tbuckley/cabot-search huggingface dataset:
Mitochondrial enzyme activities in liver biopsies from patients with alcoholic liver disease.
Authors: W J Jenkins, T J Peters
Journal: Gut (1978)

The hypothesis that mictochondrial damage is a significant factor in the pathogenesis of alcoholic liver disease (ALD) was investigated by enzymic analysis of mitochondrial fractions isolated from needle biopsy specimens from control patients, patients with fatty liver due to chronic alcoholism, and from patients with other forms of liver disease. Enzymes associated with the inner and outer mitochondrial membranes showed normal levels in ALD. Enzymes associated with the mitochondrial matrix, glutamate dehydrogenase, malate dehydrogenase and aspartate aminotransferase showed significantly raised levels in ALD, but the levels in patients with non-alcoholic liver disease was normal. In addition, analysis of the mitochondria by sucrose density gradient centrifugation revealed no differences between control tissue and liver from patients with alcoholic liver disease. These results do not indicate that there is significant mitochondrial damage in ALD. The raised mitochondrial matrix enzymes may represent an adaptive response to the ethanol load.
Urinary desmosine excretion in smokers with and without rapid decline of lung function: the Normative Aging Study.
Authors: D J Gottlieb, P J Stone, D Sparrow, M E Gale, S T Weiss, G L Snider, G T O'Connor
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

It is hypothesized that smoking-related chronic obstructive pulmonary disease (COPD) results in part from excess lung elastin degradation. Taking advantage of spirometry performed over a 12-yr period at the Normative Aging Study, we conducted a nested case-control study of elastin and collagen degradation rates in current smokers with (n = 10) and without (n = 8) rapid decline of lung function, using a biochemical assay for urinary desmosine (DES), a specific marker for mature elastin degradation, and hydroxylysylpyridinoline (HP), a specific marker for mature fibrillar collagen degradation. Mean urinary excretion of DES in rapid decliners was 36% greater than in slow decliners (9.8 +/- 0.7 [mean +/- SE] versus 7.2 +/- 0.4 microg/g creatinine, p < 0.01); after adjustment for age and lean body mass (LBM), DES excretion in rapid decliners was 30% greater than in slow decliners (9.6 +/- 0.6 versus 7.4 +/- 0.7 microg/g creatinine, p = 0.06). Among rapid decliners, there was no difference in DES excretion between those with and those without computed tomogaphic evidence of emphysema. There was no significant difference between rapid and slow decliners in mean urinary excretion of HP (24.7 +/- 1.4 versus 21.6 +/- 1.8 nmol/mmol creatinine, p = 0.18). Among all subjects, rate of decline of FEV1 was significantly correlated with DES excretion (r = 0.61, p < 0.01). In a linear regression model adjusting for age and LBM, an increase in DES excretion of 1 microg/g creatinine was associated with an excess decline of FEV1 of 10.6 ml/yr (p = 0.04). This study provides further evidence in support of the elastase-antielastase hypothesis of the pathogenesis of COPD, and it suggests a role for elastin degradation in both emphysema and small airways disease. Moreover, it suggests that urinary DES excretion may be a useful biochemical marker for the study of interventions designed to prevent the development or progression of COPD.
The Impact of Interferon Gamma Receptor Expression on the Mechanism of Escape From Host Immune Surveillance in Hepatocellular Carcinoma
Authors: Mitsuo Nagao, Yoshiyuki Nakajima, Hiromichi Kanehiro, Michiyoshi Hisanaga, Yukio Aomatsu, Saiho Ko, Yukihiro Tatekawa, Naoya Ikeda, Hideki Kanokogi, Yasuyuki Urizono, Tsunehiro Kobayashi, Takamune Shibaji, Tetsuhiro Kanamura, Sanehito Ogawa, Hiroshige Nakano
Journal: Hepatology (2000)

