tbuckley/cabot-search huggingface dataset:
Apoptotic versus autophagic cell death in heart failure
Authors: Michiel W.M. Knaapen, Michael J. Davies, Martine De Bie, Aldwyn J. Haven, Wim Martinet, Mark M. Kockx
Journal: Cardiovascular Research (2001)

Progressive loss of cardiomyocytes is one of the most important pathogenic characteristics of heart failure. Apoptosis may be an important mode of cell death in heart failure but it must be demonstrated by multiple criteria and not just TUNEL staining alone. Previously, we and others have demonstrated that besides apoptosis other phenomena like active gene transcription can result in TUNEL positivity. Moreover, other types of cell death that are caspase-independent could be important in heart failure. This study examined the hypothesis whether TUNEL labeling parallels caspase activation.Cardiac tissue of patients in the terminal stage of heart failure as a consequence of ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) were studied. Embryonic mice hearts were used for positive control for detection of the classical apoptosis.In mice embryonic hearts we could clearly find apoptotic cell death detected by TUNEL labeling and immunohistochemistry for activated caspase-3. In heart failure, TUNEL-positive cardiomyocytes were negative for active caspase-3 but showed signs of active gene transcription (SC-35). However, autophagic cell death could be found in 0.3% of the cardiomyocytes. Autophagic cell death was demonstrated by granular cytoplasmic ubiquitin inclusions, an established marker of autophagocytosis in neurons. Interestingly, these autophagic cardiomyocytes were TUNEL and activated caspase-3 negative but were also negative for C9, a marker for necrosis. Western blot analysis confirmed that in cardiomyopathies no cleavage of caspase-3 and caspase-7 occurred.The present study demonstrates two fundamentally different situations of cell death in cardiac tissue. In embryonic mice, cardiomyocytes undergo caspase-dependent cell death. However, cardiomyocytes in heart failure show caspase-independent autophagic cell death rather than apoptotic cell death.
Impact of influenza vaccination on mortality risk among the elderly
Authors: R. H. H. Groenwold, A. W. Hoes, E. Hak
Journal: European Respiratory Journal (2009)

Estimates of influenza vaccine effectiveness have mostly been derived from nonrandomised studies and therefore are potentially confounded. The aim of the current study was to estimate influenza vaccine effectiveness in preventing mortality among the elderly, taking both measured and unmeasured confounding into account. Information on patients aged ≥65 yrs from the computerised Utrecht General Practitioner database on eight influenza epidemic periods and summer periods was pooled to estimate influenza vaccine effectiveness in preventing mortality. Summer periods (during which no effect of vaccination was expected) were used as a reference to control for unmeasured confounding in epidemic periods. After adjustment for measured confounders using multivariable regression analysis, propensity score matching and propensity score regression analysis, influenza vaccination reduced mortality risk (odds ratios (ORs) 0.58 (95% confidence interval (CI) 0.46–0.72), 0.56 (95% CI 0.44–0.71) and 0.56 (95% CI 0.45–0.69), respectively). After additional adjustment for unmeasured confounding (as observed during summer periods), the association between influenza vaccination and mortality risk decreased (OR 0.69 (95% CI 0.52–0.92)). We conclude that after state-of-the-art adjustment for typical confounders such as age, sex and comorbidity status, unmeasured confounding still biased estimates of influenza vaccine effectiveness. After taking unmeasured confounding into account, influenza vaccination is still associated with substantial reduction in mortality risk.
Advances in the treatment of melanoma.
Authors: Katie E Lacy, Sophia N Karagiannis, Frank O Nestle
Journal: BMJ (1966)

#### Key Points

Melanoma incidence and mortality are increasing

Melanoma is relatively resistant to therapy with standard chemotherapeutic regimens

The small molecule inhibitor vemurafenib that targets melanomas with a common and specific mutation (BRAF V600E) has shown promise in the treatment
Localization of Atrial Natriuretic Factor Receptors in the Mesenteric Arterial Bed
Authors: Héctor de León, Marie-Chantal Bonhomme, Gaétan Thibault, Raul Garcia
Journal: Circulation Research (1995)

