tbuckley/cabot-search huggingface dataset:
Nephrogenic Diabetes Insipidus
Authors: ELENA ALBERTAZZI, DEBORAH ZANCHETTA, PASCALINE BARBIER, SARA FARANDA, ANNALISA FRATTINI, PAOLO VEZZONI, MIRELLA PROCACCIO, ALBERTO BETTINELLI, FRANCESCA GUZZI, MARCO PARENTI, BICE CHINI
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The aim of this study was to identify loss-of-function mutations of the V2 vasopressin receptor gene (AVPR2) in Italian patients affected by X-linked nephrogenic diabetes insipidus (NDI). Mutations were found in 15 of the 18 unrelated families investigated: nine of these mutations were previously unknown, including two affecting residues located in regions known to be important for determining the pharmacologic properties of the receptor, which were therefore functionally investigated. The first (A84D) involves a residue located near an aspartic acid (D85) that is highly conserved in all G protein-coupled receptors and that is believed to play a role in the process of their isomerization into functionally active and inactive states. The present study indicates that this mutation not only affects receptor folding in such a way as to lead to its retention inside the intracellular compartments but, as expected, also has profound effects on its binding and coupling properties. The second was a mutation of a tryptophan located at the beginning of the first extracellular loop (W99R) that greatly impaired the binding properties of the receptor and had a minor effect on its intracellular routing. Molecular analysis of the first extracellular loop bearing this mutation suggests that this residue plays a fundamental role in stabilizing the peptide/receptor interactions responsible for the high-affinity binding of agonists to the V2 receptor.
Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung Disease
Authors: J. Michael Collaco, Lori Vanscoy, Lindsay Bremer, Kathryn McDougal, Scott M. Blackman, Amanda Bowers, Kathleen Naughton, Jacky Jennings, Jonathan Ellen, Garry R. Cutting
Journal: JAMA (2008)

Disease variation can be substantial even in conditions with a single gene etiology such as cystic fibrosis (CF). Simultaneously studying the effects of genes and environment may provide insight into the causes of variation.To determine whether secondhand smoke exposure is associated with lung function and other outcomes in individuals with CF, whether socioeconomic status affects the relationship between secondhand smoke exposure and lung disease severity, and whether specific gene-environment interactions influence the effect of secondhand smoke exposure on lung function.Retrospective assessment of lung function, stratified by environmental and genetic factors. Data were collected by the US Cystic Fibrosis Twin and Sibling Study with missing data supplemented by the Cystic Fibrosis Foundation Data Registry. All participants were diagnosed with CF, were recruited between October 2000 and October 2006, and were primarily from the United States.Disease-specific cross-sectional and longitudinal measures of lung function.Of 812 participants with data on secondhand smoke in the home, 188 (23.2%) were exposed. Of 780 participants with data on active maternal smoking during gestation, 129 (16.5%) were exposed. Secondhand smoke exposure in the home was associated with significantly lower cross-sectional (9.8 percentile point decrease; P < .001) and longitudinal lung function (6.1 percentile point decrease; P = .007) compared with those not exposed. Regression analysis demonstrated that socioeconomic status did not confound the adverse effect of secondhand smoke exposure on lung function. Interaction between gene variants and secondhand smoke exposure resulted in significant percentile point decreases in lung function, namely in CFTR non-DeltaF508 homozygotes (12.8 percentile point decrease; P = .001), TGFbeta1-509 TT homozygotes (22.7 percentile point decrease; P = .006), and TGFbeta1 codon 10 CC homozygotes (20.3 percentile point decrease; P = .005).Any exposure to secondhand smoke adversely affects both cross-sectional and longitudinal measures of lung function in individuals with CF. Variations in the gene that causes CF (CFTR) and a CF-modifier gene (TGFbeta1) amplify the negative effects of secondhand smoke exposure.
Rate of Collagen Deposition During Healing and Ventricular Remodeling After Myocardial Infarction in Rat and Dog Models
Authors: Bodh I. Jugdutt, Michael J. Joljart, Mohammad I. Khan
Journal: Circulation (1996)

