tbuckley/cabot-search huggingface dataset:
Inhibition of Collagen Synthesis With Prolyl 4-Hydroxylase Inhibitor Improves Left Ventricular Function and Alters the Pattern of Left Ventricular Dilatation After Myocardial Infarction
Authors: John I. Nwogu, David Geenen, Maurice Bean, Mitchell C. Brenner, Xinfan Huang, Peter M. Buttrick
Journal: Circulation (2001)

Background Left ventricular (LV) remodeling after myocardial infarction (MI) is associated with fibrosis, dilatation, and dysfunction. We postulated that prevention of fibrosis after MI with a prolyl 4-hydroxylase inhibitor (P4HI) would preserve LV function and attenuate LV enlargement. Methods and Results Adult female rats (200 to 250 g) had experimental MI and were then randomized to treatment with P4HI (MI-FG041, n=29) or vehicle (MI-control, n=29) 48 hours after MI for 4 weeks in 2 phases. Echocardiograms were performed weekly with a 15-MHz linear transducer, and at 4 weeks, collagen isoform determinations and in vivo hemodynamics were performed. At randomization, the infarct size and LV function and size were similar in MI-FG041 and MI-control but significantly different from shams (n=9). At week 4, the LV function in MI-FG041 was significantly better than in MI-controls (fractional shortening 21% versus 16%, P =0.01; fractional area change 30% versus 19%, P =0.002; ejection fraction 35% versus 23%, P =0.001). In the FG041 group, LV area in systole was less ( P &lt;0.05), the dP/dt max after isoproterenol was higher ( P &lt;0.05), and types I and III collagen in noninfarcted LV were less than in MI-control. The hydroxyproline/proline ratio was increased by 64% in MI-control and reduced to the sham value in MI-FG041 rats. In the scar tissue, it was reduced by 24% in MI-FG041. Conclusions This study demonstrates that prevention of interstitial fibrosis with a P4H inhibitor alters the pattern of LV enlargement and produces partial recovery of LV function after MI.
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex
Authors: Chao-Ling Yang, Xiaoman Zhu, David H. Ellison
Journal: Journal of Clinical Investigation (2007)

The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice.
The Cochrane Collaboration's tool for assessing risk of bias in randomised trials
Authors: J. P. T. Higgins, D. G. Altman, P. C. Gotzsche, P. Juni, D. Moher, A. D. Oxman, J. Savovic, K. F. Schulz, L. Weeks, J. A. C. Sterne
Journal: BMJ (2011)

Flaws in the design, conduct, analysis, and reporting of randomised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration's tool for assessing risk of bias aims to make the process clearer and more accurate
Pulmonary manifestations of systemic sclerosis, a report from Iran
Authors: Atefeh Fakharian, Nahal Mansouri, Marjaneh Karimi, Azar Zamani, Davood Mansouri
Journal: European Respiratory Journal (2011)

Background:  Systemic sclerosis is a connective tissue disorder, manifesting as skin thickening and multi organ involvement. Scleroderma lung disease is the leading cause of death in this entity. The most common pulmonary presentations are interstitial lung disease and pulmonary hypertension,   Objectives:  We investigated different presentations of lung disease in scleroderma patients in Masih Daneshvari hospital between October 2000 and September 2009 in a retrospective study and clinical and paraclinical results were reported.   Results:  42 patients were identified with scleroderma lung disease. The majority of the patients (84%) were female and 23% were male with mean age of 47.26±14.30. The most common complain was dyspnea followed by cough and orthopnea in 93%, 69% and 19% of the patients respectively. Echocardiography demonstrated elevated pulmonary artery pressure (≥30 mmhg) in 17 patients (40.4%). Association of pneumothorax and adenocarcinoma was noted in 3 and 1 of the patients respectively. Finally, 6 patients were deceased and 3 patients are expecting lung transplantation due to advanced lung fibrosis.   Conclusion:  This study from a tertiary referral hospital in Iran illustrates similar results of pulmonary involvements in systemic sclerosis patients in comparison with previous reports.
Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation
Authors: B Brundel
Journal: Cardiovascular Research (1999)

