tbuckley/cabot-search huggingface dataset:
Unique alpha-spectrin mutant in a kindred with common hereditary elliptocytosis.
Authors: P A Lane, R L Shew, T A Iarocci, N Mohandas, T Hays, W C Mentzer
Journal: Journal of Clinical Investigation (1987)

We report here a unique variant of alpha spectrin in a kindred with hereditary elliptocytosis. This novel red blood cell-membrane protein migrated to a position between the normal alpha- and beta-spectrin subunits in SDS polyacrylamide gel electrophoresis. It was identified as an alpha spectrin by its binding to anti-alpha spectrin antibodies, by the absence of a phosphorylation site, and by the normal 1:1 stoichiometry between total alpha- and beta-spectrin molecules. The quantity of the alpha-spectrin mutant, expressed as a percentage of the total alpha spectrin, varied from 9.9-45.2% among six affected individuals. Two-dimensional electrophoretic analysis of spectrin tryptic digests was qualitatively normal but showed a decreased quantity of a normal alpha IV fragment. The variable quantity of alpha-spectrin mutant among family members correlated directly with the increased percentage of spectrin dimers in cold low ionic strength spectrin extracts (r = 0.92) and inversely with red blood cell ghost mechanical stability (r = -0.98). The data suggest that this new alpha-spectrin mutant is responsible for decreased spectrin dimer-dimer association and for red cell instability in affected individuals.
Long term effect of reduced pack sizes of paracetamol on poisoning deaths and liver transplant activity in England and Wales: interrupted time series analyses
Authors: K. Hawton, H. Bergen, S. Simkin, S. Dodd, P. Pocock, W. Bernal, D. Gunnell, N. Kapur
Journal: BMJ (2013)

<b>Objective</b> To assess the long term effect of United Kingdom legislation introduced in September 1998 to restrict pack sizes of paracetamol on deaths from paracetamol poisoning and liver unit activity. <b>Design</b> Interrupted time series analyses to assess mean quarterly changes from October 1998 to the end of 2009 relative to projected deaths without the legislation based on pre-legislation trends. <b>Setting</b> Mortality (1993-2009) and liver unit activity (1995-2009) in England and Wales, using information from the Office for National Statistics and NHS Blood and Transplant, respectively. <b>Participants</b> Residents of England and Wales. <b>Main outcome measures</b> Suicide, deaths of undetermined intent, and accidental poisoning deaths involving single drug ingestion of paracetamol and paracetamol compounds in people aged 10 years and over, and liver unit registrations and transplantations for paracetamol induced hepatotoxicity. <b>Results</b> Compared with the pre-legislation level, following the legislation there was an estimated average reduction of 17 (95% confidence interval −25 to −9) deaths per quarter in England and Wales involving paracetamol alone (with or without alcohol) that received suicide or undetermined verdicts. This decrease represented a 43% reduction or an estimated 765 fewer deaths over the 11¼ years after the legislation. A similar effect was found when accidental poisoning deaths were included, and when a conservative method of analysis was used. This decrease was largely unaltered after controlling for a non-significant reduction in deaths involving other methods of poisoning and also suicides by all methods. There was a 61% reduction in registrations for liver transplantation for paracetamol induced hepatotoxicity (−11 (−20 to −1) registrations per quarter). But no reduction was seen in actual transplantations (−3 (−12 to 6)), nor in registrations after a conservative method of analysis was used. <b>Conclusions</b> UK legislation to reduce pack sizes of paracetamol was followed by significant reductions in deaths due to paracetamol overdose, with some indication of fewer registrations for transplantation at liver units during the 11 years after the legislation. The continuing toll of deaths suggests, however, that further preventive measures should be sought.
Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes
Authors: Sophia Zoungas, John Chalmers, Bruce Neal, Laurent Billot, Qiang Li, Yoichiro Hirakawa, Hisatomi Arima, Helen Monaghan, Rohina Joshi, Stephen Colagiuri, Mark E. Cooper, Paul Glasziou, Diederick Grobbee, Pavel Hamet, Stephen Harrap, Simon Heller, Liu Lisheng, Giuseppe Mancia, Michel Marre, David R. Matthews, Carl E. Mogensen, Vlado Perkovic, Neil Poulter, Anthony Rodgers, Bryan Williams, Stephen MacMahon, Anushka Patel, Mark Woodward
Journal: New England Journal of Medicine (2014)

In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up.We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events.The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.).
Treatment of carcinoma of the bronchus by interstitial irradiation: A study of 198 patients
Authors: J. R. P. Gibbons, R. Baker
Journal: Thorax (1969)