Background We hypothesized that the rate and amount of infarct collagen deposition during healing after myocardial infarction might influence ventricular remodeling in rat and dog models. The purpose of this study was to compare rates of infarct collagen deposition and ventricular remodeling in the two models. Methods and Results Infarcted rat and dog hearts were removed at fixed time intervals between 1 and 50 days for measuring remodeling parameters and infarct and noninfarct collagen content (mg/g hydroxyproline). Collagen was less in sham rat (n=29) than dog (n=30) ventricles (3.32 versus 4.57 mg/g, P &lt;.001) and markedly lower in the rat (n=48) than dog (n=59) infarcts throughout healing and by 50 days (9.98 versus 56.74 mg/g, P &lt;.0001). Infarct collagen leveled off earlier and healing (histology) was completed sooner in the rat. Infarct scars were also thinner in the rat, with more ( P &lt;.0001) thinning and bulging (mm/g), and greater increase in ventricular volume. Although the mass to volume ratio decreased ( P &lt;.001) in both models, global remodeling was different, with greater transverse axis widening and globularity in the dog. Although infarct size, transmurality, heart rate, filling pressure, and blood pressure were greater in the rat, infarcts 10% to 30% in size in both models showed similar differences in infarct collagen and remodeling. Conclusions Compared with dog infarcts, rat infarcts exhibited faster healing and infarct collagen deposition and markedly lower infarct collagen. In addition to larger, more transmural, and thinner infarcts, and greater hemodynamic load, the lower infarct collagen in that model might be an important factor in the greater regional remodeling.
Incidence, Presentation, and Prognosis of Malignancies in Ataxia-Telangiectasia: A Report From the French National Registry of Primary Immune Deficiencies
Authors: Felipe Suarez, Nizar Mahlaoui, Danielle Canioni, Chantal Andriamanga, Catherine Dubois d'Enghien, Nicole Brousse, Jean-Philippe Jais, Alain Fischer, Olivier Hermine, Dominique Stoppa-Lyonnet
Journal: Journal of Clinical Oncology (2014)

Purpose Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series. Patients and Methods In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT. Centralized review was performed on 60% of the lymphomas. Incidence rates were compared with the French population, and risk factors were analyzed. Results Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P &lt; .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P &lt; .001). Survival was improved in patients who achieved a major response to treatment (3.46 v 0.87 years for major v minor responses, respectively; P = .011). Immunodeficiency was associated with increased risk of cancer. ATM mutation type was associated with a difference in survival in the entire cohort but not with cancer incidence or cancer survival. Conclusion B-cell NHL, HL, and acute lymphoblastic leukemia occur at a high rate and earlier age than carcinomas in AT. T-PLLs are rarer than initially reported. Prognosis is poor, but patients may benefit from treatment with an improved survival.
Faecal alpha-1-antitrypsin and excretion of 111indium granulocytes in assessment of disease activity in chronic inflammatory bowel diseases.
Authors: W Fischbach, W Becker, J Mossner, W Koch, C Reiners
Journal: Gut (1987)

Intestinal protein loss in chronic inflammatory bowel diseases may be easily determined by measurement of alpha-1-antitrypsin (alpha 1-AT) stool concentration and alpha 1-AT clearance. Both parameters were significantly raised in 36 and 34 patients respectively with chronic inflammatory bowel diseases, compared with eight patients with non-inflammatory bowel diseases, or 19 healthy volunteers. There was wide range of overlap between active and inactive inflammatory disease. Contrary to serum alpha 1-AT, faecal excretion and clearance of alpha 1-AT did not correlate with ESR, serum-albumin, orosomucoid, and two indices of disease activity. A comparison of alpha 1-AT faecal excretion and clearance with the faecal excretion of 111In labelled granulocytes in 27 patients with chronic inflammatory bowel diseases, showed no correlation between the intestinal protein loss and this highly specific marker of intestinal inflammation. Enteric protein loss expressed by faecal excretion and clearance of alpha 1-AT does not depend on mucosal inflammation only, but may be influenced by other factors.
A Randomized, Controlled Trial With 6-Month Follow-Up of Repetitive Transcranial Magnetic Stimulation and Electroconvulsive Therapy for Severe Depression
Authors: Savitha Eranti, Andrew Mogg, Graham Pluck, Sabine Landau, Rick Purvis, Richard G. Brown, Robert Howard, Martin Knapp, Michael Philpot, Sophia Rabe-Hesketh, Renee Romeo, John Rothwell, Denzil Edwards, Declan M. McLoughlin
Journal: American Journal of Psychiatry (2007)