Objective: Persistent atrial fibrillation (AF) results in an impairment of atrial function. In order to elucidate the mechanism behind this phenomenon, we investigated the gene expression of proteins influencing calcium handling. Methods: Right atrial appendages were obtained from eight patients with paroxysmal AF, ten with persistent AF (>8 months) and 18 matched controls in sinus rhythm. All controls underwent coronary artery bypass grafting, whereas most AF patients underwent Cox's MAZE surgery (n=12). All patients had a normal left ventricular function. Total RNA was isolated and reversely transcribed into cDNA. In a semi-quantitative polymerase chain reaction the cDNA of interest and of glyceraldehyde-3-phosphate dehydrogenase were coamplified and separated by ethidium bromide-stained gel electrophoresis. Slot blot analysis was performed to study protein expression. Results: L-type calcium channel α1 and sarcoplasmic reticulum Ca2+-ATPase mRNA (−57%, p=0.01 and −28%, p=0.04, respectively) and protein contents (−43%, p=0.02 and −28%, p=0.04, respectively) were reduced in patients with persistent AF compared to the controls. mRNA contents of phospholamban, ryanodine receptor type 2 and sodium/calcium exchanger were comparable. No changes were observed in patients with paroxysmal AF. Conclusions: Alterations in gene expression of proteins involved in the calcium homeostasis occur only in patients with long-term persistent AF. In the absence of underlying heart disease, the changes are rather secondary than primary to AF.
Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2
Authors: Louise A Metherell, J Paul Chapple, Sadani Cooray, Alessia David, Christian Becker, Franz Rüschendorf, Danielle Naville, Martine Begeot, Bernard Khoo, Peter Nürnberg, Angela Huebner, Michael E Cheetham, Adrian J L Clark
Journal: Nature Genetics (2005)
Identification of Tobacco- Specific Carcinogen in the Cervical Mucus of Smokers and Nonsmokers
Authors: B. Prokopczyk, J. E. Cox, D. Hoffmann, S. E. Steven E.
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: In 1996, an estimated 15 700 new cases of cancer of the uterine cervix and 4900 deaths from this disease were expected to occur in the United States. In a recent international study, human papillomavirus DNA was found in more than 90% of cervical tumor specimens examined, irrespective of the nationality of the patients from whom the samples were obtained. Although infection with human papillomavirus is the major known risk factor for the development of cervical cancer, it alone is not sufficient. Other etiologic factors that have been associated with this disease include deficiencies in micronutrients, lower socioeconomic status, oral contraceptive use, and cigarette smoking. Several compounds from cigarette smoke (nicotine and its major metabolite, cotinine) have been identified in cervical mucus, and the occurrence of smoking-related DNA damage in the cervical epithelium has been documented. Purpose: This investigation was conducted to determine for the first time whether carcinogenic tobacco-specific N-nitrosamines are present in the cervical mucus of cigarette smokers and of nonsmokers (most likely as a result of environmental exposure). Methods: Cervical mucus specimens from 15 smokers and 10 nonsmokers were subjected to supercritical fluid extraction with the use of carbon dioxide that contained 10% methanol, and the resultant extracts were analyzed for tobacco-specific nitrosamines by use of a very sensitive method that involved gas chromatography and mass spectroscopy analyses. Results: In a total of 16 samples obtained from 15 women who were current smokers (two samples from the same woman), we detected the tobaccospecific nitrosamine 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) at concentrations that ranged from 11.9 to 115.0 ng/g of mucus. Only one of a total of 10 cervical mucus specimens obtained from 10 women who claimed to be nonsmokers did not contain detectable NNK, and NNK concentrations ranged from 4.1 to 30.8 ng/g of mucus in the specimens from the remaining nine women. The concentrations of NNK in specimens from cigarette smokers were significantly higher than those from nonsmokers (mean ± standard deviation: 46.9 ± 32.5 ng/g of mucus versus 13.0 ± 9.3 ng/g of mucus; two-tailed Student's t test, P = .004). Conclusion: The cervical mucus of cigarette smokers contains measurable amounts of the potent carcinogen NNK. This compound represents the first tobacco- specific carcinogen identified in this physiologic fluid of women who smoke cigarettes. The presence of NNK in the cervical mucus of nonsmokers is likely due to environmental exposure or to the fact that some of the subjects in this study may not have revealed that they occasionally smoked cigarettes. Implications: The presence of NNK in human cervical mucus further strengthens the association between cervical cancer and tobacco smoking.
Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype
Authors: Njira L. Lugogo, John W. Hollingsworth, Druhan L. Howell, Loretta G. Que, Dave Francisco, Tony D. Church, Erin N. Potts-Kant, Jennifer L. Ingram, Ying Wang, Sin-Ho Jung, Monica Kraft
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Obesity is associated with increased prevalence and severity of asthma. Adipose tissue macrophages can contribute to the systemic proinflammatory state associated with obesity. However, it remains unknown whether alveolar macrophages have a unique phenotype in overweight/obese patients with asthma.We hypothesized that leptin levels would be increased in the bronchoalveolar lavage fluid from overweight/obese subjects and, furthermore, that leptin would alter the response of alveolar macrophages to bacterial LPS.Forty-two subjects with asthma and 46 healthy control subjects underwent research bronchoscopy. Bronchoalveolar lavage fluid from 66 was analyzed for the level of cellular inflammation, cytokines, and soluble leptin. Cultured primary macrophages from 22 subjects were exposed to LPS, leptin, or leptin plus LPS. Cytokines were measured in the supernatants.Leptin levels were increased in overweight/obese subjects, regardless of asthma status (P = 0.013), but were significantly higher in overweight/obese subjects with asthma. Observed levels of tumor necrosis factor-α were highest in overweight/obese subjects with asthma. Ex vivo studies of primary alveolar macrophages indicated that the response to LPS was most robust in alveolar macrophages from overweight/obese subjects with asthma and that preexposure to high-dose leptin enhanced the proinflammatory response. Leptin alone was sufficient to induce production of proinflammatory cytokines from macrophages derived from overweight/obese subjects with asthma.Ex vivo studies indicate that alveolar macrophages derived from overweight/obese subjects with asthma are uniquely sensitive to leptin. This macrophage phenotype, in the context of higher levels of soluble leptin, may contribute to the pathogenesis of airway disease associated with obesity.
Bronchiolitis obliterans syndrome in popcorn production plant workers
Authors: M. Akpinar-Elci, W.D. Travis, D.A. Lynch, K. Kreiss
Journal: European Respiratory Journal (2004)

