Metastatic Melanoma: A Pooled Analysis of Eastern Cooperative Oncology Group Trials
Authors: Judith Manola, Michael Atkins, Joseph Ibrahim, John Kirkwood
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To identify factors that are prognostic for survival in patients with metastatic melanoma treated in eight Eastern Cooperative Oncology Group (ECOG) trials conducted over the past 25 years. METHODS: We identified common, significant patient characteristics collected at baseline on 1,362 eligible patients for inclusion in a pooled analysis. Proportional hazards models were used to examine simultaneously the effects of multiple covariates on survival. RESULTS: Median survival was 6.4 months (95% confidence interval, 6.1 to 6.9 months.) Factors conferring the greatest increased risk of death included number of metastatic sites (relative risk [RR] = 1.12), ECOG performance status of 1 or more (RR = 1.49), or metastatic disease in the gastrointestinal (GI) tract (RR = 1.49), liver (RR = 1.44), pleura (RR = 1.35), or lung (RR = 1.19). Prior immunotherapy (RR = 0.84) and female sex (RR = 0.87) were associated with prolonged survival. Although only 12% of patients responded to protocol treatment, landmark analysis showed this to be a significant prognostic factor (RR = 0.57). A model based on three recent studies in which baseline values for alkaline phosphatase, lactate dehydrogenase (LDH), and platelets were available identified an increased number of sites of metastasis (RR = 1.30), abnormal LDH (RR = 1.89), abnormal alkaline phosphatase (RR = 1.76), abnormal platelets (RR = 1.63), and GI metastases (RR = 1.66) as prognostic for poorer survival. Response to treatment, when examined by landmark analysis of studies with laboratory parameters, was associated with decreased risk of death (RR = 0.47). CONCLUSION: This study demonstrates the importance and utility of laboratory parameters as prognostic factors for survival and confirmed the deleterious effects of multiple metastatic sites. Prior immunotherapy and female sex were associated with improved prognosis. Prognostic factors identified in this analysis are consistent with the findings of prior published studies and argue for the adoption of laboratory findings in the staging systems that are used for entry and stratification of clinical trials in the future.
APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination
Authors: Jeroen E.J. Guikema, Erin K. Linehan, Daisuke Tsuchimoto, Yusaku Nakabeppu, Phyllis R. Strauss, Janet Stavnezer, Carol E. Schrader
Journal: The Journal of Experimental Medicine (2007)

Antibody class switch recombination (CSR) occurs by an intrachromosomal deletion requiring generation of double-stranded breaks (DSBs) in switch-region DNA. The initial steps in DSB formation have been elucidated, involving cytosine deamination by activation-induced cytidine deaminase and generation of abasic sites by uracil DNA glycosylase. However, it is not known how abasic sites are converted into single-stranded breaks and, subsequently, DSBs. Apurinic/apyrimidinic endonuclease (APE) efficiently nicks DNA at abasic sites, but it is unknown whether APE participates in CSR. We address the roles of the two major mammalian APEs, APE1 and APE2, in CSR. APE1 deficiency causes embryonic lethality in mice; we therefore examined CSR and DSBs in mice deficient in APE2 and haploinsufficient for APE1. We show that both APE1 and APE2 function in CSR, resulting in the DSBs necessary for CSR and thereby describing a novel in vivo function for APE2.
Filaggrin loss-of-function mutations are not associated with atopic dermatitis that develops in late childhood or adulthood
Authors: H. Rupnik, M. Rijavec, P. Korošec
Journal: British Journal of Dermatology (2014)

The influence of filaggrin gene (FLG) mutations on early- vs. late-onset development of atopic dermatitis (AD), allergic contact dermatitis (ACD) and chronic irritant contact dermatitis (CICD) is not completely understood.To assess the association between FLG mutations and development of AD, ACD and CICD.This study assessed 241 patients with AD. AD developed during infancy in 85 patients, during childhood in 79 patients (32 early and 47 late) and during adulthood in 77 patients. We also included 100 patients with ACD and 44 with CICD, as well as 164 healthy controls. Four prevalent FLG loss-of-function mutations were genotyped (R501X, 2282del4, R2447X and S3247X).The 2282del4 mutation was significantly associated with a greater risk of AD in the entire group [odds ratio (OR) 4·33, 95% confidence interval (CI) 1·26-14·96]. However, the 2282del4 mutation was associated only with AD that developed during infancy or in early childhood (≤ 8 years: OR 20·91, 95% CI 2·73-159·9), not with AD development in late childhood or adulthood (> 8 or > 18 years), or ACD or CICD. Similar associations were also observed for the combined 2282del4 or R501X genotype. Carriers of FLG mutations also experienced a longer duration of AD and required hospitalization more often.FLG mutations are associated with only the early onset of AD, not late onset. Other factors should receive attention in patients with late-onset AD.
19 DARK CHOCOLATE ATTENUATES THE POST-PRANDIAL INCREASE IN HVPG IN PATIENTS WITH CIRRHOSIS AND PORTAL HYPERTENSION
Authors: A. De Gottardi, A. Berzigotti, S. Seijo, M. D'Amico, J. Abraldes, J.C. Garcia-Pagán, J. Bosch
Journal: Journal of Hepatology (2010)
T Cell Receptor–γ/δ Cells Protect Mice from Herpes Simplex Virus Type 1–induced Lethal Encephalitis
Authors: Roger Sciammas, P. Kodukula, Q. Tang, R.L. Hendricks, J.A. Bluestone
Journal: The Journal of Experimental Medicine (1997)

