tbuckley/cabot-search huggingface dataset:
FURTHER STUDIES ON PREPARATION AND PROPERTIES OF PHAGOCYTIN
Authors: James G. Hirsch
Journal: The Journal of Experimental Medicine (1960)

PHAGOCYTIN AND HISTONE DIFFER SIGNIFICANTLY IN THE FOLLOWING REGARDS: (a) the bactericidal action of histone is rapidly lost on peptic digestion, while that of phagocytin is but little affected; (b) the lethal effect of phagocytin on coliform bacteria is much more resistant than that of histone to antagonism by spermine or by increasing ionic strength of the medium; (c) phagocytin can be extracted from disrupted granulocytes with dilute citric acid whereas effective extraction of histone requires stronger mineral acid or strong salt solution; (d) phagocytin is limited in distribution to polymorphonuclear leucocytes while histone is demonstrable in many tissues. A new technique has been devised which permits extraction of phagocytin essentially free of lysozyme and histones. Phagocytin thus prepared kills certain Gram-positive bacteria as well as Gram-negative bacilli under appropriate in vitro test conditions. Among susceptible Gram-positive microbes are Group A streptococci and staphylococci. Phagocytin is demonstrable in citric acid extracts of granulocytes obtained from rabbit, man, horse, and guinea pig, the only species thus far investigated. Circulating blood leucocytes as well as exudate cells contain this bactericidal substance. The lethal effects of phagocytin on bacteria may be influenced, depending on the particular microorganism, by either pH or ionic strength of the medium. The bactericidal action of phagocytin is only slightly reduced following digestion with trypsin, chymotrypsin or papain. The active ingredient is, however, non-dialyzable and apparently precipitated by trichloracetic acid. Data available at present are insufficient to define the chemical nature of phagocytin.
External detection of early microvascular dysfunction after no-flow ischemia followed by reperfusion in isolated rabbit hearts.
Authors: R G Tilton, K B Larson, J R Udell, B E Sobel, J R Williamson
Journal: Circulation Research (1983)

To define relationships better between the duration of severe ischemia and microvascular functional integrity with an approach potentially applicable to studies in vivo, the effects of 30 and 60 minutes of global, no-flow ischemia on the coronary vasculature of isolated, perfused rabbit hearts were determined. Residue-detection data, analyzed with a two-compartment model, were used to estimate indices of microvascular function, including the mean-transit time (tBSA) of radiolabeled bovine serum albumin (125I-BSA), vascular into extravascular space clearance, and vascular and extravascular space volumes. It was shown that the Central Volume Principle of tracer kinetics does not hold when transport of label between vascular and extravascular spaces takes place convectively by solvent drag, and a more general expression for tBSA was derived and applied. Left ventricular end-diastolic pressure and left ventricular developed pressure were monitored with an isovolumic balloon. Aortic perfusion pressure, left ventricular end-diastolic pressure, left ventricular developed pressure and vascular space volume remained constant, while mean transit time, vascular into extravascular space clearance and extravascular space volumes increased gradually during 3-hour control perfusions. Perfusion pressure, mean transit time and extravascular space clearance increased significantly with reperfusion after 30 minutes of ischemia even though left ventricular end-diastolic and left ventricular-developed pressures returned to control levels. Vascular space volumes increased minimally, whereas extravascular space volumes increased 5-fold during reperfusion. These changes in 125I-BSA washout and permeation across endothelium with reperfusion after no-flow ischemia indicate that compromised vascular integrity is an early manifestation of ischemia with functional consequences that persist even after ischemia sufficiently brief to permit restoration of left ventricular performance.
Hemodynamic Determinants of Exercise ST-Segment Depression in Coronary Patients
Authors: JEAN-MARIE R. DETRY, FRANZ PIETTE, LUCIEN A. BRASSEUR
Journal: Circulation (1970)