One hundred and ninety-eight patients suffering from inoperable carcinoma of the bronchus who have been treated with interstitial irradiation at the Brompton Hospital are reviewed. It has been found that the quality of life of these patients may be improved by this form of treatment and that their life span is increased by it, though not to a statistically significant length, as compared with patients given either radiotherapy or no treatment at all. The advantages over radiotherapy are discussed.
BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians
Authors: B. Rueda, P. Gourh, J. Broen, S. K. Agarwal, C. Simeon, N. Ortego-Centeno, M. C. Vonk, M. Coenen, G. Riemekasten, N. Hunzelmann, R. Hesselstrand, F. K. Tan, J. D. Reveille, S. Assassi, F. J. Garcia-Hernandez, P. Carreira, M. Camps, A. Fernandez-Nebro, P. G. de la Pena, T. Nearney, D. Hilda, M. A. Gonzalez-Gay, P. Airo, L. Beretta, R. Scorza, T. R. D. J. Radstake, M. D. Mayes, F. C. Arnett, J. Martin
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objective</h3> To investigate the possible association of the <i>BANK1</i> gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. <h3>Methods</h3> A large multicentre case–control association study including 2380 patients with SSc and 3270 healthy controls from six independent case–control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional <i>BANK1</i> polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5´ allelic discrimination assay. <h3>Results</h3> A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the <i>BANK1</i> rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of <i>BANK1</i> rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). <h3>Conclusion</h3> The results suggest that the <i>BANK1</i> gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.
Enhanced Ca <sup>2+</sup> Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular Myocytes
Authors: Karin R. Sipido, Paul G. A. Volders, S. H. Marieke de Groot, Fons Verdonck, Frans Van de Werf, Hein J. J. Wellens, Marc A. Vos
Journal: Circulation (2000)

Background —Ventricular arrhythmias are a major cause of sudden death in patients with heart failure and hypertrophy. The dog with chronic complete atrioventricular block (CAVB) has biventricular hypertrophy and ventricular arrhythmias and is a useful model to study underlying cellular mechanisms. We investigated whether changes in Ca 2+ homeostasis are part of the contractile adaptation to CAVB and might contribute to arrhythmogenesis. Methods and Results —In enzymatically isolated myocytes, cell shortening, Ca 2+ release from the sarcoplasmic reticulum (SR), and SR Ca 2+ content were enhanced at low stimulation frequencies. Ca 2+ influx through L-type Ca 2+ channels was unchanged, but Ca 2+ influx via the Na/Ca exchanger was increased and contributed to Ca 2+ loading of the SR. Inward Na/Ca exchange currents were also larger. Changes in Ca 2+ fluxes were less pronounced in the right versus left ventricle. Conclusions —Enhanced Na/Ca exchange activity may improve contractile adaptation to CAVB but at the same time facilitate arrhythmias by (1) increasing the propensity to Ca 2+ overload, (2) providing more inward current leading to (nonhomogeneous) action potential prolongation, and (3) enhancing (arrhythmogenic) currents during spontaneous Ca 2+ release.
Nano-TiO<sub>2</sub>modulates the dermal sensitization potency of dinitrochlorobenzene after topical exposure
Authors: S. Smulders, L. Golanski, E. Smolders, J. Vanoirbeek, P.H.M. Hoet
Journal: British Journal of Dermatology (2014)

Little is known about the impact of engineered nanoparticles (ENPs) on skin sensitization caused by chemicals.We determined the ability of different ENPs (TiO2 , Ag and SiO2 ) and aged paint particles containing ENPs to modulate dermal sensitization by a known potent dermal sensitizer.The fur of BALB/c mice in the area around the ears was cut with scissors 1 day prior to topical exposure to ENPs (0·4, 4 or 40 mg mL(-1) ), paint particles containing ENPs (4 mg mL(-1) ) or vehicle (day 0). On days 1, 2 and 3, the mice received dermal applications on the back of both ears of 2,4-dinitrochlorobenzene (DNCB) or vehicle. The stimulation index (SI) was calculated on day 6.Topical exposure to TiO2 , Ag or SiO2 ENPs, or aged paint particles followed by vehicle treatment as a control, did not influence the SI. When 4 mg mL(-1) TiO2 ENPs were applied prior to DNCB sensitization, we found an increased SI compared with vehicle-exposed mice prior to DNCB sensitization. Furthermore, an increased titanium concentration was found in the draining lymph node cells of this group. Topical exposure to Ag or SiO2 ENPs or aged paint particles prior to DNCB sensitization did not influence the SI.We have demonstrated that topical exposure to TiO2 ENPs increases chemical-induced dermal sensitization.
Detection of Blast-Related Traumatic Brain Injury in U.S. Military Personnel
Authors: Christine L. Mac Donald, Ann M. Johnson, Dana Cooper, Elliot C. Nelson, Nicole J. Werner, Joshua S. Shimony, Abraham Z. Snyder, Marcus E. Raichle, John R. Witherow, Raymond Fang, Stephen F. Flaherty, David L. Brody
Journal: New England Journal of Medicine (2011)