Following sentinel case recognition, an excess of fixed airways obstruction was found among current workers in a microwave popcorn plant associated with butter flavouring exposures. In order to characterise the clinical presentation of sentinel cases, the medical records of sentinel cases were reviewed, interviews conducted and serial spirometric testing performed. Cases worked in microwave popcorn production, and five of the nine cases had mixed flavourings. Most had never smoked or smoked minimally. Cases showed onset of cough, shortness of breath and wheezing 5 months to 9 yrs after starting work at the popcorn plant. Initial forced expiratory volume in one second ranged 14.0-66.8% of the predicted value. Eight high-resolution computed tomography scans showed marked bronchial wall thickening and mosaic attenuation with air trapping. Open lung biopsy results were consistent with, or diagnostic of, constrictive bronchiolitis in two of three cases. Five cases are on lung transplantation waiting lists. After leaving employment, nearly all cases experienced stabilisation of their lung function within 2 yrs. Astute clinicians can help identify new causes of airways obstruction by alerting public health authorities to unexplained disease cases occurring in groups of workers.
Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomised double blind multicentre trial
Authors: W. Sterry, J.-P. Ortonne, B. Kirkham, O. Brocq, D. Robertson, R. D Pedersen, J. Estojak, C. T Molta, B. Freundlich
Journal: BMJ (2010)

