tbuckley/cabot-search huggingface dataset:
Ischemic Preconditioning Suppresses Ventricular Tachyarrhythmias After Myocardial Revascularization
Authors: Zhong-Kai Wu, Tiina Iivainen, Erkki Pehkonen, Jari Laurikka, Matti R. Tarkka
Journal: Circulation (2002)

Background— Ventricular fibrillation (VF) and tachycardia (VT) are the common and potential life-threatening complications after CABG. Ischemic preconditioning (IP) has been proved effective in reducing ischemia reperfusion arrhythmia in animals and humans. Whether IP is effective in suppressing postoperative VF/VT in patients with CABG has not been studied. Methods and Results— Eighty-six patients with CABG with stable and unstable 3-vessel disease were equally randomly assigned into an IP and a control group. The patients who received IP received 2 periods of 2-minute ischemia followed by 3-minute reperfusion. Twenty-four-hour electrocardiographic data were collected. IP resulted in fewer cases of VF after declamping (48.8% versus 79.1% in IP and control, P =0.004) and a shorter VF period (2.28±0.44 versus 4.41±0.51 minutes, P =0.002). The episodes of VT were significantly reduced in patients in the IP group during early reperfusion and 24 hours after reperfusion (0.65±0.16 versus 3.71±0.46, P =0.000 and 0.07±0.04 versus 2.12±1.41, P =0.002, respectively). De novo sustained VT occurred in 3 control patients as against none in the IP group after surgery. As a result, IP significantly curtailed the mechanical ventilation period and reduced the need for inotropes. Conclusions— IP significantly reduced postoperative VF/VT in patients with CABG with 3-vessel disease. Suppression of VT during early reperfusion and 24 hours after reperfusion suggests early and delayed IP phenomena in patients undergoing CABG surgery.
Heinz bodies induce clustering of band 3, glycophorin, and ankyrin in sickle cell erythrocytes.
Authors: S M Waugh, B M Willardson, R Kannan, R J Labotka, P S Low
Journal: Journal of Clinical Investigation (1986)

In earlier model studies we demonstrated that artificially denatured hemoglobin binds to and clusters the protein, band 3, in the plane of the erythrocyte membrane. To determine whether denatured hemoglobin also clusters band 3 in vivo, we have compared the locations of denatured hemoglobin aggregates (Heinz bodies) with band 3 in sickle cells using phase contrast and immunofluorescence microscopy. We report that where Heinz bodies are found associated with the cytoplasmic surface of the membrane, clusters of band 3 are usually colocalized within the membrane. In contrast, normal erythrocyte membranes and regions of sickle cell membranes devoid of Heinz bodies display an uninterrupted staining of band 3. Similarly, ankyrin and glycophorin are periodically seen to aggregate at Heinz body sites, but the degree of colocalization is lower than for band 3. These data demonstrate that the binding of denatured hemoglobin to the membrane forces a redistribution of several major membrane components.
Proliferative Changes in the Bronchial Epithelium of Former Smokers Treated With Retinoids
Authors: W. N. Hittelman, D. D. Liu, J. M. Kurie, R. Lotan, J. S. Lee, F. Khuri, H. Ibarguen, R. C. Morice, G. Walsh, J. A. Roth, J. Minna, J. Y. Ro, A. Broxson, W. K. Hong, J. J. Lee
Journal: JNCI Journal of the National Cancer Institute (2007)