Increased numbers of T cell receptor (TCR)-γ/δ cells have been observed in animal models of influenza and sendai virus infections, as well as in patients infected with human immunodeficiency virus and herpes simplex virus type 1 (HSV-1). However, a direct role for TCR-γ/δ cells in protective immunity for pathogenic viral infection has not been demonstrated. To define the role of TCR-γ/δ cells in anti–HSV-1 immunity, TCR-α−/− mice treated with anti– TCR-γ/δ monoclonal antibodies or TCR-γ/δ × TCR-α/β double-deficient mice were infected with HSV-1 by footpad or ocular routes of infection. In both models of HSV-1 infection, TCR-γ/δ cells limited severe HSV-1–induced epithelial lesions and greatly reduced mortality by preventing the development of lethal viral encephalitis. The observed protection resulted from TCR-γ/δ cell–mediated arrest of both viral replication and neurovirulence. The demonstration that TCR-γ/δ cells play an important protective role in murine HSV-1 infections supports their potential contribution to the immune responses in human HSV-1 infection. Thus, this study demonstrates that TCR-γ/δ cells may play an important regulatory role in human HSV-1 infections.
Reply to Jyotirmoy Das, Sudhir Kumar, Sangeeta Khanna, and Yatin Mehta's Letter to the Editor re: Mani Menon, Akshay Sood, Mahendra Bhandari, et al. Robotic Kidney Transplantation with Regional Hypothermia: A Step-by-step Description of the Vattikuti Urology Institute–Medanta Technique (IDEAL Phase 2a). Eur Urol 2014;65:991–1000
Authors: Rajesh Ahlawat, Guruswamy Balakrishnan, Vijay Kher, Mani Menon
Journal: European Urology (2014)
Early Glucose Abnormalities in Cystic Fibrosis Are Preceded by Poor Weight Gain
Authors: Shihab Hameed, John R. Morton, Adam Jaffé, Penny I. Field, Yvonne Belessis, Terence Yoong, Tamarah Katz, Charles F. Verge
Journal: Diabetes Care (2009)

OBJECTIVE Progressive β-cell loss causes catabolism in cystic fibrosis. Existing diagnostic criteria for diabetes were based on microvascular complications rather than on cystic fibrosis–specific outcomes. We aimed to relate glycemic status in cystic fibrosis to weight and lung function changes. RESEARCH DESIGN AND METHODS We determined peak blood glucose (BGmax) during oral glucose tolerance tests (OGTTs) with samples every 30 min for 33 consecutive children (aged 10.2–18 years). Twenty-five also agreed to undergo continuous glucose monitoring (CGM) (Medtronic). Outcome measures were change in weight standard deviation score (wtSDS), percent forced expiratory volume in 1 s (%FEV1), and percent forced vital capacity (%FVC) in the year preceding the OGTT. RESULTS Declining wtSDS and %FVC were associated with higher BGmax (both P = 0.02) and with CGM time &amp;gt;7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG120 min. A decline in %FEV1 was related to CGM time &amp;gt;7.8 mmol/l (P = 0.02). Using receiver operating characteristic (ROC) analysis to determine optimal glycemic cutoffs, CGM time above 7.8 mmol/l ≥4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BGmax ≥8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG120 min did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG120 min ≥11.1 mmol/l, the decline in wtSDS was worse if BGmax was ≥8.2 mmol/l (−0.3 ± 0.4 vs. 0.0 ± 0.4 for BGmax &amp;lt;8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was ≥4.5% (−0.3 ± 0.4 vs. 0.1 ± 0.2 for time &amp;lt;4.5%, P = 0.01). CONCLUSIONS BGmax ≥8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l ≥4.5% are associated with declining wtSDS and lung function in the preceding 12 months.
THE DISTRIBUTION OF S35-LABELED BOVINE SERUM ALBUMIN IN NEWBORN AND IMMUNOLOGICALLY TOLERANT ADULT RABBITS
Authors: Justine S. Garvey, Donald V. Eitzman, Richard T. Smith
Journal: The Journal of Experimental Medicine (1960)