Abstract Although receptors for atrial natriuretic factor (ANF) and angiotensin II (Ang II) have been reported in rat mesenteric arteries, both peptides induce weak biological responses. Endothelin-1 (ET-1) evokes a potent vasoconstriction in the mesenteric artery. To identify the tissue localization of ANF, Ang II, and ET-1 receptors, radioligand binding experiments with 125 I-ANF, 125 I–[Sar 1 ,Ile 8 ]Ang II, and 125 I–ET-1 were performed in defatted mesenteric arteries and in the surrounding adipose tissue. 125 I-ANF binding assays in adipose tissue showed a single class of high-affinity binding sites (B max , 420±16 fmol/mg protein; K d , 343±16 pmol/L). In vascular membranes, most 125 I-ANF binding was nonspecific. The majority of receptors present in adipose tissue recognized ANF, C-type natriuretic peptide (CNP), and des-[Gln 18 ,Ser 19 ,Gly 20 ,Leu 21 ,Gly 22 ]ANF-(4-23) (C-ANF) with close affinities, with C-ANF competing for &gt;98% of the binding sites. In adipocytes, ANF and CNP stimulated cGMP generation. cGMP production by mesenteric arteries was stimulated by sodium nitroprusside but not by ANF or CNP. Autoradiographic localization of 125 I-ANF and 125 I–ET-1 showed that in the case of ANF, most specific binding occurred in adipocytes, whereas for ET-1, specific binding was present in both adipose tissue and mesenteric arteries. Cross-linking of 125 I-ANF followed by SDS-PAGE revealed two receptor species of 130 and 70 kD in adipose membranes and none in vascular tissue. Both were completely displaced by ANF, CNP, and C-ANF. 125 I–[Sar 1 ,Ile 8 ]Ang II binding assays in adipose tissue exhibited a single class of binding sites (B max , 211±4 fmol/mg protein; K d , 520±10 pmol/L). In mesenteric arteries, 125 I–[Sar 1 ,Ile 8 ]Ang II saturation assays showed little specific binding. The profile of ligands competing for 125 I–[Sar 1 ,Ile 8 ]Ang II was consistent with an AT 1 receptor subtype. 125 I–ET-1 binding assays demonstrated high-affinity binding sites in both mesenteric arteries and adipose tissue (B max , 179±21 and 312±7 fmol/mg protein, respectively; K d , 215±45 and 180±111 pmol/L, respectively), the majority corresponding to BQ-123–sensitive sites. Thus, ANF and Ang II binding sites were either absent or barely expressed in the mesenteric artery. Binding sites for ET-1 were abundantly expressed in the mesenteric artery. Adipose tissue expressed high-affinity binding sites for ANF, Ang II, and ET-1, but their biological role, if any, remains to be defined.
Effects of a thromboxane A2 analogue and prostacyclin on lung fluid balance in newborn lambs.
Authors: K Yoshimura, M L Tod, K G Pier, L J Rubin
Journal: Circulation Research (1989)