<b>Objectives</b> To compare the efficacy over 12 weeks of two different etanercept regimens in treating the skin manifestations of psoriasis in patients who also have psoriatic arthritis and to evaluate efficacy and safety over an additional 12 weeks of open label etanercept treatment. <b>Design </b>Randomised double blind multicentre outpatient study. <b>Setting</b> 98 outpatient facilities in Europe, Latin America, and the Asia Pacific region. <b>Participants </b>752 patients with both psoriasis (evaluated by dermatologists) and psoriatic arthritis (evaluated by rheumatologists). <b>Interventions</b> During the blinded portion of the study, participants were randomised to receive etanercept 50 mg twice weekly (n=379) or 50 mg once weekly (n=373) for 12 weeks by subcutaneous injection. All participants then received open label etanercept 50 mg once weekly for 12 additional weeks, while remaining blinded to the regimen. <b>Main outcome measures</b> The primary efficacy end point was the proportion of participants achieving “clear” or “almost clear” on the physician’s global assessment of psoriasis at week 12. Secondary efficacy analyses included psoriasis area and severity index, American College of Rheumatology responses, psoriatic arthritis response criteria, and improvement in joint and tendon disease manifestations. <b>Results</b> At week 12, 46% (176/379) of participants receiving etanercept 50 mg twice weekly achieved a physician’s global assessment of psoriasis of “clear” or “almost clear” compared with 32% (119/373) in the group treated with 50 mg once weekly (P&lt;0.001). In contrast, an equally high percentage of participants in both groups achieved psoriatic arthritis response criteria (77% (284/371) in the twice weekly/once weekly group versus 76% (282/371) in the once weekly/once weekly group). Participants treated with 50 mg twice weekly/once weekly had greater mean reductions from baseline in the psoriasis area and severity index at week 12 compared with those who received 50 mg once weekly/once weekly (71% <i>v</i> 62%, P&lt;0.001), with less difference at week 24 (78% <i>v</i> 74%, P&lt;0.110). Joint and tendon disease manifestations improved from baseline in both groups to a similar extent. No new safety signals were seen in either etanercept treatment group, and no significant difference in the safety profiles was observed. <b>Conclusions</b> In participants with active psoriasis and psoriatic arthritis, initial treatment of the psoriasis with etanercept 50 mg twice weekly may allow for more rapid clearance of skin lesions than with 50 mg once weekly. A regimen of 50 mg once weekly seems to be appropriate for treatment of joint and tendon rheumatic symptoms. The choice of regimen should be determined by the clinical needs of the individual patient. <b>Trial registration </b>Clinical trials NCT00245960.
Inhibition of miR-17 and miR-20a by Oridonin Triggers Apoptosis and Reverses Chemoresistance by Derepressing BIM-S
Authors: Hengyou Weng, Huilin Huang, Bowen Dong, Panpan Zhao, Hui Zhou, Lianghu Qu
Journal: Cancer Research (2014)

Abstract Cancer cell chemoresistance arises in part through the acquisition of apoptotic resistance. Leukemia cells resistant to chemotherapy-induced apoptosis have been found to be sensitive to oridonin, a natural agent with potent anticancer activity. To investigate its mechanisms of action in reversing chemoresistance, we compared the response of human leukemia cells with oridonin and the antileukemia drugs Ara-C and VP-16. Compared with HL60 cells, K562 and K562/ADR cells displayed resistance to apoptosis stimulated by Ara-C and VP-16 but sensitivity to oridonin. Mechanistic investigations revealed that oridonin upregulated BIM-S by diminishing the expression of miR-17 and miR-20a, leading to mitochondria-dependent apoptosis. In contrast, neither Ara-C nor VP-16 could reduce miR-17 and miR-20a expression or could trigger BIM-S–mediated apoptosis. Notably, silencing miR-17 or miR-20a expression by treatment with microRNA (miRNA; miR) inhibitors or oridonin restored sensitivity of K562 cells to VP-16. Synergistic effects of oridonin and VP-16 were documented in cultured cells as well as mouse tumor xenograft assays. Inhibiting miR-17 or miR-20a also augmented the proapoptotic activity of oridonin. Taken together, our results identify a miRNA-dependent mechanism underlying the anticancer effect of oridonin and provide a rationale for its combination with chemotherapy drugs in addressing chemoresistant leukemia cells. Cancer Res; 74(16); 4409–19. ©2014 AACR.
Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two-residue contact motif.
Authors: H Kropshofer, H Max, C A Müller, F Hesse, S Stevanovic, G Jung, H Kalbacher
Journal: The Journal of Experimental Medicine (1992)