Eight patients with coronary heart disease were studied during two periods of exercise separated by 30 min of rest; workload was increased in a stepwise fashion every minute of exercise up to a level that produced limiting symptoms of angina, fatigue, or dyspnea. The magnitude of ST-segment depression and the central aortic pressure were measured during exercise and recovery periods, and myocardial oxygen requirements were estimated by the pressure-time index (systolic aortic pressure x heart rate x ejection time). Seven of the eight patients exhibited a close relationship (r ranged from 0.74 to 0.98) between magnitude of exercise ST-segment depression and indices expressing myocardial oxygen requirements; heart rate, blood pressure, and ejection time were also related to magnitude of exercise ST-segment depression. These relationships were reproducible during two consecutive exercises. Like onset of angina, magnitude of exercise ST-segment depression is usually related to hemodynamic factors influencing myocardial oxygen needs. Consequently, comparisons of exercise-induced ST depression before and after therapy (drugs, physical training, and surgery) are valid only if ECG findings are compared at the same level of myocardial oxygen requirements. In contrast, absence of such a relationship during recovery suggests an important difference in mechanisms of the post-exercise electrocardiogram.
Molecular Evolution of a Y Chromosome to Autosome Gene Duplication in Drosophila
Authors: K. A. Dyer, B. E. White, M. J. Bray, D. G. Pique, A. J. Betancourt
Journal: Molecular Biology and Evolution (2010)

In contrast to the rest of the genome, the Y chromosome is restricted to males and lacks recombination. As a result, Y chromosomes are unable to respond efficiently to selection, and newly formed Y chromosomes degenerate until few genes remain. The rapid loss of genes from newly formed Y chromosomes has been well studied, but gene loss from highly degenerate Y chromosomes has only recently received attention. Here, we identify and characterize a Y to autosome duplication of the male fertility gene kl-5 that occurred during the evolution of the testacea group species of Drosophila. The duplication was likely DNA based, as other Y-linked genes remain on the Y chromosome, the locations of introns are conserved, and expression analyses suggest that regulatory elements remain linked. Genetic mapping reveals that the autosomal copy of kl-5 resides on the dot chromosome, a tiny autosome with strongly suppressed recombination. Molecular evolutionary analyses show that autosomal copies of kl-5 have reduced polymorphism and little recombination. Importantly, the rate of protein evolution of kl-5 has increased significantly in lineages where it is on the dot versus Y linked. Further analyses suggest this pattern is a consequence of relaxed purifying selection, rather than adaptive evolution. Thus, although the initial fixation of the kl-5 duplication may have been advantageous, slightly deleterious mutations have accumulated in the dot-linked copies of kl-5 faster than in the Y-linked copies. Because the dot chromosome contains seven times more genes than the Y and is exposed to selection in both males and females, these results suggest that the dot suffers the deleterious effects of genetic linkage to more selective targets compared with the Y chromosome. Thus, a highly degenerate Y chromosome may not be the worst environment in the genome, as is generally thought, but may in fact be protected from the accumulation of deleterious mutations relative to other nonrecombining regions that contain more genes.
Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart
Authors: Stefano Toldo, Eleonora Mezzaroma, Matthew D. McGeough, Carla A. Peña, Carlo Marchetti, Chiara Sonnino, Benjamin W. Van Tassell, Fadi N. Salloum, Norbert F. Voelkel, Hal M. Hoffman, Antonio Abbate
Journal: Cardiovascular Research (2014)

The NLRP3 inflammasome is activated in the ischaemic heart promoting caspase-1 activation, inflammation, and cell death.Ischaemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation).Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown.The aim of this study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in the absence of ischaemia or myocardial injury. Methods and resultsWe used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreT mice).The mice were treated for 10 days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome.Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V.The components of the inflammasome were significantly less expressed in the heart compared with the spleen.Subclinical low-dose lipopolysaccharide (LPS; 2 mg/kg) in Nlrp3-A350V/CreT mice induced the expression of the components of the inflammasome ( priming), measured using real-time PCR and western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low-dose LPS was insufficient to induce LV systolic dysfunction in wild-type mice (all P , 0.01 for mutant vs. wild-type mice). ConclusionThe signalling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction.
Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use
Authors: Elisabeth R. Pomp, Frits R. Rosendaal, Carine J.M. Doggen
Journal: American Journal of Hematology (2007)