We have previously shown that the pulmonary venoconstriction produced by a stable thromboxane A2 analogue (STA2) is attenuated by prostacyclin (PGI2), but PGI2 increases the STA2-induced edema. The present study was designed to determine the effects of STA2 and PGI2 on the fluid balance in isolated blood-perfused newborn lamb lungs. Vascular permeability was evaluated by use of the fluid filtration coefficient (Kf) and the osmotic reflection coefficient for total proteins (sigma, hematocrit-protein double indicator technique), and pulmonary capillary pressure (Pc) was estimated by the double occlusion technique. All lungs had a period of hydrostatic stress induced by elevation of the left atrial pressure from 5 to 20 mm Hg to promote fluid filtration, and the rate of lung weight gain (delta W/delta T) during this period was determined. Studies were made in four groups; before the hydrostatic stress, lungs were given 1) STA2 (50 micrograms, n = 6), 2) PGI2 (0.4 micrograms/kg/min, n = 6), 3) both PGI2 and STA2 (n = 6), or 4) vehicles (control, n = 5). Measurements of Kf were made at the baseline period and after the hydrostatic stress. Kf was significantly increased by 76% with STA2, by 121% with PGI2, and by 157% with both PGI2 and STA2, but remained constant in controls. In comparison with control lungs, a similar delta W/delta T was observed with less of an increase in Pc during the hydrostatic stress in the STA2 group, and greater values of delta W/delta T were obtained with smaller elevations in Pc in the groups receiving PGI2 or both PGI2 and STA2.(ABSTRACT TRUNCATED AT 250 WORDS)
Protease inhibitors selectively block T cell receptor-triggered programmed cell death in a murine T cell hybridoma and activated peripheral T cells.
Authors: A Sarin, D H Adams, P A Henkart
Journal: The Journal of Experimental Medicine (1993)

The hypothesis that cytoplasmic proteases play a functional role in programmed cell death was tested by examining the effect of protease inhibitors on the T cell receptor-mediated death of the 2B4 murine T cell hybridoma and activated T cells. The cysteine protease inhibitors trans-epoxysuccininyl-L-leucylamido-(4-guanidino) butane (E-64) and leupeptin, the calpain selective inhibitor acetyl-leucyl-leucyl-normethional, and the serine protease inhibitors diisopropyl fluorophosphate and phenylmethylsulfonyl fluoride, all showed dose-dependent blocking of the 2B4 death response triggered by the T cell receptor complex and by anti-Thy-1. These protease inhibitors enhanced rather than inhibited IL-2 secretion triggered by T cell receptor cross-linking, showing that they did not act by preventing signal transduction. Growth inhibition induced by cross-linking the 2B4 T cell receptor, measured by inhibition of thymidine incorporation, was not generally blocked by these protease inhibitors. All five of these protease inhibitors enhanced rather than blocked 2B4 cell death triggered by dexamethasone, an agent previously shown to have a death pathway antagonistic with that of the TCR. 2B4 cytolysis by the cytotoxic agents staphylococcal alpha-toxin and dodecyl imidazole, and that caused by hypotonic conditions, was not significantly affected by the five protease inhibitors tested. The selected protease inhibitors blocked both the apoptotic nuclear morphology changes and DNA fragmentation induced by T cell receptor cross-linking, and enhanced both these properties induced by dexamethasone in 2B4 cells. The T cell receptor-induced death of activated murine lymph node T cells and human peripheral blood CD4+ T cells was blocked by both cysteine and serine protease inhibitors, showing that the protease-dependent death pathway also operates in these systems.
A Comparison of Medication Side Effect Reports by Panic Disorder Patients With and Without Concomitant Cognitive Behavior Therapy
Authors: Sue M. Marcus, Jack Gorman, M. Katherine Shear, David Lewin, Jose Martinez, Susan Ray, Raymond Goetz, Serge Mosovich, Lauren Gorman, David Barlow, Scott Woods
Journal: American Journal of Psychiatry (2007)

Objective: The authors assessed whether adding cognitive behavior therapy (CBT) to imipramine for patients with panic disorder decreased the severity of side effects and dropouts from side effects. Method: Data were analyzed for 172 panic disorder patients who were randomly assigned to receive imipramine alone, imipramine plus CBT, or placebo. Mixed-effects models were used to assess longitudinal differences among the treatment groups with respect to side effect burden and dropout rates during the acute, maintenance, and follow-up phases of treatment. Results: Patients treated with imipramine plus CBT experienced less severe fatigue/weakness, dry mouth, and sweating and had a lower rate of dropout due to side effects compared with those treated with imipramine only. Conclusions: The addition of CBT to medication treatment with imipramine was associated with less severe side effects and fewer dropouts due to perceived side effects than treatment with imipramine alone.
Transgenic Mice Overexpressing the 5-Hydroxytryptamine Transporter Gene in Smooth Muscle Develop Pulmonary Hypertension
Authors: Christophe Guignabert, Mohamed Izikki, Ly Ieng Tu, Zhenlin Li, Patricia Zadigue, Anne-Marie Barlier-Mur, Naïma Hanoun, David Rodman, Michel Hamon, Serge Adnot, Saadia Eddahibi
Journal: Circulation Research (2006)