Peptide fragments of foreign and self-proteins are of great immunologic importance as their binding to major histocompatibility complex (MHC) class I or II molecules makes an interaction with a corresponding T cell receptor possible. Recently, allele-specific peptide sequence motifs proved to be responsible for MHC binding, no matter whether self- or non-self-antigens were involved. Up to now, all investigated human class II-associated peptides were derived from foreign antigenic proteins. Therefore, we undertook sequence and binding analyses with a 16-mer self-peptide (SP3) that has been eluted from HLA-DR1. Here we demonstrate, by synthetic polyalanine-based 13-mer analogues of SP3, that two bulky hydrophobic anchor residues with relative spacing i, i + 8 are sufficient for high affinity binding. This is consistent with the hydrophobic i, i + 8 binding pattern recently found for DR-restricted T cell epitopes. Nevertheless, highly helical alanine-based design peptides with anchor spacing i, i + 9 exhibit maximal affinity, whereas replacement of alanine by helix destabilizing proline abrogates binding. Thus, a two-residue contact motif is the common minimal requirement of self- and foreign peptides for high affinity anchoring to HLA-DR1. In contrast to class I, the anchor spacing of DR1-associated peptides seems to bear some variability due to conformational diversity.
RESULTS AND OBSERVATIONS ON THE INSULIN-SHOCK TREATMENT OF SCHIZOPHRENIA
Authors: EARL D. BOND, JOSEPH HUGHES, JAMES A. FLAHERTY
Journal: American Journal of Psychiatry (1939)

1. In every hospital using insulin-shock the patients treated should be followed for five years. Another group of patients, or other groups, as near alike as possible should be followed for the same time as controls. It seems certain that relapses after favorable responses will follow in all groups. 2. In the valuable paper just published by Malamud and Render9 it is stated that a study of the course and prognosis in schizophrenia should include the criteria used by the author in diagnosis. We take a little exception to this statement because it might give encouragement to more varying personal standards for schizophrenia. After all, it is safer for psychiatrists to use the criteria put down in the official Statistical Manual,10 and to work toward a definition which all can use. 3. Insulin-shock therapy is not a complete answer. But the transformation of the patient's condition is so immediate and favorable in a majority of cases that it will have place in, or provide suggestions for a future therapy, and this without regard to whether good results last for an afternoon or indefinitely. It is only fair to remember that Sakel spoke of insulin-shock as the artillery in a general combined attack on the disease process. 4. Insulin in convulsive doses alters the metabolic processes of nerve.
The intestinal mucosa as a target and trigger for enteric reflexes
Authors: D Grundy
Journal: Gut (2000)

The gastrointestinal tract must balance the ostensibly conflicting needs of nutrient assimilation and protection against potentially harmful pathogens, enterotoxins, and antigens. Furthermore, it must provide a functional barrier for the latter but allow nutrients, electrolytes, and water to cross the mucosa readily in order to meet the eventual metabolic demands of the individual (fig 1). Apparent in these conflicting needs is the ability to sense luminal contents in order to establish, through reflex and endocrine mechanisms, the appropriate motor and secretory activity either to facilitate uptake or to dilute and rapidly expel contents through diarrhoea and/or emesis.



Figure 1 
Conflicting mucosal functions.



Enteroendocrine cells may be secondary sense cells for sensory signal transduction. Their apical microvilli could detect the mechanical and chemical environment in the lumen, and in response to an appropriate stimulus would release mediators across the basolateral membrane. These mediators could then act as paracrine agents on neighbouring cells, including the terminals of afferent fibres situated below the mucosal epithelium or act in an endocrine fashion following diffusion into the systemic …