Interferon gamma (IFN-γ) plays an important role in host defense mechanism and participates in the progression of chronic liver disease. IFN-γ exerts its pleiotrophic effects by transcriptional regulation of expression of numerous genes, such as major histocompatibility complex (MHC) class I and Fas, through interaction with IFN-γ receptor (IFN-γ-R). Although hepatocytes in normal liver express weak or no IFN-γ-R, those in acute and chronic liver disease up-regulate its expression. A study using IFN-γ-R α-chain knock-out mice revealed the actions of IFN-γ on tumor cells as an extrinsic tumor-suppressor mechanism. However, it is unclear whether or how hepatocellular carcinoma (HCC) blocks the signal transduction of IFN-γ to evade host immune surveillance. We examined the expression of IFN-γ-R and IFN-γ-inducible genes in 44 cases with HCC using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. In noncancerous liver tissues (n = 38), IFN-γ-R expression on the cell surface was up-regulated in 27 cases. In IFN-γ-R-negative cases (n = 15), tumor size was larger ( P = .032), serum α-fetoprotein (AFP) level was higher ( P = .001), intrahepatic and extrahepatic metastasis was more common ( P = .044 and .013, respectively), and Ki-67 labeling index (LI) was higher ( P = .041), compared with IFN-γ-R-positive cases. Accordingly, the evasion mechanism may play an important role in progression, especially metastasis, in HCC. The significant correlation between the status of IFN-γ-R and the expression of Fas and MHC implies that the loss of IFN-γ-R might contribute to the mechanism of escape from host immune rejection in HCC.
Acetaldehyde Stimulates Collagen and Noncollagen Protein Production by Human Fibroblasts
Authors: Kenneth Holt, Michael Bennett, Mario Chojkier
Journal: Hepatology (1984)

The mechanisms responsible for the increased hepatic collagen deposition in alcoholic cirrhosis remain unknown. The question of whether ethanol or acetaldehyde has a direct effect on collagen and noncollagen protein production was investigated in human fibroblasts with no detectable activity of alcohol dehydrogenase to distinguish the effects of these metabolites. To eliminate environmental factors, protein production by confluent human skin, fetal and hepatic fibroblasts was studied after three passages. Cells were labeled with [5− 3 H]proline for 4 hr in the presence of 0.2 m M ascorbate alone or with addition of either ethanol (50 m M ) or acetaldehyde (0 to 300 μ M ). Rates of protein production were calculated from the radioactivities of collagenase-sensitive and collagenase-resistant proteins. Skin fibroblasts from alcoholic individual either with cirrhosis or without liver disease have comparable rates of collagen and noncollagen protein production. Acetaldehyde, in a concentration found in the liver during ethanol abuse, significantly increased collagen production by human skin fibroblasts (up to 140%), fetal fibroblasts (up to 240%) and hepatic fibroblasts (up to 70%) but the addition of ethanol had no significant effect on basal collagen production. The effect of acetaldehyde was dose-related and affected noncollagen protein production in a similar manner. Acetaldehyde did not cause changes in either proline transport or the specific activity of the proline precursor pool. This newly recognized stimulation of collagen production by acetaldehyde may be a possible mechanism of fibrogenesis in alcoholic individuals.
Statin Treatment in Children With Familial Hypercholesterolemia
Authors: Jessica Rodenburg, Maud N. Vissers, Albert Wiegman, A. S. Paul van Trotsenburg, Anouk van der Graaf, Eric de Groot, Frits A. Wijburg, John J.P. Kastelein, Barbara A. Hutten
Journal: Circulation (2007)

Background— We previously demonstrated in a randomized placebo-controlled trial that 2-year pravastatin treatment induced a significant regression of carotid intima-media thickness (IMT) in 8- to 18-year-old children with familial hypercholesterolemia. Subsequently, we continued to follow up these children to explore the relation between the age of statin initiation and carotid IMT after follow-up on statin treatment. We also examined safety aspects of statin therapy during this long-term follow-up. Methods and Results— All 214 children who initially participated in the previous placebo-controlled study were eligible for the follow-up study. After completion of the placebo-controlled study, all children continued treatment with pravastatin 20 or 40 mg, depending on their age. Blood samples were taken on a regular basis for lipids and safety parameters, and a carotid IMT measurement was performed after an average treatment period of 4.5 years. Follow-up data for 186 children were available for the statistical analyses. Multivariate analyses revealed that age at statin initiation was an independent predictor for carotid IMT after follow-up with adjustment for carotid IMT at initiation of statin treatment, sex, and duration of treatment. Early initiation of statin treatment was associated with a subsequently smaller IMT. Furthermore, no serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation. Conclusions— These data indicate that early initiation of statin treatment delays the progression of carotid IMT in adolescents and young adults. The present study shows for the first time that early initiation of statin therapy in children with familial hypercholesterolemia might be beneficial in the prevention of atherosclerosis in adolescence.
A Novel Strategy for Myocardial Protection by Combined Antibody Therapy Inhibiting Both P-Selectin and Intercellular Adhesion Molecule-1 Via Retrograde Intracoronary Route
Authors: Satsuki Fukushima, Steven R. Coppen, Anabel Varela-Carver, Kenichi Yamahara, Padmini Sarathchandra, Ryszard T. Smolenski, Magdi H. Yacoub, Ken Suzuki
Journal: Circulation (2006)