One intrinsic abnormality of pulmonary artery smooth muscle cells (PA-SMCs) in human idiopathic pulmonary hypertension (iPH) is an exaggerated proliferative response to internalized serotonin (5-HT) caused by increased expression of the 5-HT transporter (5-HTT). To investigate whether 5-HTT overexpression in PA-SMCs is sufficient to produce PH, we generated transgenic mice overexpressing 5-HTT under the control of the SM22 promoter. Studies in SM22-LacZ(+) mice showed that the transgene was expressed predominantly in SMCs of pulmonary and systemic vessels. Compared with wild-type mice, SM22-5-HTT(+) mice exhibited a 3- to 4-fold increase in lung 5-HTT mRNA and protein, together with increased lung 5-HT uptake activity, but no changes in platelet 5-HTT activity or blood 5-HT levels. At 8 weeks of age, SM22-5-HTT(+) mice exhibited PH, with marked increases in right ventricular systolic pressure (RVSP), right ventricle/left ventricle+septum ratio, and muscularization of distal pulmonary vessels, but no changes in systemic arterial pressure. PH worsened with age. Except a marked decrease in Kv channels, no changes in the lung expression of mediators of pulmonary vascular remodeling were observed in SM22-5-HTT(+) mice. Compared with wild-type mice, SM22-5-HTT(+) mice showed depressed hypoxic pulmonary vasoconstriction contrasting with greater severity of hypoxia- or monocrotaline-induced PH. These results show that increased 5-HTT expression in PA-SMCs, to a level close to that found in human iPH, lead to PH in mice. They further support a central role for 5-HTT in the pathogenesis of PH, making 5-HTT a potential therapeutic target.
Mitochondrion as a Novel Target of Anticancer Chemotherapy
Authors: P. Costantini
Journal: JNCI Journal of the National Cancer Institute (2000)

Mitochondrial membrane permeabilization is a critical event in the process leading to physiologic or chemotherapy-induced apoptosis (programmed cell death). This permeabilization event is, at least in part, under the control of the permeability transition pore complex (PTPC). Oncoproteins from the Bcl-2 family and tumor suppressor proteins from the Bax family interact with PTPC to inhibit or facilitate membrane permeabilization, respectively. Conventional chemotherapeutic agents elicit mitochondrial permeabilization in an indirect fashion by induction of endogenous effectors that are involved in the physiologic control of apoptosis. However, an increasing number of experimental anticancer drugs, including lonidamine, arsenite, betulinic acid, CD437, and several amphipathic cationic α-helical peptides, act directly on mitochondrial membranes and/or on the PTPC. Such agents may induce apoptosis in circumstances in which conventional drugs fail to act because endogenous apoptosis induction pathways, such as those involving p53, death receptors, or apical caspase activation, are disrupted. However, stabilization of the mitochondrial membrane by antiapoptotic Bcl-2-like proteins reduces the cytotoxic potential of most of these drugs. Targeting of specific PTPC components may overcome this Bcl-2-mediated apoptosis inhibition. One strategy involves cross-linking of critical redox-sensitive thiol groups within the PTPC; another involves the use of ligands to the mitochondrial benzodiazepine receptor. Thus, the design of mitochondrion-targeted cytotoxic drugs may constitute a novel strategy for overcoming apoptosis resistance.
Dynamic Oxygen-Enhanced Magnetic Resonance Imaging is Not Useful in Assessing Severity or Airway Inflammation in Asthmatic Children
Authors: T.F. Leung, W.C.W. Chu, C.W.Y. Kam, D.T. Yeung, C.Y. Li, G.W.K. Wong, P.C. Ng
Journal: Journal of Allergy and Clinical Immunology (2007)
A Randomized Trial of Multivitamin Supplements and HIV Disease Progression and Mortality
Authors: Wafaie W. Fawzi, Gernard I. Msamanga, Donna Spiegelman, Ruilan Wei, Saidi Kapiga, Eduardo Villamor, Davis Mwakagile, Ferdinand Mugusi, Ellen Hertzmark, Max Essex, David J. Hunter
Journal: New England Journal of Medicine (2004)

