tbuckley/cabot-search huggingface dataset:
Transgenic Mice Overexpressing Mutant <i>PRKAG2</i> Define the Cause of Wolff-Parkinson-White Syndrome in Glycogen Storage Cardiomyopathy
Authors: Michael Arad, Ivan P. Moskowitz, Vickas V. Patel, Ferhaan Ahmad, Antonio R. Perez-Atayde, Douglas B. Sawyer, Mark Walter, Guo H. Li, Patrick G. Burgon, Colin T. Maguire, David Stapleton, Joachim P. Schmitt, X.X. Guo, Anne Pizard, Sabina Kupershmidt, Dan M. Roden, Charles I. Berul, Christine E. Seidman, J.G. Seidman
Journal: Circulation (2003)

Mutations in the gamma2 subunit (PRKAG2) of AMP-activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities: Wolff-Parkinson-White syndrome (WPW) and progressive degenerative conduction system disease. Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance.To elucidate the mechanism by which PRKAG2 mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways consistent with WPW. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation.Our data establish PRKAG2 mutations as a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiological findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe, Danon, and other glycogen storage diseases.
Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy
Authors: M. J. Overbeek, M. C. Vonk, A. Boonstra, A. E. Voskuyl, A. Vonk-Noordegraaf, E. F. Smit, B. A. C. Dijkmans, P. E. Postmus, W. J. Mooi, Y. Heijdra, K. Grünberg
Journal: European Respiratory Journal (2009)

Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a worse prognosis and response to pulmonary arterial hypertension (PAH) therapy than idiopathic PAH (IPAH). These differences have not yet been explained. Knowledge concerning histological pulmonary vasculopathy in SScPAH is limited in contrast to IPAH. Therefore, we explored patterns of vasculopathy in SScPAH compared with IPAH. Parameters of vasculopathy were assessed from lung tissue of eight PAH patients with limited cutaneous systemic sclerosis and 11 IPAH patients. Lung tissue was obtained at autopsy (n = 15), explantation (n = 3) and biopsy (n = 1). Pulmonary arterial/arteriolar intimal fibrosis was identified in all SScPAH patients and in three IPAH patients (p = 0.003). Fibrosis of pulmonary veins/venules was found in all SScPAH patients and in three IPAH patients (p = 0.003). In four SScPAH patients, fibrosis of veins/venules was focal and associated with capillary congestion as in pulmonary veno-occlusive disease (PVOD). Of the IPAH patients, 10 had unequivocal evidence of plexogenic arteriopathy compared with none of the SScPAH patients (p = 0.001). SScPAH is characterised by small vessel intimal fibrosis, which is associated with a PVOD-like pattern in some cases. This might explain its different clinical behaviour from IPAH. Small vessel intimal fibrosis may provide clues to elucidation of differences in pathogenetic mechanisms between the groups.
Thalidomide in the Treatment of the Mucocutaneous Lesions of the Behcet Syndrome
Authors: Vedat Hamuryudan
Journal: Annals of Internal Medicine (1998)