Background— Antibody therapy to inhibit either P-selectin or intercellular adhesion molecule-1 (ICAM-1) has been reported to provide myocardial protection against leukocyte-mediated reperfusion injury. Because these molecules play different roles in the leukocyte-endothelial interaction, co-inhibition of both may achieve further enhanced cardioprotection. In addition, the therapeutic efficacy of such antibody therapy may be affected by the delivery route used. Retrograde intracoronary infusion will offer an effective, direct access to the postcapillary venules, where the target event (leukocyte–endothelial interaction) takes place. We investigated the feasibility and efficiency of the combined antibody therapy targeting both P-selection and ICAM-1 via the retrograde intracoronary route to attenuate myocardial ischemia-reperfusion injury. Methods and Results— Lewis rats underwent 30-minute left coronary artery occlusion. Just before reperfusion, anti-P-selectin monoclonal antibody (150 μg/kg), anti-ICAM-1 monoclonal antibody (200 μg/kg), both antibodies together, or control antibody were retrogradely infused into the left cardiac vein. At 24 hours after reperfusion, administration of either anti-P-selectin or anti-ICAM-1 antibody significantly ( P &lt;0.05) improved left ventricular ejection fraction and attenuated infarct size (40.6±3.2% and 34.8±3.5%, respectively) compared with the control (56.8±3.4%). This was associated with reduced leukocyte accumulation and improved regional blood flow in the ischemic area. Noticeably, co-administration of both antibodies achieved a much greater reduction in infarct size (19.1±3.6%), associated with greater attenuation in leukocyte infiltration, compared with administration of either single antibody. Conclusions— Combined antibody therapy inhibiting both P-selectin and ICAM-1 via the retrograde intracoronary route could be a promising new strategy for myocardial protection against ischemia-reperfusion injury.
Drug Abuse and the Schools
Authors: J. THOMAS UNGERLEIDER, HASKELL L. BOWEN
Journal: American Journal of Psychiatry (1969)

The authors describe some of the observations they made while working with California high school students in the area of drug abuse. Preventive programs, they emphasize, must include the development of open communication about drugs. Applying the ombudsman approach to drug problems within the schools is one effective way of achieving this. Several illustrations of this approach are cited.
Mechanisms of histamine stimulated secretion in rabbit ileal mucosa.
Authors: B D Linaker, J S McKay, N B Higgs, L A Turnberg
Journal: Gut (1981)

Histamine is present in high concentrations in the intestine and we investigated the possibility that it might have a role here in intestinal transport. When added to the basal side of rabbit ileal mucosa in vitro histamine (10(-4)M) induced a short-lived increase in electrical potential difference and short circuit current. It inhibited net chloride absorption but did not influence sodium transport. Alkali secretion, measured by a pH stat technique, was inhibited, suggesting that bicarbonate secretion was reduced. Both the electrical and ion flux responses to histamine were blocked by the H1 receptor blocker diphenhydramine, but not by the H2 receptor blocker cimetidine. The presence of specific H1 histamine receptors was further supported by shifts in the dose-response curve to histamine by four different concentrations of diphenhydramine. Calculation of a pA2 value from these "Schild9 plots provided a figure of 7.85, which is similar to that for H1 receptors in other tissues. Aminoguanidine, a histaminase blocker, had no electrical effects alone but shifted the histamine dose response curve to the left. These studies indicate that histamine inhibits chloride absorption and alkali secretion, possibly by influencing a chloride/bicarbonate exchange process, through specific mucosal H1 receptors. Enhancement of histamine effects by a histaminase inhibitor suggests that histaminases are present in the intestinal mucosa and supports the possibility of a role for endogenous histamine in influencing ion transport. The observations indicate a mechanism by which absorption might be impaired in diseases in which histamine is liberated locally in the intestine.
Familial Pseudoxanthoma Elasticum and Valvular Heart Disease
Authors: JAY D. COFFMAN, SHELDON C. SOMMERS
Journal: Circulation (1959)