Results from observational studies suggest that micronutrient status is a determinant of the progression of human immunodeficiency virus (HIV) disease.
Differential Effect of Glycemia on the Incidence of Hypertension by Sex
Authors: Tina Costacou, Trevor J. Orchard
Journal: Diabetes Care (2012)

Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications analyses demonstrated that intensive insulin therapy was inversely associated with incident hypertension. We thus sought to confirm these observations and, given sex differences in other type 1 diabetes complications and risk factors, assessed whether any such associations differ by sex.Participants of a prospective cohort of childhood-onset type 1 diabetes, free of hypertension at study entry (baseline mean age, 28 years; diabetes duration, 19 years), were selected for study (n = 510). Hypertension incidence was defined as blood pressure >140/90 mmHg or use of hypertension medications in two consecutive visits. Intensive insulin therapy was defined as three or more injections (or pump) and four or more glucose tests daily. Baseline predictors of hypertension were examined using Cox proportional hazards models. Models with time-dependent updated means of baseline significant variables were also constructed.Hypertension incidence over 18 years of follow-up was marginally higher in men than in women (43.2 vs. 35.4%, P = 0.07). A significant interaction was noted between sex and HbA(1c), and separate models were constructed by sex. Multivariably, elevated HbA(1c) was a significant predictor only in men (hazard ratio 1.48 [95% CI 1.28-1.71]). In time-dependent models, although a significant effect of HbA(1c) was also seen in women (1.21 [1.00-1.46]), the effect of glycemic control on hypertension development remained stronger in men (1.59 [1.29-1.97], P interaction <0.0001).Although hyperglycemia is a risk factor for hypertension, its effect is stronger in men compared with women with type 1 diabetes.
Parmodulins inhibit thrombus formation without inducing endothelial injury caused by vorapaxar
Authors: Omozuanvbo Aisiku, Christian G. Peters, Karen De Ceunynck, Chandra C. Ghosh, James R. Dilks, Susanna F. Fustolo-Gunnink, Mingdong Huang, Chris Dockendorff, Samir M. Parikh, Robert Flaumenhaft
Journal: Blood (2015)
Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment
Authors: S Nishida, K Hagihara, Y Shima, M Kawai, Y Kuwahara, J Arimitsu, T Hirano, M Narazaki, A Ogata, K Yoshizaki, I Kawase, T Kishimoto, T Tanaka
Journal: Annals of the Rheumatic Diseases (2009)

AA amyloidosis is a serious complication of chronic inflammatory and infectious diseases.1 Amyloid fibril deposition causes progressive deterioration in various organs.

In October 2007, a 50-year-old woman was admitted to our hospital with severe diarrhoea and weight loss. She had had rheumatoid arthritis (RA) for 12 years. Despite vigorous treatment with prednisolone and disease-modifying anti-rheumatic drugs (DMARDs), including bucillamine, sulfasalazine, auranofin, leflunomide and methotrexate or tacrolimus, her disease remained active.