Retinoids have shown antiproliferative and chemopreventive activity. We analyzed data from a randomized, placebo-controlled chemoprevention trial to determine whether a 3-month treatment with either 9- cis -retinoic acid (RA) or 13- cis -RA and α-tocopherol reduced Ki-67, a proliferation biomarker, in the bronchial epithelium. Former smokers (n = 225) were randomly assigned to receive 3 months of daily oral 9- cis -RA (100 mg), 13- cis -RA (1 mg/kg) and α-tocopherol (1200 IU), or placebo. Bronchoscopic biopsy specimens obtained before and after treatment were immunohistochemically assessed for changes in the Ki-67 proliferative index (i.e., percentage of cells with Ki-67–positive nuclear staining) in the basal and parabasal layers of the bronchial epithelium. Per-subject and per–biopsy site analyses were conducted. Multicovariable analyses, including a mixed-effects model and a generalized estimating equations model, were used to investigate the treatment effect (Ki-67 labeling index and percentage of bronchial epithelial biopsy sites with a Ki-67 index ≥ 5%) with adjustment for multiple covariates, such as smoking history and metaplasia. Coefficient estimates and 95% confidence intervals (CIs) were obtained from the models. All statistical tests were two-sided. In per-subject analyses, Ki-67 labeling in the basal layer was not changed by any treatment; the percentage of subjects with a high Ki-67 labeling in the parabasal layer dropped statistically significantly after treatment with 13- cis -RA and α-tocopherol treatment ( P = .04) compared with placebo, but the drop was not statistically significant after 9- cis -RA treatment ( P = .17). A similar effect was observed in the parabasal layer in a per-site analysis; the percentage of sites with high Ki-67 labeling dropped statistically significantly after 9- cis -RA treatment (coefficient estimate = −0.72, 95% CI = –1.24 to –0.20; P = .007) compared with placebo, and after 13- cis -RA and α-tocopherol treatment (coefficient estimate = −0.66, 95% CI = –1.15 to –0.17; P = .008). In per-subject analyses, treatment with 13- cis -RA and α-tocopherol, compared with placebo, was statistically significantly associated with reduced bronchial epithelial cell proliferation; treatment with 9- cis -RA was not. In per-site analyses, statistically significant associations were obtained with both treatments.
In vitro generation of tumor-specific cytotoxic lymphocytes. Secondary allogeneic mixed tumor lymphocyte culture of normal murine spleen cells
Authors: S Gillis, KA Smith
Journal: The Journal of Experimental Medicine (1977)

In vivo or in vitro immunity to murine leukemia virus (MuLV)-induced leukemia cells which do not effectively produce virus, has been difficult to demonstrate. Because immunizations with allogeneic murine leukemia cells have been used to confer syngeneic tumor immunity to virus- producing cells, we attempted to generate lymphocytes, cytotoxic to syngeneic nonproducer leukemia cells, by stimulating normal murine spleen cells with allogeneic nonproducer leukemia cells in mixed tumor lymphocyte culture (MTLC) reactions in vitro. Secondary allogeneic MTLC of normal C57BL/6 or DBA/2 spleen cells effectively produced syngeneic tumor-specific cytotoxic lymphocytes. Target cells lysed in lymphocyte- mediated cytolysis (LMC) assays, included both Friend and Rauscher virus- induced syngeneic murine leukemia cells and chemically-induced hematopoietic tumor cells. Syngeneic tumor cells were lysed regardless of whether they produced infectious MuLV or expressed viral antigens gp-71, p-30, or p-12 at the cell surface. Syngeneic normal cells (thymus, lymph node, or Concanavalin A-stimulated spleen cells) used as targets in LMC assays were uneffected by lymphocytes harvested from secondary allogeneic MTLC. Several other in vitro culture treatments including secondary syngeneic MTLC and repetitive mixed lymphocyte culture stimulations were incapable of generating tumor-specific cytotoxic lymphocytes. Based upon these results, we propose that secondary MTLC stimulation of normal spleen cells with allogeneic nonproducer leukemia cells selects for the proliferation of two subpopulations of antigen-specific cytotoxic lymphocytes. The population capable of effecting syngeneic tumor cell lysis is directed against tumor-associated cell surface antigens which may be distinct from viral structural proteins or glycoproteins. The growth of these tumor-specific cytotoxic lymphocytes may be enhanced by a soluble allogeneic effect factor produced by the proliferation of the second subpopulation of lymphocytes generated in repetitive allogeneic MTLC, namely those lymphocytes with specificities directed against differing histocompatibility antigens.
Beneficial Effects of Adding Spironolactone to Recommended Antihypertensive Treatment in Diabetic Nephropathy
Authors: Kasper Rossing, Katrine J. Schjoedt, Ulla M. Smidt, Frans Boomsma, Hans-Henrik Parving
Journal: Diabetes Care (2005)