The fate of injected S(35)-labeled sulfanilic acid-azoalbumin in the serum, various organs, and liver fractions was compared in the newborn and adult rabbit and in specifically unresponsive and normal adult rabbits. Exponential decay of the injected antigen without the usual immune phase of elimination was observed in newborn and unresponsive adult animals. Comparison of organ distribution of radioactivity in adults and animals injected at birth and 21 days of age showed persistence in the liver at least as long as 3 weeks in all groups (which was the time chosen for observation). The slight differences in spleen and thymus concentrations with age are of undetermined significance. Comparison of the organ distribution of antigen in unresponsive adult rabbits and in normal ones showed slight differences which were similar to those predicted from previous immunization of adults which gave low grade antibody response. There was a slight selective accumulation of antigen in the nuclear fraction of liver homogenates of unresponsive animals, but no other differences were observed.
Global burden of chronic pulmonary aspergillosis complicating sarcoidosis
Authors: David W. Denning, Alex Pleuvry, Donald C. Cole
Journal: European Respiratory Journal (2012)

Chronic pulmonary aspergillosis (CPA) may complicate pulmonary sarcoidosis. We re-estimated the global burden of sarcoidosis and the burden of CPA complicating sarcoidosis. We searched the literature and reference lists of retrieved papers to identify all published sarcoidosis incidence and prevalence data. We estimated the frequency of CPA from 11 papers relating to &gt;3,000 patients with sarcoidosis to derive CPA patient numbers. We applied an annual attrition rate of 15% (range 10–25%) to estimate the global burden of CPA. We estimate that the annual incidence of sarcoidosis is 344,000 patients worldwide and the prevalence is ∼1,238,000 cases, distributed as follows: 165,979 in Europe, 224,000 in the Americas, 492,892 in Africa, 80,023 in the Eastern Mediterranean, 41,660 in the West Pacific and 234,010 in Southeast Asia. CPA complicates sarcoidosis in 3–12% of cases. Using a 6% frequency, we estimate a global burden of 71,907 (range 35,954–143,815 (3–12%)) CPA cases complicating sarcoidosis, with 24% and 37% of cases estimated to be present in the Americas and Africa, because of the higher incidence of sarcoidosis in black people. As CPA responds to long-term antifungal therapy, which may prevent life-threatening haemoptysis, screening periodically for CPA in those with pulmonary sarcoidosis may be important, especially in patients requiring corticosteroid therapy.
Restricted use of albumin for spontaneous bacterial peritonitis
Authors: S. H Sigal, C. M Stanca, J. Fernandez, V. Arroyo, M. Navasa
Journal: Gut (2007)

Spontaneous bacterial peritonitis (SBP) may precipitate deterioration of circulatory function with severe hepatic insufficiency, hepatic encephalopathy, and type-1 hepatorenal syndrome (HRS) and has 30% hospital mortality despite infection resolution.1 Predictors of this acute-on-chronic liver failure include ascitic fluid concentrations of granulocytes and cytokines and renal and hepatic insufficiency at diagnosis.1–3 Endotoxemia and the inflammatory response precipitate renal failure (RF) by accentuating splanchnic vasodilatation and impairing cardiac function.3–5 Compensatory activation of the renin-angiotensin and sympathetic nervous systems further decrease renal perfusion. Volume expansion with albumin (1.5 g/kg day one, 1 g/kg day three) significantly reduces the incidence of HRS and hospital mortality.2

In the sole reported trial, only patients with serum bilirubin (bili) >68.4 μmol/l, blood urea nitrogen (BUN) >30 mg/dl or serum creatinine (Cr) >88.4 μmol/l appeared …
Oxaliplatin-Mediated Increase in Spleen Size As a Biomarker for the Development of Hepatic Sinusoidal Injury
Authors: Michael J. Overman, Dipen M. Maru, Chusilp Charnsangavej, Evelyn M. Loyer, Huamin Wang, Priyanka Pathak, Cathy Eng, Paulo M. Hoff, Jean-Nicolas Vauthey, Robert A. Wolff, Scott Kopetz
Journal: Journal of Clinical Oncology (2010)

Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury, with resultant sinusoidal damage and portal hypertension. We sought to explore the relationship between oxaliplatin induced hepatic sinusoidal injury, increases in spleen size, and the subsequent development of thrombocytopenia.We retrospectively assessed the relationship between chemotherapy exposure, changes in spleen size (determined by volumetric measurements), and platelet counts in 136 patients treated with adjuvant fluorouracil and oxaliplatin (FOLFOX) or fluoropyrimidine for stage II or III colorectal adenocarcinoma. Hepatic sinusoidal injury and changes in spleen size were graded in a separate population of 63 patients with metastatic colorectal cancer receiving fluoropyrimidine and oxaliplatin before liver resection.Spleen size increased in 86% of patients treated with adjuvant FOLFOX (P < .001), with a > or = 50% increase in 24% of patients. Spleen size did not significantly increase in patients treated with adjuvant fluoropyrimidine. Increases in spleen size correlated with cumulative oxaliplatin dose (P = .003). Patients with splenic enlargement > or = 50% had higher rates of thrombocytopenia in the first year after completion of chemotherapy (27% v 5%; P = .003). In patients with hepatic metastases treated with preoperative fluoropyrimidine and oxaliplatin, increases in spleen size was a predictor of higher histologic grades of sinusoidal injury in both univariate (P = .03) and multivariate (P = .02) analyses.Increases in spleen size correlate with increasing grade of hepatic sinusoidal injury and can serve as a simple method for identifying patients at risk for this toxicity. Oxaliplatin-induced increases in spleen size should be recognized as a potential etiology of persistent thrombocytopenia after oxaliplatin treatment.
Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter
Authors: Yoichi Miyazaki, Keisuke Oshima, Agnes Fogo, Brigid L.M. Hogan, Iekuni Ichikawa
Journal: Journal of Clinical Investigation (2000)

In the normal mouse embryo, Bmp4 is expressed in mesenchymal cells surrounding the Wolffian duct (WD) and ureter stalk, whereas bone morphogenetic protein (BMP) type I receptor genes are transcribed either ubiquitously (Alk3) or exclusively in the WD and ureter epithelium (Alk6). Bmp4 heterozygous null mutant mice display, with high penetrance, abnormalities that mimic human congenital anomalies of the kidney and urinary tract (CAKUT), including hypo/dysplastic kidneys, hydroureter, ectopic ureterovesical (UV) junction, and double collecting system. Analysis of mutant embryos suggests that the kidney hypo/dysplasia results from reduced branching of the ureter, whereas the ectopic UV junction and double collecting system are due to ectopic ureteral budding from the WD and accessory budding from the main ureter, respectively. In the cultured metanephros deprived of sulfated glycosaminoglycans (S-GAGs), BMP4-loaded beads partially rescue growth and elongation of the ureter. By contrast, when S-GAGs synthesis is not inhibited, BMP4 beads inhibit ureter branching and expression of Wnt 11, a target of glial cell-derived neurotrophic factor signaling. Thus, Bmp4 has 2 functions in the early morphogenesis of the kidney and urinary tract. One is to inhibit ectopic budding from the WD or the ureter stalk by antagonizing inductive signals from the metanephric mesenchyme to the illegitimate sites on the WD. The other is to promote the elongation of the branching ureter within the metanephros, thereby promoting kidney morphogenesis.
Evidence of Recombination in Putative Ancient Asexuals
Authors: A. Gandolfi
Journal: Molecular Biology and Evolution (2003)

Ancient asexuals have been considered to be a contradiction of the basic tenets of evolutionary theory. Barred from rearranging genetic variation by recombination, their reduced number of gene arrangements is thought to hamper their response to changing environments. For the same reason, it should be difficult for them to avoid the build-up of deleterious mutations. Several groups of taxonomically diverse organisms are thought to be ancient asexuals, although clear evidence for or against the existence of recombination events is scarce. Several methods have recently been developed for predicting recombination events by analyzing aligned sequences of a given region of DNA that all originate from one species. The methods are based on phylogenetic, substitution, and compatibility analyses. Here we present the results of analyses of sequence data from different loci studied in several groups of evolutionarily distant species that are considered to be ancient asexuals, using seven different types of analysis. The groups of organisms were the arbuscular mycorrhizal fungi (Glomales), Darwinula stevensoni (Darwinuloidea crustacean ostracods) and the bdelloid rotifers (Bdelloidea), which are thought to have been asexual for the last 400, 25–100, and 35–40 Myr, respectively. The seven different analytical methods evaluated the evolutionary relationships among haplotypes, and these methods had previously been shown to be reliable for predicting the occurrence of recombination events. Despite the different degree of genetic variation among the different groups of organisms, at least some evidence for recombination was found in all species groups. In particular, predictions of recombination events in the arbuscular mycorrhizal fungi were frequent. Predictions of recombination were also found for sequence data that have previously been used to infer the absence of recombination in bdelloid rotifers. Although our results have to be taken with some caution because they could signal very ancient recombination events or possibly other genetic variation of nonrecombinant origin, they suggest that some cryptic recombination events may exist in these organisms.