Abstract The results of studies investigating the relationship of smoking with venous thrombosis are inconsistent. Therefore, in the MEGA study, a large population‐based case–control study, we evaluated smoking as a risk factor for venous thrombosis and the joint effect with oral contraceptive use and the factor V Leiden mutation. Consecutive patients with a first venous thrombosis were included from six anticoagulation clinics. Partners of patients were asked to participate and additional controls were recruited using a random digit dialing method. Participants completed a standardized questionnaire. Individuals with known malignancies were excluded from the analyses, leaving a total of 3,989 patients and 4,900 controls. Current and former smoking resulted in a moderately increased risk of venous thrombosis (odds ratio (OR) current 1.43, 95% confidence interval (CI95) 1.28–1.60, OR former 1.23, CI95 1.09–1.38) compared with nonsmoking. Adjustment for fibrinogen levels did not substantially change these risk estimates. A high number of pack‐years resulted in the highest risk among young current smokers (OR ≥20 pack‐years 4.30, CI95 2.59–7.14) compared with young nonsmokers. Women who were current smokers and used oral contraceptives had an 8.8‐fold higher risk (OR 8.79, CI95 5.73–13.49) than nonsmoking women who did not use oral contraceptives. Relative to nonsmoking noncarriers, the joint effect of factor V Leiden and current smoking led to a 5.0‐fold increased risk; for the prothrombin 20210A mutation this was a 6.0‐fold increased risk. In conclusion, smoking appears to be a risk factor for venous thrombosis with the greatest relative effect among young women using oral contraceptives. Am. J. Hematol., 2008. © 2007 Wiley‐Liss, Inc.
Mouse Model of <i>SCN5A</i> -Linked Hereditary Lenègre’s Disease
Authors: Anne Royer, Toon A.B. van Veen, Sabrina Le Bouter, Céline Marionneau, Violaine Griol-Charhbili, Anne-Laure Léoni, Marja Steenman, Harold V.M. van Rijen, Sophie Demolombe, Catharine A. Goddard, Christine Richer, Brigitte Escoubet, Thérèse Jarry-Guichard, William H. Colledge, Daniel Gros, Jacques M.T. de Bakker, Andrew A. Grace, Denis Escande, Flavien Charpentier
Journal: Circulation (2005)

Background— We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenègre’s disease) to a loss-of-function mutation in the gene encoding the main cardiac Na + channel, SCN5A . In the present study, we investigated heterozygous Scn5a -knockout mice ( Scn5a +/− mice) as a model for hereditary Lenègre’s disease. Methods and Results— In Scn5a +/− mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre’s disease. Old but not young Scn5a +/− mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals. In old Scn5a +/− mice, fibrosis was accompanied by heterogeneous expression of connexin 43 and upregulation of hypertrophic markers, including β-MHC and skeletal α-actin. Global connexin 43 expression as assessed with Western blots was similar to wild-type mice. Decreased connexin 40 expression was seen in the atria. Using pangenomic microarrays and real-time PCR, we identified in Scn5a +/− mice an age-related upregulation of genes encoding Atf3 and Egr1 transcription factors. Echocardiography and hemodynamic investigations demonstrated conserved cardiac function with aging and lack of ventricular hypertrophy. Conclusions— We conclude that Scn5a +/− mice convincingly recapitulate the Lenègre’s disease phenotype, including progressive impairment with aging of atrial and ventricular conduction associated with myocardial rearrangements and fibrosis. Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies.
Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial
Authors: Hermine I Brunner, Nicolino Ruperto, Zbigniew Zuber, Caroline Keane, Olivier Harari, Andrew Kenwright, Peng Lu, Ruben Cuttica, Vladimir Keltsev, Ricardo M Xavier, Inmaculada Calvo, Irina Nikishina, Nadina Rubio-Pérez, Ekaterina Alexeeva, Vyacheslav Chasnyk, Gerd Horneff, Violetta Opoka-Winiarska, Pierre Quartier, Clovis A Silva, Earl Silverman, Alberto Spindler, Eileen Baildam, M Luz Gámir, Alan Martin, Christoph Rietschel, Daniel Siri, Elzbieta Smolewska, Daniel Lovell, Alberto Martini, Fabrizio De Benedetti
Journal: Annals of the Rheumatic Diseases (2014)

Objective To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). Methods This three-part, randomised, placebo-controlled, double-blind withdrawal study ( NCT00988221 ) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) &lt;30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. Results In part 1, 188 patients received tocilizumab (&lt;30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: −0.21; 95% CI −0.35 to −0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). Conclusions Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. Trial registration number: NCT00988221.
Thin Primary Cutaneous Malignant Melanoma: A Prognostic Tree for 10-Year Metastasis Is More Accurate Than American Joint Committee on Cancer Staging
Authors: Phyllis A. Gimotty, DuPont Guerry, Michael E. Ming, Rosalie Elenitsas, Xiaowei Xu, Brian Czerniecki, Francis Spitz, Lynn Schuchter, David Elder
Journal: Journal of Clinical Oncology (2004)

The majority of invasive primary melanomas are thin (< or = 1.00 mm). Since the current staging system imperfectly predicts outcome in patients with such lesions, we sought to develop a more effective classification scheme to better identify both patients at high risk of metastasis who are candidates for further staging and therapy and those with little risk.This prospective cohort study included 884 patients who had thin invasive melanomas. A tree-structured analysis of 10-year metastasis was used to develop a new classification scheme.The overall 10-year metastasis rate was 6.5% (95% CI, 4.8% to 8.1%). The prognostic tree defined four risk groups: high-risk: men with vertical growth phase (VGP) lesions that had mitotic rates (MRs) greater than 0, and for whom the 10-year metastasis rate was 31% (22% to 42%; n = 90); moderate-risk: women with VGP lesions that had MRs greater than 0 and for whom the rate was 13% (9% to 18%; n = 136); low-risk: patients with VGP lesions that had MR of 0 for whom the rate was 4% (2% to 7%; n = 247); and minimal-risk: patients with invasive lesions without VGP for whom the rate was 0.5% (0% to 1.2%; n = 411). Survival curves differed significantly among the four groups (P <.001).Growth phase, mitotic rate, and sex are important prognostic factors for patients with thin melanomas, and they identify subgroups at substantial risk for metastasis. After validation in other populations, the proposed prognostic tree will be useful in the design of clinical trials and clinical management.
Histologic Changes in Liver Tissue From Patients With Chronic Hepatitis B and Minimal Increases in Levels of Alanine Aminotransferase: A Meta-analysis and Systematic Review
Authors: Long H. Nguyen, David Chao, Joseph K. Lim, Walid Ayoub, Mindie H. Nguyen
Journal: Clinical Gastroenterology and Hepatology (2013)
The role of motor-sensory feedback in the evolution of mind
Authors: Bruce Bridgeman
Journal: Behavioral and Brain Sciences (2008)

Abstract Seemingly small changes in brain organization can have revolutionary consequences for function. An example is evolution's application of the primate action-planning mechanism to the management of communicative sequences. When feedback from utterances reaches the brain again through a mechanism that evolved to monitor action sequences, it makes another pass through the brain, amplifying the human power of thinking.
STUDIES ON TUBERCLE BACILLUS-MONOCYTE RELATIONSHIP
Authors: Jacob Fong, Dennis Chin, Hajime J. Akiyama, Sanford S. Elberg
Journal: The Journal of Experimental Medicine (1959)

Studies of the relationship of protective serum factor to cellular resistance and to tuberculin skin sensitivity have demonstrated that protective serum factor may exist independently of a high level of cellular resistance, and that both protective factor and cellular resistance may be demonstrable without a concomitant hypersensitivity of the delayed type. The experiments with absorbed sera and the globulin fraction of immune serum indicated no specific association of protective serum factor with antibody globulin. The protective factor in immune serum was found to be thermostable and non-dialyzable. In vitro exposure of virulent tubercle bacilli to the immune serum from BCG-immunized animals failed to alter the bacterial capacity for destruction of monocytes and for intracellular proliferation. In vitro cultivation of normal and immune monocytes in normal or immune serum was not effective in changing the native susceptibility or resistance of these cells. Effective manifestation of resistance to virulent tubercle bacilli by immune monocytes was found to require the continuous presence of immune serum. The intracellular passage of virulent tubercle bacilli in an immune system (immune monocytes cultivated in immune serum) resulted in a decreased bacterial potential for destruction of normal monocytes when these were cultivated in the presence of immune serum.
Efficacy and Safety of Oral Methazolamide in Patients With Type 2 Diabetes: A 24-Week, Placebo-Controlled, Double-Blind Study
Authors: Richard W. Simpson, Geoffrey C. Nicholson, Joseph Proietto, Alana Sarah, Kerrie M. Sanders, Gabrielle Phillips, Jo Chambers, Rob MacGinley, Neil Orford, Ken Walder, Guy Krippner, Kathy Skoff, Vincent J. Wacher
Journal: Diabetes Care (2014)

To evaluate the safety and efficacy of methazolamide as a potential therapy for type 2 diabetes.This double-blind, placebo-controlled study randomized 76 patients to oral methazolamide (40 mg b.i.d.) or placebo for 24 weeks. The primary efficacy end point for methazolamide treatment was a placebo-corrected reduction in HbA1c from baseline after 24 weeks (ΔHbA1c).Mean ± SD baseline HbA1c was 7.1 ± 0.7% (54 ± 5 mmol/mol; n = 37) and 7.4 ± 0.6% (57 ± 5 mmol/mol; n = 39) in the methazolamide and placebo groups, respectively. Methazolamide treatment was associated with a ΔHbA1c of -0.39% (95% CI -0.82, 0.04; P < 0.05) (-4.3 mmol/mol [-9.0, 0.4]), an increase in the proportion of patients achieving HbA1c ≤6.5% (48 mmol/mol) from 8 to 33%, a rapid reduction in alanine aminotransferase (∼10 units/L), and weight loss (2%) in metformin-cotreated patients.Methazolamide is the archetype for a new intervention in type 2 diabetes with clinical benefits beyond glucose control.
Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1–transformed T cells
Authors: Osamu Yoshie, Ryuichi Fujisawa, Takashi Nakayama, Hitomi Harasawa, Hideaki Tago, Dai Izawa, Kunio Hieshima, Youichi Tatsumi, Kouji Matsushima, Hitoshi Hasegawa, Akihisa Kanamaru, Shimeru Kamihira, Yasuaki Yamada
Journal: Blood (2002)
Cysteamine protects gastric epithelial cell monolayers against drug induced damage: evidence for direct cellular protection by sulphydryl compounds.
Authors: M Romano, M Razandi, A Raza, S Szabo, J Ivey
Journal: Gut (1992)

The sulphydryl containing drug cysteamine protects gastric mucosa in vivo against acute injury. It is not known whether this protection includes a direct effect on gastric cells. Using gastric epithelial cell monolayers derived from a well differentiated human cell line, we evaluated whether cysteamine protects against taurocholate or indomethacin induced damage in conditions which completely exclude the influence of vascular, hormonal, and neural factors. The effect of cysteamine on prostaglandin production by monolayer cells in vitro was also assessed. Cysteamine decreased damage brought about by sodium taurocholate and indomethacin by 40% (p less than 0.01) and 50% (p less than 0.01) respectively. The sulphydryl blocker iodoacetamide prevented the protective effect of cysteamine. Pretreatment with indomethacin, which inhibited prostaglandin E2 output by 60%, did not prevent protection by cysteamine; incubation with cysteamine decreased prostaglandin E2 production by cultured cells. We conclude that (i) cysteamine directly protected gastric epithelial cells in vitro (ii) this protection occurred with indomethacin, which interferes with cellular metabolism of prostaglandins, and taurocholate, whose damaging action at neutral pH is unrelated to interference with prostanoid metabolism, (iii) cysteamine protection in vitro is unrelated to endogenous prostaglandins and is probably mediated by endogenous sulphydryl compounds.