OBJECTIVE—The objective of this study was to evaluate the safety and short-term effect of adding spironolactone to conventional antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor or an angiotensin II receptor blocker (ARB) on albuminuria and blood pressure in type 2 diabetic patients with nephropathy. RESEARCH DESIGN AND METHODS—Twenty-one type 2 diabetic patients with nephropathy were enrolled in a randomized, double-masked, cross-over study. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 8 weeks, respectively, in addition to ongoing antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor and/or an ARB. At the end of each treatment period, albuminuria, 24-h ambulatory blood pressure (ABP), and glomerular filtration rate (GFR) were determined. RESULTS—During the addition of placebo, values were as follows: albuminuria (geometric mean [range]) 1,566 [655–7,762] mg/24 h, ABP (mean ± SE) 138 ± 3/71 ± 1 mmHg, and GFR (mean ± SE) 74 ± 6 ml/min per 1.73 m2. During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25–41) (P &amp;lt; 0.001), fractional clearance of albumin by 40% (24–53) (P &amp;lt; 0.001), and 24-h ABP by 6 mmHg (2–10) for systolic and 4 mmHg (2–6) for diastolic (P &amp;lt; 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r = 0.19, P = 0.42) or diastolic 24-h ABP (r = 0.01, P = 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m2 (−0.3 to 6) (P = 0.08). One patient was excluded from the study due to hyperkalemia. Otherwise treatment was well tolerated. CONCLUSIONS—Our study suggests that spironolactone safely adds to the reno- and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and blood pressure in type 2 diabetic patients with nephropathy.
Ventilator associated pneumonia: quality of nonbronchoscopic bronchoalveolar lavage sample affects diagnostic yield
Authors: R.P. Baughman, R.E. Spencer, B.O. Kleykamp, M.C. Rashkin, M.m Douthit
Journal: European Respiratory Journal (2000)

The importance of predefined criteria for acceptable samples of respiratory therapists obtained lower respiratory samples were studied, using a nonbronchoscopic bronchoalveolar lavage (BAL) protocol for ventilated patients in the intensive care unit. Therapists were instructed and asked to follow guidelines for obtaining samples. Over one year, 219 samples were obtained by respiratory therapists. Of these, 115 were considered to be adequate samples using the following criteria: 60 mL of instilled volume, at least 5 mL of fluid aspirated, specimens sent for semiquantitative culture, a differential cell count of <5% bronchial epithelial cells. Overall, 52 samples grew one or more pathogen at >10,000 colony forming units (cfu).mL(-1) of BAL. The most common pathogen was Staphylococcus aureus (S. aureus) (11 samples), although Gram-negative bacilli were the single pathogen in 21 specimens. Of the 115 acceptable samples, 40 (35%) grew > or =1 pathogen at >10,000 cfu.mL(-1). For the 80 not acceptable samples which were sent for appropriate culture, 12 (15%) grew >10,000 cfu.mL(-1) BAL. This difference was significant (Chi-squared=9.44, p<0.01). Nonbronchoscopic bronchoalveolar lavage can be safely performed by respiratory therapists'. The authors recommend that a protocol be used to evaluate the quality of a bronchoalveolar lavage sample in the same manner sputum samples are screened prior to interpretation.
Mesenchymal Stem Cells: Mechanisms of Inflammation
Authors: Nora G. Singer, Arnold I. Caplan
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

In adults, human mesenchymal stem cells (hMSCs) are found in vivo at low frequency and are defined by their capacity to differentiate into bone, cartilage, and adipose tissue, depending on the stimuli and culture conditions under which they are expanded. Although MSCs were initially hypothesized to be the panacea for regenerating tissues, MSCs appear to be more important in therapeutics to regulate the immune response invoked in settings such as tissue injury, transplantation, and autoimmunity. MSCs have been used therapeutically in clinical trials and subsequently in practice to treat graft-versus-host disease following bone marrow transplantation. Reports of successful immune modulation suggest efficacy in a wide range of autoimmune conditions, such as demyelinating neurological disease (multiple sclerosis), systemic lupus erythematosus, and Crohn's disease, among others. This review provides background information about hMSCs and also describes their putative mechanisms of action in inflammation. We provide a summary of ongoing clinical trials to allow (a) full comprehension of the range of diseases in which hMSC therapy may be beneficial and (b) identification of gaps in our knowledge about the mechanisms of action of therapeutic MSCs in disease.
Alpha-1-Antitrypsin Deficiency: Importance of Proteasomal and Autophagic Degradative Pathways in Disposal of Liver Disease–Associated Protein Aggregates
Authors: David H. Perlmutter
Journal: Annual Review of Medicine (2010)

Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic and/or environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease.
A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease
Authors: Rachelle S. Doody, Rema Raman, Martin Farlow, Takeshi Iwatsubo, Bruno Vellas, Steven Joffe, Karl Kieburtz, Feng He, Xiaoying Sun, Ronald G. Thomas, Paul S. Aisen, Eric Siemers, Gopalan Sethuraman, Richard Mohs
Journal: New England Journal of Medicine (2013)

Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease.
L1 and HERV-W retrotransposons are hypomethylated in human ovarian carcinomas.
Authors: Laura Menendez, Benedict B Benigno, John F McDonald
Journal: Molecular Cancer (2004)

Wide-spread hypomethylation of CpG dinucleotides is characteristic of many cancers. Retrotransposons have been identified as potential targets of hypomethylation during cellular transformation. We report the results of an preliminary examination of the methylation status of CpG dinucleotides associated with the L1 and HERV-W retrotransposons in benign and malignant human ovarian tumors. We find a reduction in the methylation of CpG dinucleotides within the promoter regions of these retroelements in malignant relative to non-malignant ovarian tissues. Consistent with these results, we find that relative L1 and HERV-W expression levels are elevated in representative samples of malignant vs. non-malignant ovarian tissues.
Tumor-Induced Oxidative Stress Perturbs Nuclear Factor-κB Activity-Augmenting Tumor Necrosis Factor-α–Mediated T-Cell Death: Protection by Curcumin
Authors: Sankar Bhattacharyya, Debaprasad Mandal, Gouri Sankar Sen, Suman Pal, Shuvomoy Banerjee, Lakshmishri Lahiry, James H. Finke, Charles S. Tannenbaum, Tanya Das, Gaurisankar Sa
Journal: Cancer Research (2007)

Cancer patients often exhibit loss of proper cell-mediated immunity and reduced effector T-cell population in the circulation. Thymus is a major site of T-cell maturation, and tumors induce thymic atrophy to evade cellular immune response. Here, we report severe thymic hypocellularity along with decreased thymic integrity in tumor bearer. In an effort to delineate the mechanisms behind such thymic atrophy, we observed that tumor-induced oxidative stress played a critical role, as it perturbed nuclear factor-kappaB (NF-kappaB) activity. Tumor-induced oxidative stress increased cytosolic IkappaBalpha retention and inhibited NF-kappaB nuclear translocation in thymic T cells. These NF-kappaB-perturbed cells became vulnerable to tumor-secreted tumor necrosis factor (TNF)-alpha (TNF-alpha)-mediated apoptosis through the activation of TNF receptor-associated protein death domain-associated Fas-associated protein death domain and caspase-8. Interestingly, TNF-alpha-depleted tumor supernatants, either by antibody neutralization or by TNF-alpha-small interfering RNA transfection of tumor cells, were unable to kill T cell effectively. When T cells were overexpressed with NF-kappaB, the cells became resistant to tumor-induced apoptosis. In contrast, when degradation-defective IkappaBalpha (IkappaBalpha super-repressor) was introduced into T cells, the cells became more vulnerable, indicating that inhibition of NF-kappaB is the reason behind such tumor/TNF-alpha-mediated apoptosis. Curcumin could prevent tumor-induced thymic atrophy by restoring the activity of NF-kappaB. Further investigations suggest that neutralization of tumor-induced oxidative stress and restoration of NF-kappaB activity along with the reeducation of the TNF-alpha signaling pathway can be the mechanism behind curcumin-mediated thymic protection. Thus, our results suggest that unlike many other anticancer agents, curcumin is not only devoid of immunosuppressive effects but also acts as immunorestorer in tumor-bearing host.
Structural and reactivity alterations of the renal vasculature of spontaneously hypertensive rats prior to and during established hypertension.
Authors: J S Smeda, R M Lee, J B Forrest
Journal: Circulation Research (1988)