Objective: Repetitive transcranial magnetic stimulation (rTMS) has been reported to be as effective as electroconvulsive therapy (ECT) for major depression. The authors conducted a multicenter randomized, controlled trial to test the equivalence of rTMS with ECT. Method: Forty-six patients with major depression referred for ECT were randomly assigned to either a 15-day course of rTMS of the left dorsolateral prefrontal cortex (N=24) or a standard course of ECT (N=22). The primary outcome measures were the score on the 17-item Hamilton Depression Rating Scale (HAM-D) and the proportion of patients with remissions (Hamilton score, ≤8) at the end of treatment. Secondary outcomes included mood self-ratings on the Beck Depression Inventory-II and visual analogue mood scales, Brief Psychiatric Rating Scale (BPRS) score, and both self-reported and observer-rated cognitive changes. The patients were followed up after 6 months. Results: HAM-D scores at the end of treatment were significantly lower for ECT, with 13 patients (59.1%) achieving remission in the ECT group and four (16.7%) in the rTMS group. However, at 6 months the HAM-D scores did not differ between groups. Beck scale, visual analogue mood scale, and BPRS scores were lower for ECT at the end of treatment and remained lower after 6 months. Self- and observer-rated cognitive measures were similar in the two groups. Conclusions: rTMS was not as effective as ECT, and ECT was substantially more effective for the short-term treatment of depression.
Febrile temperatures can synchronize the growth of Plasmodium falciparum in vitro.
Authors: D Kwiatkowski
Journal: The Journal of Experimental Medicine (1989)

To investigate the possibility that the host fever response in malaria may affect parasite development, we studied the effect of temperature on Plasmodium falciparum in erythrocytic culture in vitro. Growth was markedly suppressed at 40 degrees C compared with 37 degrees C, due to disruption of the second half of the 48-h erythrocytic cycle. However, young intraerythrocytic parasites, which are highly exposed to fever during natural infection, appeared to develop normally at 40 degrees C. Because of the differential temperature sensitivity within the erythrocytic cycle, asynchronous cultures could be synchronized by transient elevations of temperature. Pronounced synchronization was observed when cultures were exposed to periodic elevations of temperature that simulated the 48-h fever cycle of tertian malaria. These findings indicate that malaria fever might act to promote parasite synchronization in vivo.
Early Predictors of Corticosteroid Treatment Failure in Icteric Presentations of Autoimmune Hepatitis Δ
Authors: Andrew D. Yeoman, Rachel H. Westbrook, Yoh Zen, Paola Maninchedda, Bernard C. Portmann, John Devlin, John G. O'Grady, Phillip M. Harrison, Michael A. Heneghan
Journal: Hepatology (2010)

Abstract Autoimmune hepatitis (AIH) typically responds to treatment in 90% of patients. Early prediction of treatment outcome would be advantageous in clinical practice. We evaluated whether parameters at initiation of therapy or changes in these parameters at day 3 and day 7 following corticosteroid initiation predicted treatment failure. Treatment-naive, jaundiced patients presenting to our tertiary unit between 1999-2009 were identified and mathematical models of prognosis in liver disease scores calculated at day 0, day 3, and day 7. Overall, 72 patients were identified (48 women, 24 men). Treatment failure occurred in 18% (13/72) of patients. At diagnosis, higher median bilirubin (451 μmol/L versus 262 μmol/L, P = 0.02), INR (1.62 versus 1.33, P = 0.005), model for endstage liver (MELD) score (26 versus 20, P = 0.02), MELD-sodium (Na) score (27 versus 22, P = 0.03) and United Kingdom endstage liver disease score (UKELD) score (59 versus 57, P = 0.01) significantly correlated with treatment failure. Analysis of area under the receiver operator characteristic curve (AUROC) values at day 7 identified change (Δ) bilirubin (AUROC 0.68), Δ creatinine (0.69), Δ MELD (0.79), Δ MELD-Na (0.83) and Δ UKELD (0.83) best predicted treatment failure. Specifically, a fall in UKELD of less than 2 points predicted treatment failure with a sensitivity of 85% and specificity of 68%. Of 13 treatment failures, nine required second-line immunosuppression, three required emergency transplant, and one died of sepsis. In total, four patients died in the treatment failure group compared with one in the responder group (4/13 = 31% versus 1/59 = 1.7%, P = 0.003). Conclusion: Approximately 20% of icteric AIH presentations fail corticosteroid therapy. This is associated with significant mortality and the need for emergency transplantation. Treatment failure is best predicted by change in MELD-Na and UKELD at day 7. Early identification of nonresponders may allow timely escalation of immunosuppression to prevent clinical deterioration. (Hepatology 2011;)
Preventing, Delaying, or Masking Type 2 Diabetes With Metformin in the Diabetes Prevention Program?
Authors: André J. Scheen
Journal: Diabetes Care (2003)