The clinical and pathologic findings are presented of a patient with pseudoxanthoma elasticum leading to fatal valvular heart disease. The literature concerning the involvement of the heart by this disease is reviewed and reveals that valvular heart disease has not been described as a clinical problem heretofore. The occurrence of the condition in the relatives of the patient is described.
Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus.
Authors: T Forst, T Kunt, T Pohlmann, K Goitom, M Engelbach, J Beyer, A Pfützner
Journal: Journal of Clinical Investigation (1998)

19 insulin-dependent diabetes mellitus (IDDM) patients participated in a randomized double-blind crossover investigation to investigate the impact of human C-peptide on skin microvascular blood flow. The investigation was also carried out with 10 healthy volunteers. Blood pressure, heart rate, blood sugar, and C-peptide levels were monitored during a 60-min intravenous infusion period of C-peptide (8 pmol kg-1 min-1) or saline solution (154 mmol liter-1 NaCl), and 30 min after stopping the infusion. During the same time period, capillary blood cell velocity (CBV), laser Doppler flux (LDF), and skin temperature were assessed in the feet. In the verum arm, C-peptide levels increased after starting infusion to reach a maximum of 2.3+/-0.2 nmol liter-1 after 45 min, but remained below 0. 15 nmol liter-1 during the saline treatment. Baseline CBV was lower in diabetic patients compared with healthy subjects (147+/-3.6 vs. 162+/-4.2 micron s-1; P < 0.01). During C-peptide administration, CBV in IDDM patients increased progressively from 147+/-3.6 to 167+/-3.7 micron s-1; P < 0.001), whereas no significant change occurred during saline infusion or in healthy subjects. In contrast to the CBV measurements, the investigation of LDF, skin temperature, blood pressure, heart rate, or blood sugar did not demonstrate any significant change during the study. Replacement of human C-peptide in IDDM patients leads to a redistribution in skin microvascular blood flow levels comparable to levels in healthy subjects by increasing the nutritive CBV relative to subpapillary arteriovenous shunt flow.
Auscultation of the Normally Functioning Prosthetic Valve
Authors: NEALE D. SMITH
Journal: Annals of Internal Medicine (1981)

ExcerptBefore prosthetic function can be adequately assessed, physicians must be acquainted with the normal acoustic events associated with these devices. The auscultatory findings of the most commonly used devices—ball, disk, porcine, and bileaflet valves—are reviewed. The mechanisms of sound production and their timing are discussed....
Six-Month Versus 12-Month Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents
Authors: Hyeon-Cheol Gwon, Joo-Yong Hahn, Kyung Woo Park, Young Bin Song, In-Ho Chae, Do-Sun Lim, Kyoo-Rok Han, Jin-Ho Choi, Seung-Hyuk Choi, Hyun-Jae Kang, Bon-Kwon Koo, Taehoon Ahn, Jung-Han Yoon, Myung-Ho Jeong, Taek-Jong Hong, Woo-Young Chung, Young-Jin Choi, Seung-Ho Hur, Hyuck-Moon Kwon, Dong-Woon Jeon, Byung-Ok Kim, Si-Hoon Park, Nam-Ho Lee, Hui-Kyung Jeon, Yangsoo Jang, Hyo-Soo Kim
Journal: Circulation (2011)