The renal vasculature of Wistar Kyoto spontaneously hypertensive rats (SHR), prior to (4-5 week) and during established hypertension (21 week) and those of age-matched Wistar Kyoto normotensive rats (WKY) were morphometrically and pharmacologically studied. Under dilated conditions, the vascular resistances (RVR) of the isolated kidneys of young and adult SHR were similar to WKY. Morphometric measurements of renal vasculature indicated that the cross-sectional area of the intima and adventitia and its subcomponents were similar in adult SHR and WKY. With the exception of the preglomerular arterioles, all the renal arteries of adult SHR exhibited elevated cross-sectional quantities of total media, medial smooth muscle cells (SMCs), and extracellular space. Analysis of the SMCs indicated the presence of increased numbers of SMC layers and/or an increase in the SMC volume-to-surface area ratio in arteries sampled from adult SHR. Vascular contraction produced by infusing norepinephrine, BaCl2, angiotensin II, or by stimulating the renal nerves elevated the RVR to a greater degree in adult SHR than in WKY. The sensitivity of the renal vasculature to the various contractile agents was similar in adult SHR and WKY. When compared with WKY, prehypertensive SHR also exhibited increased cross-sectional quantities of arterial media and elevated amplitudes of RVR change in response to norepinephrine and renal nerve stimulation. However, the vascular contractile sensitivity to norepinephrine was reduced. Our results indicate that renovascular wall thickening and the hypercontractile reactivity associated with such a change precedes hypertension in SHR. In prehypertensive SHR, elevations in RVR might be counterbalanced by a decreased norepinephrine sensitivity. An increase in the norepinephrine contractile sensitivity and further vascular thickening with age could elevate the RVR and establish hypertension.
The Pseudoautosomal Regions of the U/V Sex Chromosomes of the Brown Alga<i>Ectocarpus</i>Exhibit Unusual Features
Authors: Rémy Luthringer, Agnieszka P. Lipinska, Denis Roze, Alexandre Cormier, Nicolas Macaisne, Akira F. Peters, J. Mark Cock, Susana M. Coelho
Journal: Molecular Biology and Evolution (2015)

The recombining regions of sex chromosomes (pseudoautosomal regions, PARs) are predicted to exhibit unusual features due to their being genetically linked to the nonrecombining, sex-determining region. This phenomenon is expected to occur in both diploid (XY, ZW) and haploid (UV) sexual systems, with slightly different consequences for UV sexual systems because of the absence of masking during the haploid phase (when sex is expressed) and because there is no homozygous sex in these systems. Despite a considerable amount of theoretical work on PAR genetics and evolution, these genomic regions have remained poorly characterized empirically. We show here that although the PARs of the U/V sex chromosomes of the brown alga Ectocarpus recombine at a similar rate to autosomal regions of the genome, they exhibit many genomic features typical of nonrecombining regions. The PARs were enriched in clusters of genes that are preferentially, and often exclusively, expressed during the sporophyte generation of the life cycle, and many of these genes appear to have evolved since the Ectocarpales diverged from other brown algal lineages. A modeling-based approach was used to investigate possible evolutionary mechanisms underlying this enrichment in sporophyte-biased genes. Our results are consistent with the evolution of the PAR in haploid systems being influenced by differential selection pressures in males and females acting on alleles that are advantageous during the sporophyte generation of the life cycle.
Suturing versus conservative management of lacerations of the hand: randomised controlled trial
Authors: J. Quinn
Journal: BMJ (2002)

Objective: To assess the difference in clinical outcome between lacerations of the hand closed with sutures and those treated conservatively. Design : Randomised controlled trial. Setting : Emergency department in a tertiary hospital. Participants : Consecutive patients presenting between 16 February and 30 November 2000 with uncomplicated lacerations of the hand (full thickness <2 cm; without tendon, joint, fracture, or nerve complications) who would normally require sutures. 154 patients were eligible, 58 refused, and 5 were missed; 91 patients with 95 lacerations were enrolled. Intervention : Participants were randomised to suturing or conservative treatment. Main outcome measures : Primary outcome was cosmetic appearance after three months, rated on a previously validated visual analogue scale. Duration of treatment, pain during treatment, patients' assessment of their outcome, and the time for patients to resume normal activities were also measured. Results : Participants treated with sutures and those treated conservatively did not differ significantly in the assessment of cosmetic appearance by independent blinded doctors after three months: 83 mm v 80 mm, (mean difference 3 (95% confidence interval −1 to 8) mm) on the visual analogue scale. The mean time to resume normal activities was the same in both groups (3.4 days). Patients treated conservatively had less pain (difference 18 (12 to 24) mm) and treatment time was 14 (10 to 18) min shorter. Conclusion : Similar cosmetic and functional outcomes result from either conservative treatment or suturing of small uncomplicated lacerations of the hand, but conservative treatment is faster and less painful.