Blast-related traumatic brain injuries have been common in the Iraq and Afghanistan wars, but fundamental questions about the nature of these injuries remain unanswered.
An electronic nose in the discrimination of patients with lung cancer and controls
Authors: Maris Bukovskis, Gunta Strazda, Uldis Kopeika, Normunds Jurka, Liga Balode, Immanuels Taivans
Journal: European Respiratory Journal (2012)

Background  Lung cancer is a leading cause of death in men suffering from oncological diseases. Exhaled breath contains hundreds of volatile organic compounds (VOCs) that could serve as biomarkers of lung disease. Electronic nose can distinguish VOC mixtures by pattern recognition.  Objective  We hypothesized that an electronic nose can discriminate exhaled air of patients with lung cancer from healthy controls.  Methods  25 patients with clinicaly and histologicaly verified lung cancer and 45 controls were included in a study with sampling of exhaled breath. Subjects inspired VOC-filtered air by tidal breathing for 5 minutes, and a single expiratory vital capacity was collected into polyethylene terephthalate bag that was sampled by electronic nose (Cyranose 320) within 5 minutes. Smellprints were analyzed by multifactorial logistic regression analysis (MLRA). Optimal detector parameter combination for diagnosis of laung cancer was calculated by MLRA backward stepwise method. Sensitivity, specificty, PPV and NPV of the method were calculated.  Results  Optimal detector parameters for discrimination of lung cancer were maximum of detectors number 6, 13. and 23. and area under curve of detectors 2, 6, 24 and 29. 22 out of 25 or 88.0% of lung cancer cases were predicted correctly by MLRA. Sensitivity of the method was 88.0%, specificity 91.1%, PPV 84.6% and NPV 93.2%.  Conclusions  The electronic nose appears to be able to discriminate exhaled breath from subjects with lung cancer and healthy controls. Analysis of exhaled breath coud be used as the lung cancer screening method in the future.  Ackowledgements  Study was sponsored by ERAF activity Nb. 2.1.1.1.0. Project Nb. 2010/0303/2DP/2.1.1.1.0/10/APIA/VIAA/043.
Naringenin: A Potential Immunomodulator for Inhibiting Lung Fibrosis and Metastasis
Authors: Gangjun Du, Lingtao Jin, Xiaofen Han, Zihui Song, Hongyan Zhang, Wei Liang
Journal: Cancer Research (2009)

Abstract Patients with idiopathic pulmonary fibrosis have a high incidence of lung cancer and a worse prognosis for clinical treatment. A few molecules with antifibrosis properties have been shown promoting cancer progression in clinical trials. The objective of this study was to determine whether there is a similar tendency in mice as in human beings and whether these mice models may be used to find new therapeutic agents with antifibrotic properties but not cancer-promoting properties. We used bleomycin to induce pulmonary fibrosis in mice with or without naringenin treatment and measured the immune-associated lymphocytes and their secreted cytokines using flow cytometry and ELISA from lung tissue. Both passive and spontaneous metastatic models in bleomycin-treated C57BL/6 and BALB/c mice were used to test the hypothesis that mice with pulmonary fibrosis could have an increased risk of lung cancer and associated cancer progression. Here, we show that mice with lung fibrosis challenged using tumors show an increased incidence of lung metastasis and shorter life spans compared with the mice without lung fibrosis. A fibrotic environment in the lung results in increased abundance of transforming growth factor-β1 and CD4+CD25+Foxp3+ regulatory T cells and a decreased proportion of activated effector T cells. This grave immunosuppressive environment favors tumor localization and growth. Naringenin significantly reduces lung metastases in mice with pulmonary fibrosis and increases their survival by improving the immunosuppressive environment through down-regulating transforming growth factor-β1 and reducing regulatory T cells. Naringenin could be an ideal therapeutic agent in the treatment of both cancer and fibrosis. [Cancer Res 2009;69(7):3205–12]
Involvement of Mitochondrial and Akt Signaling Pathways in Augmented Apoptosis Induced by a Combination of Low Doses of Celecoxib and <i>N</i>-(4-Hydroxyphenyl) Retinamide in Premalignant Human Bronchial Epithelial Cells
Authors: Claudia P. Schroeder, Humam Kadara, Dafna Lotan, Jong K. Woo, Ho-Young Lee, Waun Ki Hong, Reuben Lotan
Journal: Cancer Research (2006)