In January 2007, treatment was started with biological drugs. Subcutaneous injection of 25 mg of etanercept twice weekly for 2 months and, subsequently, intravenous injection of 3 mg/kg infliximab for 5 months combined with 20 mg of prednisolone …
Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II)
Authors: Carlo Briguori, Gabriella Visconti, Amelia Focaccio, Flavio Airoldi, Marco Valgimigli, Giuseppe Massimo Sangiorgi, Bruno Golia, Bruno Ricciardelli, Gerolama Condorelli
Journal: Circulation (2011)

The RenalGuard System, which creates high urine output and fluid balancing, may be beneficial in preventing contrast-induced acute kidney injury.The Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II) trial is a randomized, multicenter, investigator-driven trial addressing the prevention of contrast-induced acute kidney injury in high-risk patients. Patients with an estimated glomerular filtration rate ≤30 mL · min(-1) · 1.73 m(-2) and/or a risk score ≥11 were randomly assigned to sodium bicarbonate solution and N-acetylcysteine (control group) or hydration with saline and N-acetylcysteine controlled by the RenalGuard System and furosemide (RenalGuard group). The primary end point was an increase of ≥0.3 mg/dL in the serum creatinine concentration at 48 hours after the procedure. The secondary end points included serum cystatin C kinetics and rate of in-hospital dialysis. Contrast-induced acute kidney injury occurred in 16 of 146 patients in the RenalGuard group (11%) and in 30 of 146 patients in the control group (20.5%; odds ratio, 0.47; 95% confidence interval, 0.24 to 0.92). There were 142 patients (48.5%) with an estimated glomerular filtration rate ≤30 mL · min(-1) · 1.73 and 149 patients (51.5%) with only a risk score ≥11. Subgroup analysis according to inclusion criteria showed a similarly lower risk of adverse events (estimated glomerular filtration rate ≤30 mL · min(-1) · 1.73 m(-2): odds ratio, 0.44; risk score ≥11: odds ratio, 0.45; P for interaction=0.97). Changes in cystatin C at 24 hours (0.02±0.32 versus -0.08±0.26; P=0.002) and 48 hours (0.12±0.42 versus 0.03±0.31; P=0.001) and the rate of in-hospital dialysis (4.1% versus 0.7%; P=0.056) were higher in the control group.RenalGuard therapy is superior to sodium bicarbonate and N-acetylcysteine in preventing contrast-induced acute kidney injury in high-risk patients.URL: http://www.clinicaltrial.gov. Unique identifier: NCT01098032.
Effects of neomycin on absorption, synthesis, and/or flux of cholesterol in man.
Authors: A Sedaghat, P Samuel, J R Crouse, E H Ahrens
Journal: Journal of Clinical Investigation (1975)

The mode of action of the hypocholesteremic drug neomycin (2 g/day) was studied in four patients. All showed a significant reduction in plasma cholesterol concentrations (mean 25 percent, range 18-31 percent), and in one of three patients with hyperglyceridemia there was a decrease of plasma triglycerides of 26 percent. Cholesterol absorption was measured in three of four patients: there was a marked decrease. Sterol balance studies in four patients showed an unabating increase in fecal neutral steroid excretion (mean increase 345 mg/day, range 323-361) for 3-5 wk after plasma cholesterol levels had reached a new and lower plateau. Fecal acidic steroid excretion increased temporarily in two patients, with a sustained increase of 93 mg/day in only one. Daily stool weights increased significantly in three of four patients, though none had steatorrhea; there was a significant reduction in excretion of secondary bile acids; neutral sterol degradation rates were not affected by the drug. Slopes of plasma cholesterol-specific activity time curves did not change. These results fail to support the suggestion that neomycin acts as a bile acid precipitant. The finding of increased fecal neutral steroid excretion is consistent with decreased cholesterol absorption, but also with increased cholesterol absorption, but also with increased cholesterol synthesis (secondary to release of negative feedback control), with increased flux of cholesterol from tissues, or with a combination of all three actions.
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer
Authors: Sarah Reid, Detlev Schindler, Helmut Hanenberg, Karen Barker, Sandra Hanks, Reinhard Kalb, Kornelia Neveling, Patrick Kelly, Sheila Seal, Marcel Freund, Melanie Wurm, Sat Dev Batish, Francis P Lach, Sevgi Yetgin, Heidemarie Neitzel, Hany Ariffin, Marc Tischkowitz, Christopher G Mathew, Arleen D Auerbach, Nazneen Rahman
Journal: Nature Genetics (2006)