Background— The optimal duration of dual antiplatelet therapy (DAPT) after implantation of drug-eluting coronary stents remains undetermined. We aimed to test whether 6-month DAPT would be noninferior to 12-month DAPT after implantation of drug-eluting stents. Methods and Results— We randomly assigned 1443 patients undergoing implantation of drug-eluting stents to receive 6- or 12-month DAPT (in a 1:1 ratio). The primary end point was a target vessel failure, defined as the composite of cardiac death, myocardial infarction, or ischemia-driven target vessel revascularization at 12 months. Rates of target vessel failure at 12 months were 4.8% in the 6-month DAPT group and 4.3% in the 12-month DAPT group (the upper limit of 1-sided 95% confidence interval, 2.4%; P =0.001 for noninferiority with a predefined noninferiority margin of 4.0%). Although stent thrombosis tended to occur more frequently in the 6-month DAPT group than in the 12-month group (0.9% versus 0.1%; hazard ratio, 6.02; 95% confidence interval, 0.72–49.96; P =0.10), the risk of death or myocardial infarction did not differ in the 2 groups (2.4% versus 1.9%; hazard ratio, 1.21; 95% confidence interval, 0.60–2.47; P =0.58). In the prespecified subgroup analysis, target vessel failure occurred more frequently in the 6-month DAPT group than in the 12-month group (hazard ratio, 3.16; 95% confidence interval, 1.42–7.03; P =0.005) among diabetic patients. Conclusions— Six-month DAPT did not increase the risk of target vessel failure at 12 months after implantation of drug-eluting stents compared with 12-month DAPT. However, the noninferiority margin was wide, and the study was underpowered for death or myocardial infarction. Our results need to be confirmed in larger trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00698607.
IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses
Authors: Michelle A. Linterman, Laura Beaton, Di Yu, Roybel R. Ramiscal, Monika Srivastava, Jennifer J. Hogan, Naresh K. Verma, Mark J. Smyth, Robert J. Rigby, Carola G. Vinuesa
Journal: The Journal of Experimental Medicine (2010)

During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1+ GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.
Ulcerogenicity of piroxicam: an analysis of spontaneously reported data
Authors: E A Bortnichak, A J Gordon, E A Stevens
Journal: BMJ (1987)

interpret and, not surprisingly, has varied con- siderably in different communities around the world.Our data on middle aged British men suggest that alcohol is not a risk factor for ischaemic heart disease and that the apparent protective effect of light, regular drinking reflects the many advantageous characteristics of men who drink in this fashion.In this British community there is no convincing evidence of a protective effect directly due to alcohol intake.
No incentives for new NHS commissioners to act for children
Authors: W. Caan
Journal: BMJ (2012)

Bronchiolitis Obliterans syndrome-(BOS) is a major cause of mortality and morbidity after lung transplantation (LTx). Montelukast has been shown to be effective in small case series in patients with BOS after LTx and bone marrow transplantation. A retrospective single center analysis was performed in all LTx-recipients treated with Montelukast since 1.10.2010 as a rescue therapy for progressive BOS. Montelukast was used in a dose of 10 mg daily as a long-term therapy. All patients with at least 3 weeks of therapy were included. Response and progress were defined as a confirmed FEV1 of &lt;90% and &gt;110% baseline, respectively. Broncho-alveolar lavage (BAL)-neutrophilia was recorded at baseline. 38 patients (17 female, 31 double LTx recipients, median age 52 years,) were included with a median follow-up was 74 (interquartile 37-95) days. Median FEV1 at baseline was 55 (33-69)% best. Previous BOS treatment consisted of azithromycin in 100% (3 initial responders) and photopheresis (ECP) in 13 (34%, 2 responders). Median neutrophils in BAL at baseline was 20 (9-50)%, 21 (55%) subjects had neutrophils above 15%. Four patients responded to montelukast after 21-66 days, 10 patients were progressive after 20 - 100 days, 4 pts died from respiratory failure during follow up. Neutrophils in BAL was not different between responder and non-responder to montelukast. Response to azithromycin, montelukast or ECP was highly variable. 8 (21%) of progressive BOS pts. responded to any form of therapy. Montelukast is an additional treatment option in LTx recipients with BOS refractory to other treatment options. BAL-neutrophils did not predict response.
Cholesterol and Mortality-Reply
Authors: Keaven M. Anderson
Journal: JAMA (1987)

<h3>In Reply.—</h3> Dr Hainer raises a legitimate question that is not discussed in our article. Adjusting for the problem of regression to the mean produces results similar to those presented there, however. The following analysis adjusts for the fact that individuals with higher cholesterol levels are more likely to experience a decline in cholesterol level. The analysis uses the same data set and age groups as in Table 4 of our article. Two variables are considered: (1) the maximum cholesterol level over the first eight Framingham study examinations and (2) the percent fall from this maximum to the cholesterol level observed at examination 8. Cox regressions using stratification by age group and maximum cholesterol level (grouped into 20 mg/dL—wide categories) with percent fall from maximum as the independent variable were performed (Table). This stratification compares mortality only within the age and maximum cholesterol level categories and thus lessens or eliminates