Background: Recurrent oral and genital ulcers are the most frequent problem in the management of the Behcet syndrome. Uncontrolled experience suggests that thalidomide may help prevent recurrences of these ulcers. Objective: To determine the efficacy of two thalidomide dosages in the treatment of mucocutaneous lesions of the Behcet syndrome. Design: Randomized, double-blind, placebo-controlled trial. Setting: Specialist outpatient clinic for the Behcet syndrome in Turkey. Patients: 96 male patients with the Behcet syndrome who primarily had mucocutaneous lesions without major organ involvement. Intervention: Thalidomide, 100 mg/d or 300 mg/d, or placebo for 24 weeks. Measurements: Sustained absence of any oral and genital ulceration during treatment (complete response) and changes in the number of mucocutaneous lesions. An additional evaluation was done 4 weeks after treatment ended. Results: A complete response occurred in 2 of the 32 patients (6% [95% CI, 0.8% to 20.8%]) receiving thalidomide, 100 mg/d; in 5 of the 31 patients (16% [CI, 5.5% to 33.7%]) receiving thalidomide, 300 mg/d; and in none of the 32 patients (0% [CI, 0% to 10.9%]) receiving placebo (P = 0.031). The suppressive effect of thalidomide with either dosage was evident at 4 weeks for oral ulcers (P < 0.001) and at 8 weeks for genital ulcers (P < 0.001) and follicular lesions (P = 0.008). This effect persisted during treatment but diminished rapidly after treatment was discontinued. Both thalidomide dosages led to significant increases in the number of erythema nodosum lesions during the first 8 weeks of treatment (P = 0.03). Polyneuropathy developed in 4 patients (1 in the 100-mg/d group and 3 in the 300-mg/d group); in 3 of these patients, the condition was diagnosed after the trial had ended. Conclusions: Thalidomide is effective for treating the oral and genital ulcers and follicular lesions of the Behcet syndrome. A dosage of 100 mg/d is as effective as a dosage of 300 mg/day.
High-mobility group box 1 (HMGB1)-toll-like receptor (TLR)4-interleukin (IL)-23-IL-17A axis in drug-induced damage-associated lethal hepatitis: Interaction of γδ T cells with macrophages
Authors: Xuefu Wang, Rui Sun, Haiming Wei, Zhigang Tian
Journal: Hepatology (2012)

Abstract Acetaminophen overdose causes acute liver inflammation with neutrophil infiltration; however, the mechanism of damage-associated inflammation has not been elucidated. In this study we found that the HMGB1-TLR4-IL-23-IL-17A axis played a crucial role in acetaminophen-induced infiltration of neutrophils and liver injury. Notably, interleukin (IL)-17A and IL-23 significantly increased after acetaminophen challenge. A neutralizing antibody against IL-17A attenuated the recruitment of neutrophils, accompanied by reduced liver injury. Only IL-17A + CD3 + γδ T cell receptor (TCR) + cells were significantly increased in the liver, and depletion of γδ T cells, but not CD4 + T cells or natural killer (NK)T cells significantly reduced IL-17A production, attenuated liver injury, and decreased the number of neutrophils in the liver. Furthermore, a neutralizing IL-23 p19 antibody or p40-deficiency significantly decreased the levels of IL-17A and infiltration of neutrophils. After in vitro stimulation, the percentage of IL-17A-producing γδ T cells and the levels of supernatant IL-17A from total hepatic lymphocytes or purified γδ T cells markedly increased in the presence with IL-23. Importantly, IL-23 and IL-17A were reduced after inhibition of macrophages and could not be induced in Toll-like receptor TLR4 −/− mice after acetaminophen challenge. Meanwhile, serum high-mobility group box 1 (HMGB1), a damage-associated molecule released from necrotic hepatocytes, increased after acetaminophen challenge, and the HMGB1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and the recruitment of hepatic neutrophils. HMGB1 stimulated the production of IL-23 by TLR4 +/+ but not by TLR4 −/− macrophages. Conclusion : The HMGB1-TLR4-IL-23 pathway in macrophages makes the generation of IL-17-producing γδ T cells, which mediates neutrophil infiltration and damage-induced liver inflammation. (Hepatology 2013)
Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes
Authors: Pinelopi Manousou, Evangelos Cholongitas, Dimitrios Samonakis, Emmanuel Tsochatzis, Alice Corbani, A P Dhillon, Janice Davidson, Manuel Rodríguez-Perálvarez, D Patch, J O'Beirne, D Thorburn, TuVinh Luong, K Rolles, Brian Davidson, P A McCormick, Peter Hayes, Andrew K Burroughs
Journal: Gut (2013)

<h3>Objective</h3> Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA). <h3>Design</h3> 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy. <h3>Results</h3> No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted. <h3>Conclusions</h3> Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. <h3>ISRCTN94834276</h3> —Randomised study for immunosuppression regimen in liver transplantation.
Hepatic Arterial Oxaliplatin Infusion Plus Intravenous Chemotherapy in Colorectal Cancer With Inoperable Hepatic Metastases: A Trial of the Gastrointestinal Group of the Fédération Nationale des Centres de Lutte Contre le Cancer
Authors: Michel Ducreux, Marc Ychou, Agnès Laplanche, Erick Gamelin, Philippe Lasser, Fares Husseini, François Quenet, Frédéric Viret, Jacques-Henri Jacob, Valérie Boige, Dominique Elias, Jean-Robert Delperro, Monique Luboinski
Journal: Journal of Clinical Oncology (2005)

Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks).Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m(2) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months.Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively.The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.
How political should a general medical journal be?
Authors: T. Delamothe
Journal: BMJ (2002)

The first anniversary of the attacks on the World Trade Center and the Pentagon passed without a word from the BMJ . We decided to mark the anniversary not by a minute's silence but by a whole issue's, judging we could add nothing of value to the tower of words that had already been erected in the victims' memory. In the week after the attacks, we restricted our coverage to two first person accounts written by people who had been in New York and Washington at the time. By contrast, the Lancet devoted nine articles to the attacks in its issue of 22 September 2001, with another 13 marking the first anniversary. Some of these articles contained very little medicine. So has the Lancet overdone it, confusing its role with that of a political weekly, or have we underdone it, neglecting the huge implications of the attacks?

Just how political should a general medical journal be? We define the BMJ 's scope as covering the “clinical, scientific, social, political, and economic factors affecting health.”1 This means that our content ranges over such …
Electrophysiological effects accompanying regression of left ventricular hypertrophy
Authors: A Botchway
Journal: Cardiovascular Research (2003)

Objective: The aim of this study was to investigate changes following regression of left ventricular hypertrophy (LVH). Methods: Electrophysiolological changes were recorded in isolated guinea-pig myocardial preparations. LVH was induced by constriction of the thoracic aorta and regression was followed after removal of the constriction. Sham-operated animals served as controls. Results: During 42 days constriction, heart/body weight ratio increased (3.19±0.49 vs. 3.85±0.83 g kg−1) and was accompanied by an increase of cell size. Forty-two days after clip removal, values had returned to control values. LVH increased action potential (AP) duration (mean 112% of control) and decreased conduction velocity (60.4±3.3 vs. 45.9±4.6 cm−1). These changes did not return to control after regression of LVH. The changes to condition velocity were attributed solely to increases of intracellular resistivity. The positive staircase response also decreased with LVH, but did recover upon regression. In isolated whole hearts, no changes to subepicardial action potential duration, QRS complex duration or AP refractory period were observed in LVH or its regression. During low-flow ischaemia AP duration shortened reversibly, the rate of shortening was more rapid in hypertrophied hearts but similar to control in regressed hearts. The incidence of ventricular tachyarrhythmias of fibrillation during low-flow ischaemia was similar in control, hypertrophied and regressed hearts. Conclusion: Morphological regression of LVH is not accompanied by reversal of electrophysiological changes measured in isolated preparations, whereas some aspects of contractile function to recover.
Suramin, an Active Drug for Prostate Cancer: Interim Observations in a Phase I Trial
Authors: M. A. Eisenberger, L. M. Reyno, D. I. Jodrell, V. J. Sinibaldi, K. H. Tkaczuk, R. Sridhara, E. G. Zuhowski, M. H. Lowitt, S. C. Jacobs, M. J. Egorin
Journal: JNCI Journal of the National Cancer Institute (1993)

Background : Previous studies indicate that suramin may be an active agent for treatment of solid tumors. The clinical use of suramin is complicated by a broad spectrum of toxic effects and complex pharmacology. Studies have suggested that the dose-limiting neurotox-icity of this agent is closely related to sustained plasma drug concentrations of 350 μg/mL or more. Purpose : This phase I clinical trial in patients with solid tumors was designed to determine whether plasma concentrations resulting in both antitumor activity and manageable toxicity could be achieved with short, intermittent infusions of suramin. Methods : Thirty-seven patients, including 33 with metastatic, hormone-refractory prostate cancer, collectively received 43 courses of suramin designed to maintain a plasma concentration range of 200–300, 175–275, or 150–250 (μg/mL. Patients received a test dose of 200 mg and an initial loading dose of 1000 mg/m 2 on day 1 of therapy. Subsequent suramin doses and schedules were individually determined using a strategy of adaptive control with feedback, which used a maximum a posteriori Bayesian algorithm to estimate individual pharmacokinetic parameters. Patients were treated until dose-limiting toxicity or progressive disease developed. Results : Thirty-five of the 37 study patients and 31 of the 33 with prostate cancer were assessable for toxicity and response. Treatment was discontinued in 28 patients because of dose-limiting toxicity consisting of a syndrome of malaise, fatigue, and lethargy; recurrent reduction in creatinine clearance of 50% or more; or axonal neuropathy. Evidence of major antitumor activity was observed in patients with prostate cancer treated at all three plasma drug concentrations. Measurable responses (one complete response and five partial responses) were noted in six of 12 patients with measurable disease. Twentyfour (77%) of 31 patients had a reduction in prostate-specific antigen of 50% or more, and 17 (55%) of 31 had a reduction of 75% or more. Twenty (83%) of 24 patients reported reduction in pain. Conclusions : Suramin can be safely administered as an intermittent bolus injection by use of adaptive control with feedback to control plasma drug concentrations; toxicity is significant but manageable and reversible. Suramin is active against hormone-refractory prostate cancer. Implications : Future trials should address the role and necessary extent of therapeutic drug monitoring; the optimal plasma drug concentration range and duration of therapy; and the activity of suramin in combination with other agents, in earlier stages of prostate cancer, and in other tumor types. [J Natl Cancer Inst 85:611–621, 1993]
Anthropometric and Hormonal Risk Factors for Male Breast Cancer: Male Breast Cancer Pooling Project Results
Authors: L. A. Brinton, M. B. Cook, V. McCormack, K. C. Johnson, H. Olsson, J. T. Casagrande, R. Cooke, R. T. Falk, S. M. Gapstur, M. M. Gaudet, J. M. Gaziano, G. Gkiokas, P. Guenel, B. E. Henderson, A. Hollenbeck, A. W. Hsing, L. N. Kolonel, C. Isaacs, J. H. Lubin, K. B. Michels, E. Negri, D. Parisi, E. T. Petridou, M. C. Pike, E. Riboli, H. D. Sesso, K. Snyder, A. J. Swerdlow, D. Trichopoulos, G. Ursin, P. A. van den Brandt, S. K. Van Den Eeden, E. Weiderpass, W. C. Willett, M. Ewertz, D. B. Thomas
Journal: JNCI Journal of the National Cancer Institute (2014)

The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. In the Male Breast Cancer Pooling Project, a consortium of 11 case–control and 10 cohort investigations involving 2405 case patients (n = 1190 from case–control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design–specific (case–control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided. Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86). Consistent findings across case–control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones.
Electrical activity of human atrial fibres at frequencies corresponding to atrial flutter
Authors: P. LAURIBE, E. DENIS, R. NOTTIN, E. CORABOEUF
Journal: Cardiovascular Research (1989)

Little information is available about rate dependent changes in electrical activity of human myocardial cells. We therefore studied, in vitro, the electrical activity of adult human atrial fibres driven at frequencies near that of atrial flutter by means of the standard microelectrode technique. Thirty two atrial samples exhibiting “normal” responses with fast upstroke were selected. At very high frequencies, the action potential (AP) upstroke arose from the repolarisation phase of the preceding AP in spite of marked frequency induced shortening of the plateau. As the stimulation rate was progressively increased, the take off potential (TOP) was less and less negative and the maximal rate of depolarisation (Vmax) decreased. Moreover, in most preparations, a clear alternation between two types of action potentials occurred. Calcium channel inhibitors cobalt (5 mM) or diltiazem (5.10−6 M) shortened AP duration, increased Vmax and markedly reduced alternation. Sodium channel inhibitors, tetrodotoxin (7.5 10−6 M) or lignocaine (10−5 M) shortened AP duration and induced a transient increase in Vmax. Ouabain (10−6 M) prolonged AP duration, decreased Vmax, enhanced alternation and finally suppressed the 1:1 capture of the atrial tissue. Our results show that, at high driving rates corresponding to the frequencies of atrial flutter, slight variations in action potential duration induced by drugs are associated with marked concomitant variations in Vmax and probably with consequent modifications of the conduction velocity.