The secondary analysis of the Diabetes Prevention Program (DPP) showed that withdrawal of metformin for 1–2 weeks resulted in a trend to a higher conversion rate from impaired glucose tolerance to diabetes as compared with the placebo group (1). This resulted in a reduction by 26% of the so-called prevention effect of metformin, i.e., from 31% in the primary analysis (2) to 25% in the secondary analysis, a reduction in the incidence of diabetes that, however, remained highly significant as compared with placebo. The same trend was observed in the Study to Prevent (STOP)- NIDDM trial with acarbose after a longer washout …
Tenofovir salvage for nucleoside experienced patients: muddy waters?
Authors: D. Mutimer
Journal: Gut (2011)

Nucleoside and nucleotide analogues (NAs) have transformed the management of chronic hepatitis B virus (HBV) infection. Lamivudine was the first to be licensed for this purpose. Unfortunately, monotherapy was associated with a high rate of virological breakthrough due to selection of HBV with specific polymerase mutations.1 This makes it unsuitable for use in most circumstances, though low cost and widespread availability maintain its popularity in many countries. Adefovir was next to be licensed. Though less prone to the selection of drug-resistant species, many treated patients exhibited a partial response, and persistent serum HBV DNA positivity was frequently observed for those with high pre-treatment titres.2 Many patients with treatment failure due to lamivudine resistance were ‘rescued’ by switching to adefovir. It was then noted that the risk for selection and emergence of adefovir resistance mutations was greater in the lamivudine pre-treated cohort than had been observed during adefovir treatment of nucleoside treatment-naive patients.3 This was the first evidence that the outcome of HBV antiviral treatment might be compromised by the prior unsuccessful use of NAs. Subsequently, telbivudine, entecavir and tenofovir were licensed. The resistance profile of telbivudine is disappointing.4 However, both entecavir and tenofovir are potent antivirals and with little or no selection of resistant species during prolonged therapy.5–7 Thus, a number of expert guidelines recommend either entecavir or tenofovir for first-line oral treatment of treatment-naive patients with chronic HBV.8 9 Cost and availability have determined that many patients have had exposure to both lamivudine and adefovir, and a proportion of these have clinically significant levels of viral replication (ie, levels likely to be associated with progressive liver damage). Emerging data are examining the impact of prior lamivudine and adefovir exposure on response to tenofovir or entecavir.

For instance, in this issue of Gut , …
Modulated vasodilator responses to natriuretic peptides in rats exposed to chronic hypoxia
Authors: Y. Mitani, J. Maruyama, A. Yokochi, K. Maruyama, T. Yoshimoto, M Naruse, M Sakurai
Journal: European Respiratory Journal (2000)

Natriuretic peptides (NPs), such as atrial natriuretic peptide (ANP), C-type natriuretic peptide (CNP), and adrenomedullin (ADM), are endogenous vasodilators acting via specific receptors. This study addressed the question of how pulmonary artery (PA) responses to these peptides and the gene expression of their receptors are modulated in pulmonary hypertension rat models exposed to chronic hypoxia. In this study, isometric tension was measured in PA rings exposed to these NPs and 8-bromoguanosine 3', 5'-cyclic monophosphate (8-bromo-cGMP). It was compared with messenger ribonucleic acid (mRNA) levels of NP-A and -B receptors, which bind to ANP and CNP, respectively, as determined by ribonuclease (RNase) protection assay. Chronic hypoxia increased the maximal relaxation elicited by ANP, but the responses to CNP and 8-bromo-cGMP were unchanged. Chronic hypoxia did not change NP-A and -B receptor mRNA levels. The results showed that pulmonary artery response to atrial natriuretic peptide is selectively enhanced, possibly via a post-transcriptional modulation of its receptor in chronically hypoxia rats. These pharmacological characteristics of atrial natriuretic peptide are consistent with the hypothesis that the atrial natriuretic peptide system is protective against the progression of pulmonary hypertension.
Targeting the Mitogen-Activated Protein Kinase Pathway in the Treatment of Malignant Melanoma
Authors: David J. Panka, Michael B. Atkins, James W. Mier
Journal: Clinical Cancer Research (2006)

Abstract The mitogen-activated protein kinase (MAPK; i.e., Ras–Raf–Erk) pathway is an attractive target for therapeutic intervention in melanoma due to its integral role in the regulation of proliferation, invasiveness, and survival and the recent availability of pharmaceutical agents that inhibit the various kinases and GTPases that comprise the pathway. Genetic studies have identified activating mutations in either B-raf or N-ras in most cutaneous melanomas. Other studies have delineated the contribution of autocrine growth factors (e.g., hepatocyte growth factor and fibroblast growth factor) to MAPK activation in melanoma. Still, others have emphasized the consequences of the down-modulation of endogenous raf inhibitors, such as Sprouty family members (e.g., SPRY2) and raf-1 kinase inhibitory protein, in the regulation of the pathway. The diversity of molecular mechanisms used by melanoma cells to ensure the activity of the MAPK pathway attests to its importance in the evolution of the disease and the likelihood that inhibitors of the pathway may prove to be highly effective in melanoma treatment. MAPK inhibition has been shown to result in the dephosphorylation of the proapoptotic Bcl-2 family members Bad and Bim. This process in turn leads to caspase activation and, ultimately, the demise of melanoma cells through the induction of apoptosis. Several recent studies have identified non–mitogen-activated protein/extracellular signal-regulated kinase kinase–binding partners of raf and suggested that the prosurvival effects of raf and the lethality of raf inhibition are mediated through these alternative targets, independent of the MAPK pathway. Other studies have suggested that endothelial cells are the primary targets of raf inhibitors in vivo and that the antitumor effect of these agents are largely attributable to angiogenesis inhibition. This article reviews the genetic and biochemical factors contributing to MAPK activation in melanoma, the mechanisms by which inhibition of the pathway might prove deleterious to tumor cells, and the potential of MAPK inhibitors in the treatment of the disease.
Decreased miR-29 Suppresses Myogenesis in CKD
Authors: Xiaonan H. Wang, Zhaoyong Hu, Janet D. Klein, Liping Zhang, Fude Fang, William E. Mitch
Journal: Journal of the American Society of Nephrology (2011)

The mechanisms underlying the muscle wasting that accompanies CKD are not well understood. Animal models suggest that impaired differentiation of muscle progenitor cells may contribute. Expression of the myogenesis-suppressing transcription factor Ying Yang-1 increases in muscle of animals with CKD, but the mechanism underlying this increased expression is unknown. Here, we examined a profile of microRNAs in muscles from mice with CKD and observed downregulation of both microRNA-29a (miR-29a) and miR-29b. Because miR-29 has a complementary sequence to the 3′-untranslated region of Ying Yang-1 mRNA, a decrease in miR-29 could increase Ying Yang-1. We used adenovirus-mediated gene transfer to express miR-29 in C2C12 myoblasts and measured its effect on both Ying Yang-1 and myoblast differentiation. An increase in miR-29 decreased the abundance of Ying Yang-1 and improved the differentiation of myoblasts into myotubes. Similarly, using myoblasts isolated from muscles of mice with CKD, an increase in miR-29 improved differentiation of muscle progenitor cells into myotubes. In conclusion, CKD suppresses miR-29 in muscle, which leads to higher expression of the transcription factor Ying Yang-1, thereby suppressing myogenesis. These data suggest a potential mechanism for the impaired muscle cell differentiation associated with CKD.
941 ALKALINE PHOSPHATASE VALUES ARE A SURROGATE MARKER IN PREDICTION OF TRANSPLANT FREE SURVIVAL IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS – AN INTERNATIONAL, COLLABORATIVE ANALYSIS
Authors: W.J. Lammers, H.R. van Buuren, G.M. Hirschfield, A. Parès, T. Kumagi, L. Caballeria, P. Invernizzi, A. Lleo, P.M. Battezzati, C. Corpechot, A. Floreani, N. Cazzagon, M.J. Mayo, J.A. Talwalkar, M. Imam, A.K. Burroughs, G. Pieri, F. Nevens, A.L. Mason, R. Poupon, H.L.A. Janssen, K.D. Lindor, B.E. Hansen
Journal: Journal of Hepatology (2013)