Abstract Celecoxib is being evaluated as a chemopreventive agent. However, its mechanism of action is not clear because high doses were used for in vitro studies to obtain antitumor effects. We found that celecoxib inhibited the growth of premalignant and malignant human bronchial epithelial cells with IC50 values between 8.9 and 32.7 μmol/L, irrespective of cyclooxygenase-2 (COX-2) expression. Normal human bronchial epithelial cells were less sensitive to celecoxib. Because these concentrations were higher than those attainable in vivo (≤5.6 μmol/L), we surmised that combining celecoxib with the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR) might improve its efficacy. Treatment of premalignant lung cell lines with combinations of clinically relevant concentrations of celecoxib (≤5 μmol/L) and 4HPR (≤0.25 μmol/L) resulted in greater growth inhibition, apoptosis induction, and suppression of colony formation than did either agent alone. This combination also decreased the levels of Bcl-2, induced the release of mitochondrial cytochrome c, activated caspase-9 and caspase-3, and induced cleavage of poly(ADP-ribose)polymerase at concentrations at which each agent alone showed no or minimal effects. Furthermore, combinations of celecoxib and 4HPR suppressed the phosphorylation levels of serine/threonine kinase Akt and its substrate glycogen synthase kinase-3β more effectively than the single agents did. Accordingly, overexpression of constitutively active Akt protected bronchial epithelial cells from undergoing apoptosis after incubation with both celecoxib and 4HPR. These findings indicate that activation of the mitochondrial apoptosis pathway and suppression of the Akt survival pathway mediate the augmented apoptosis and suggest that this combination may be useful for lung cancer chemoprevention. (Cancer Res 2006; 66(19): 9762-70)
Hyperglycemic Crises in Adult Patients With Diabetes: A Consensus Statement From the American Diabetes Association
Authors: Viktor Rosival
Journal: Diabetes Care (2007)

In the recent consensus statement by Kitabchi et al. (1) is a serious contradiction. In diagnosis, the authors write that “the initial laboratory evaluation of patients with suspected [diabetic keotacidosis] … should include determination of … osmolality … Studies on serum osmolality and mental alteration have established a positive linear relationship between osmolality and mental …
Collapsibility of the relaxed pharynx and risk of sleep apnoea
Authors: A. Oliven, E. Aspandiarov, I. Gankin, L. Gaitini, N. Tov
Journal: European Respiratory Journal (2008)

The present study measured hypotonic pharyngeal collapsibility in subjects not known to have obstructive sleep apnoea (OSA), and assessed the variables that affect collapsibility and the relationship with OSA. The critical value of positive end-expiratory pressure ( P crit ) was measured under the hypotonic condition of anaesthesia in 227 subjects who underwent elective surgery. The risk of OSA in this population was estimated using the Berlin questionnaire. The mean P crit for all subjects was positive (above atmospheric), ranging from 0.69 (95% confidence interval (CI) -7.39–8.77) to 4.0 (CI -4.82–12.82) cmH 2 O for subjects with low and high prevalence of OSA, respectively. P crit ≤-5 cmH 2 O was only found in 3.1% of the study subjects. In the general population, P crit was similar in males and females and correlated positively with increasing age, while a correlation with neck circumference was found only in males. P crit accounted for only 12.25% of the variability in OSA risk score. In conclusion, subjects with high critical value of positive end-expiratory pressure are at an increased risk for developing obstructive sleep apnoea. However, the human pharynx is prone to collapse and occludes in most people in the absence of neuromuscular support. Therefore, in most subjects, the level of neuromuscular activity may ultimately determine the occurrence of sleep apnoea.
Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome
Authors: Wataru Shimizu, Charles Antzelevitch
Journal: Circulation (1998)

Background —This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by β-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome. Methods and Results —A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific I Ks blocker, dose-dependently (1 to 100 μmol/L) prolonged the QT interval and action potential duration (APD 90 ) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 μmol/L abbreviated the APD 90 of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the I Ks blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 μmol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 μmol/L abbreviated the APD 90 of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP. Conclusions —This experimental model of LQT1 indicates that a deficiency of I Ks alone does not induce TdP but that the addition of β-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual I Ks in epicardial and endocardial cells but not in M cells, in which I Ks is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of β-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome.