tbuckley/cabot-search huggingface dataset:
Ketanserin inhibits depolarization-activated outward potassium current in rat ventricular myocytes.
Authors: Z H Zhang, M Boutjdir, N el-Sherif
Journal: Circulation Research (1994)

Ketanserin (KT), an antihypertensive agent, has been shown to prolong action potential duration (APD) and QT interval and to induce torsade de pointes in some patients. We previously suggested that the prolongation of APD could be due to KT inhibition of the fast component of the delayed rectifier current (IKr) in guinea-pig myocytes. However, in other tissue such as human atrium, Purkinje fibers, epicardial cells, and rat ventricular myocytes, the transient outward potassium current (Ito) is one of the major repolarizing currents. We investigated the possibility that KT could also increase APD by blocking Ito. Action potentials and membrane currents were recorded from rat ventricular myocytes known to have a large Ito by using whole-cell patch-clamp techniques. We found that KT (50 mumol/L) significantly prolonged APD at 50% repolarization by 218% (P &lt; .05) and APD at 90% repolarization by 256% (P &lt; .05) with no significant effect on other action potential parameters. Time-dependent Ito and sustained current (ISus) were measured in the presence of 400 nmol/L nisoldipine during depolarizing pulses to 40 mV from a holding potential of -100 mV every 10 seconds. KT resulted in a concentration- and time-dependent inhibition of charge area of Ito evaluated by integration with an EC50 of 8.3 mumol/L. The inhibitory effect of KT (10 mumol/L) was seen at voltages from 0 to 80 mV without any shift of the current-voltage relation of peak Ito. KT did not significantly change activation, inactivation, and reactivating curves of Ito. Kinetic analysis of Ito showed a biexponential fit of inactivation in 80.5% of total tracings studied at voltages between -30 and 80 mV (n = 149, R = .99 +/- .01). The inhibitory effect of KT was more prominent on charge areas of the slow component (Qs) than the fast component (Qf) of Ito (Qf = 33.2 +/- 6.2 s.pA and Qs = 235.5 +/- 7.4 s.pA for the control condition; 12.4 +/- 4.3 and 59.6 +/- 17 s.pA for KT at 40 mV; n = 4). The binding association (k) and dissociation (l) constants at 40 mV were 9.0 +/- 0.9x10(6) M-1.s-1 and 86.6 +/- 0.3 s-1, respectively. KT also blocked ISus in a dose-dependent manner with an EC50 of 11.2 mumol/L and had no significant effect on both the inward rectifier potassium current and the L-type calcium current.(ABSTRACT TRUNCATED AT 400 WORDS)
Human Urinary Exosomes as Innate Immune Effectors
Authors: Thomas F. Hiemstra, Philip D. Charles, Tannia Gracia, Svenja S. Hester, Laurent Gatto, Rafia Al-Lamki, R. Andres Floto, Ya Su, Jeremy N. Skepper, Kathryn S. Lilley, Fiona E. Karet Frankl
Journal: Journal of the American Society of Nephrology (2014)

Exosomes are small extracellular vesicles, approximately 50 nm in diameter, derived from the endocytic pathway and released by a variety of cell types. Recent data indicate a spectrum of exosomal functions, including RNA transfer, antigen presentation, modulation of apoptosis, and shedding of obsolete protein. Exosomes derived from all nephron segments are also present in human urine, where their function is unknown. Although one report suggested in vitro uptake of exosomes by renal cortical collecting duct cells, most studies of human urinary exosomes have focused on biomarker discovery rather than exosome function. Here, we report results from in-depth proteomic analyses and EM showing that normal human urinary exosomes are significantly enriched for innate immune proteins that include antimicrobial proteins and peptides and bacterial and viral receptors. Urinary exosomes, but not the prevalent soluble urinary protein uromodulin (Tamm–Horsfall protein), potently inhibited growth of pathogenic and commensal Escherichia coli and induced bacterial lysis. Bacterial killing depended on exosome structural integrity and occurred optimally at the acidic pH typical of urine from omnivorous humans. Thus, exosomes are innate immune effectors that contribute to host defense within the urinary tract.
Association of HLA-Aw31 and HLA-DR1 with adult rheumatoid arthritis.
Authors: B Schiff, Y Mizrachi, S Orgad, M Yaron, E Gazit
Journal: Annals of the Rheumatic Diseases (1982)

Forty-nine Israeli Jewish patients with rheumatoid arthritis (RA) were studied for their HLA A, B, C, DR antigen frequency. A significant increase in HLA Aw31 and HLA DR1 was observed (p less than 5.10(-5) and p less than 5.10(-3) respectively). 45% of Aw31 positive patients were sero-negative for rheumatoid factor, while most HLA DR1 positive individuals were seropositive. DR5 was found to be significantly decreased (p less than 5.10(-4)). Contrary to previous reports, DRw4 was found to be within the range of antigen frequency of the controls (34.7% vs. 32%). It is suggested that in our population of patients Aw31 and DR1 and not DR4 are highly associated with adult onset of RA.
Effects of a standard hyperbaric oxygen treatment protocol on pulmonary function
Authors: E Thorsen, L Aanderud, TB Aasen
Journal: European Respiratory Journal (1998)

The prescription of hyperbaric oxygen (HBO) therapy for disorders not related to diving is increasing. Pulmonary oxygen toxicity is well known, but the effect of the cumulative oxygen exposure corresponding to a standard HBO treatment protocol has not been quantified before. Twenty patients (10 male) had 21 HBO treatments at a partial pressure of oxygen of 240 kPa for 90 min daily. None had any previous lung disease and all had normal chest radiography and lung function at the start of the study. Dynamic lung volumes, forced expiratory flows and the transfer factor of the lung for carbon monoxide (TL,CO) were measured before the HBO treatment, on days 7, 14 and 21 during treatment and then 3-4 weeks after treatment. Four patients (one male) reported nonproductive coughing during the last week of treatment. There was a progressive reduction in forced expiratory volume in one second (FEV1) (p<0.001), mean forced mid-expiratory flow rate (FEF25-75%) (p<0.001) and forced expiratory flows at 50 and 75% of forced vital capacity (FVC) expired during HBO treatment. The reduction in FEV1 on day 21 was 4.4+/-1.7% and in FEF25-75% 10.3+/-6.1%. Four weeks after treatment there was a partial normalization. There were no changes in FVC or peak expiratory flow (PEF). TL,CO was slightly reduced on day 21 of treatment only (p<0.01) and fully normalized 1 month later. A reduction in small airways conductance is consistent with other studies where total oxygen exposures have been below the limit causing toxic pulmonary effects traditionally measured as a reduction in vital capacity. This effect is not considered to be of any clinical significance for patients treated with hyperbaric oxygen unless repeated treatment series are to be given.
Foxo Transcription Factors Blunt Cardiac Hypertrophy by Inhibiting Calcineurin Signaling
Authors: Yan G. Ni, Kambeez Berenji, Na Wang, Misook Oh, Nita Sachan, Asim Dey, Jun Cheng, Guangrong Lu, David J. Morris, Diego H. Castrillon, Robert D. Gerard, Beverly A. Rothermel, Joseph A. Hill
Journal: Circulation (2006)

Background— Cellular hypertrophy requires coordinated regulation of progrowth and antigrowth mechanisms. In cultured neonatal cardiomyocytes, Foxo transcription factors trigger an atrophy-related gene program that counters hypertrophic growth. However, downstream molecular events are not yet well defined. Methods and Results— Here, we report that expression of either Foxo1 or Foxo3 in cardiomyocytes attenuates calcineurin phosphatase activity and inhibits agonist-induced hypertrophic growth. Consistent with these results, Foxo proteins decrease calcineurin phosphatase activity and repress both basal and hypertrophic agonist-induced expression of MCIP1.4, a direct downstream target of the calcineurin/NFAT pathway. Furthermore, hearts from Foxo3-null mice exhibit increased MCIP1.4 abundance and a hypertrophic phenotype with normal systolic function at baseline. Together, these results suggest that Foxo proteins repress cardiac growth at least in part through inhibition of the calcineurin/NFAT pathway. Given that hypertrophic growth of the heart occurs in multiple contexts, our findings also suggest that certain hypertrophic signals are capable of overriding the antigrowth program induced by Foxo. Consistent with this, multiple hypertrophic agonists triggered inactivation of Foxo proteins in cardiomyocytes through a mechanism requiring the PI3K/Akt pathway. In addition, both Foxo1 and Foxo3 are phosphorylated and consequently inactivated in hearts undergoing hypertrophic growth induced by hemodynamic stress. Conclusions— This study suggests that inhibition of the calcineurin/NFAT signaling cascade by Foxo and release of this repressive action by the PI3K/Akt pathway are important mechanisms whereby Foxo factors govern cell growth in the heart.
An unusual case of chronic blood loss in the small intestine
Authors: G. Wurm Johansson, A. Nemeth, J. Nielsen, H. Thorlacius, E. Toth
Journal: Gut (2011)

A 62-year-old man presented with a 1-year history of fatigue and iron-deficiency anaemia. He had a history of ischaemic heart disease, chronic heart failure and hypertension. He reported normal appetite, normal bowel functions and denied weight loss. Physical examination revealed normal vital parameters, a non-tender abdomen without signs of organomegaly, and normal breathing sounds. Laboratory tests showed iron-deficiency anaemia with slightly decreased values of haemoglobin (115 g/l), mean corpuscular volume (MCV; 76 fl), ferritin (7.4 μg/l), iron (7 μmol/l), iron saturation (0.09), and increased levels …
Causes of death in COPD patients in primary care setting - 6 years follow-up
Authors: Robert Plywaczewski, Janusz Maciejewski, Michal Bednarek, Jan Zielinski, Pawel Sliwinski
Journal: European Respiratory Journal (2014)

COPD is a one of most frequent respiratory diseases responsible for patients disability and mortality. In 2005 in primary care practice COPD was diagnosed in 183 out of 1960 eligible subjects ≥ 40 years (9.3%), Bednarek M. et al. Thorax 2008; 63: 402-407.  The aim of this study was to assess mortality rate and reasons of death in this group after 6 years. In 2011 we studied only 74 subjects (40.4%), 43 subjects died (23.5%) and 66 subjects were lost from the follow-up (36.1%).  Cardiovascular diseases were most frequent reasons of death - 21 subjects (48.8%) (heart attack - 8 pts and stroke - 8 pts). Respiratory failure in the course of COPD was reason of 10 death (23.3%). Neoplasmatic diseases causes 9 death (20.9%) (lung cancer 7 pts). Renal insufficiency was responsible for one death (2.35%) and unknown reasons of 2 death (4.65%).  We compare data of subgroups (alive and died pts) from 2005 to assess relationship between COPD severity, age, smoking habits, dyspnea and risk of death (table below):  Conclusions: More than 20% of COPD pts died during six years follow-up in single primary care practice. Main reasons of death were: respiratory failure, heart attack, stroke and lung cancer (together 76.7%). Patients who died were older, had lower FEV1 (more than 30% of them had severe or very severe obstruction) and higher MRC score.
Central role for ornithine decarboxylase in β-adrenoceptor mediated hypertrophy
Authors: Klaus-Dieter Schlüter, Karen Frischkopf, Markus Flesch, Stephan Rosenkranz, Gerhild Taimor, Hans Michael Piper
Journal: Cardiovascular Research (2000)

Objective: TGF-β stimulation of cardiac myocytes induces a hypertrophic responsiveness to β-adrenoceptor stimulation. This study investigates whether this β-adrenoceptor mediated effect depends on induction of ornithine decarboxylase (ODC). Methods: Isolated adult ventricular cardiomyocytes from rats were used as an experimental model. Cells were either cultured in 20% (v/v) FCS to activate autocrine released TGF-β or used without pre-treatment. The hypertrophic response was characterized by an increased 14C-phenylalanine incorporation, RNA and protein mass or by an increased expression of atrionatriurectic factor and ODC. The results on cell cultures were compared to those achieved by isoprenaline perfused mice hearts from transgenic mice overexpressing TGF-β1. Results: ODC activity and expression increased within 2 h in TGF-β1 pre-treated cells under isoprenaline. In the presence of ODC inhibitors (α-methylornithine or difluoromethylornithine) this increase remained absent and the increases in 14C-phenylalanine incorporation, protein and RNA mass under isoprenaline were abolished. In cells not exposed to TGF-β no induction of ODC was observed. Isoprenaline also induced ODC in isolated perfused ventricles from transgenic mice overexpressing TGF-β1, but not in ventricles from their nontransgenic counterparts. Conclusions: This study shows first, a pivotal role for ODC induction in the hypertrophic response of cardiomyocytes to β-adrenoceptor stimulation and second, that ODC induction in vivo and in vitro requires pre-treatment of cardiomyocytes with TGF-β. It is concluded that TGF-β induces a hypertrophic responsiveness to β-adrenoceptor stimulation that is characterized by ODC induction.
T‐cell activation during exacerbations: a longitudinal study in refractory asthma
Authors: E. Mamessier, A. Nieves, A.‐M. Lorec, P. Dupuy, D. Pinot, C. Pinet, D. Vervloet, A. Magnan
Journal: Allergy (2008)

Background: Asthma exacerbations represent the main source of costs and morbidity in asthma care, and drugs specifically designed to prevent exacerbations are needed. A prerequisite is to dispose of a precise knowledge of inflammatory events leading to exacerbations. Objective: To study T‐cell activation during exacerbations from severe refractory asthmatics. Methods: Proportions of blood T‐cell interleukin (IL)‐13, interferon‐γ, IL‐4, IL‐5, IL‐10 production and of CD4+CD25+ high CD62L+CD45RO+ [T regulatory (Treg)] cells were determined by flow cytometry. Blood cytokine mRNA was studied by reverse transcription‐polymerase chain reaction and the respective protein levels were determined by cytokine beads array. Depletion of Treg cells was performed to study their activation. T‐cell cytokines were detected in parallel in induced sputum. Results: At baseline, T helper 2 (Th2) cells were increased in asthmatics, whereas T helper 1 (Th1) and Treg T cells were decreased. T helper 2 cells increased before exacerbations, followed by Th1 cells, in blood and induced sputum, albeit Treg cells decreased in parallel with IL‐10‐producing T cells. Concordant results were found at the mRNA level. The suppressive activity of Treg cells was impaired during exacerbations compared to baseline. Conclusions: New insights are given into pathophysiology of asthma exacerbations: Although at baseline T‐cell activation is Th2‐biased, a mixed Th1/Th2 activation occurs during exacerbations. The Treg cell deficiency found at baseline in SRA increases during exacerbations.
FGF-23 Associates with Death, Cardiovascular Events, and Initiation of Chronic Dialysis
Authors: Jessica Kendrick, Alfred K. Cheung, James S. Kaufman, Tom Greene, William L. Roberts, Gerard Smits, Michel Chonchol
Journal: Journal of the American Society of Nephrology (2011)

Concentrations of the phosphate-regulating hormone fibroblast growth factor-23 (FGF-23) are elevated in patients with chronic kidney disease (CKD), but whether higher plasma FGF-23 concentrations associate with all-cause mortality, cardiovascular events, or initiation of chronic dialysis is not completely understood. Here, we measured FGF-23 concentration in stored plasma samples from 1099 patients with advanced CKD who participated in The Homocysteine in Kidney and End Stage Renal Disease study. Mean serum phosphorus concentration was 4.3 mg/dl, median FGF-23 concentration was 392 RU/ml, and mean GFR was 18 ml/min/1.73 m(2). During a median follow-up of 2.9 yr, 453 (41%) patients died from any cause, 215 (20%) had a cardiovascular event, and 615 (56%) initiated chronic dialysis. Compared with the lowest quartile of FGF-23, each subsequent quartile associated with a progressively higher risk for death, adjusted for confounders (HR [95% CI] of 1.24 [0.91 to 1.69], 1.76 [1.28 to 2.44], and 2.17 [1.56 to 3.08] for the second through fourth quartiles, respectively). In addition, compared with the lowest quartile, the two highest quartiles of FGF-23 also associated with a significantly elevated risk for cardiovascular events and initiation of chronic dialysis. In conclusion, in advanced CKD, FGF-23 strongly and independently associates with all-cause mortality, cardiovascular events, and initiation of chronic dialysis.
Similarity in seasonal appearance between atmospheric birch‐pollen grains and allergen in paucimicronic, size‐fractionated ambient aerosol
Authors: F Th, M Spieksma, AH Nikkels
Journal: Allergy (1999)

Background : Specific allergen from various pollen types has been found to be carried through the outdoor air, not only by intact pollen grains, but also by much smaller, paucimicronic particles. There is no complete agreement on whether, for birch ( Betula ), the seasonal appearance of atmospheric pollen allergen follows the fluctuation pattern of the pollen season. Methods : Assessment of birch‐pollen allergen in size‐fractionated ambient aerosol was performed by descending elution of allergen from impaction strips of a five‐stage cascade impactor, and compared with atmospheric birch‐pollen concentrations as measured with a volumetric pollen trap. Results : An overall similarity in the courses of the seasonal presence was found for both birch pollen and allergen in particles of all paucimicronic size fractions, although some airborne allergen was detected before and after the birch‐pollen season. Conclusions : Transfer of pollen allergen to both natural and pollutant environmental dust particles is thought to be the probable explanation of secondary allergen carriage by paucimicronic particles. Until simple techniques for direct and rapid assessment of atmospheric pollen allergen become available, the pollen count gives sufficiently reliable information about the seasonal course of airborne pollen allergen.
Impact of molecular biology on clinical genetics.
Authors: M Pembrey
Journal: BMJ (1987)

The central activity of clinical genetics is genetic counselling, the aim of which is to provide information about the risks to offspring at a time appropriate to considering the options available for modifying the outcome and to put those risks in perspective. There is much evidence to show that with serious or life threatening disorders genetic counselling causes many couples to modify their reproductive behaviour, even when the options available are far from satisfactory. Our recently acquired ability to use deoxyribonucleic acid (DNA) probes (radiolabelled single stranded DNA fragments that bind only to specific genes or DNA sequences from the subject's total DNA) to analyse mutations or track the inheritance of genes through families has enormous potential as an aid to genetic counselling. Couple this with the development of chorionic villus sampling in the first trimester of pregnancy and the effect for some families is nothing short of revolutionary. DNA analysis was first used in the prenatal diagnosis of the haemoglobinopathies. Kan and Dozy reported the diagnosis of sickle cell anaemia on amniotic cells taken in the second trimester,1 and Old et al were first to report fetal diagnosis of ? thalassaemia in the first trimester based on the analysis of chorionic villus DNA.2 Since then so many monogenic disorders have become amenable to this approach that it is not possible to give a comprehensive up to date list. Schmidtke and Cooper provide a regular listing of cloned human genes or DNA sequences that can be used as DNA markers.3 Their list of independently cloned DNA sequences published in April 1987 contains nearly 3000 entries. The table gives those common conditions in which prenatal or carrier tests are already being used and which constitute most of the activity of genetics units providing DNA analysis as a clinical service. There is no correlation between the incidence of a disorder and the chances that the relevant gene has been mapped or even cloned. No matter how rare the genetic disease specific inquiries on behalf of a family at risk should always be made, especially in X linked disorders. The interval between gene localisation and clinical application of this information can be very short. Within months of the cystic fibrosis mutation being mapped to the 7q22-31 region of chromosome 7 some lucky couples who had not risked a pregnancy since the diagnosis was made in their child were having prenatal diagnosis in the first trimester.41 say lucky couples because gene tracking (see below) with DNA probes usually helps only certain families. These couples were also lucky because the service was offered to them. The National Health Service is not
CPSARST: an efficient circular permutation search tool applied to the detection of novel protein structural relationships
Authors: Wei-Cheng Lo, Ping-Chiang Lyu
Journal: Genome biology (2008)

Circular permutation of a protein can be visualized as if the original amino- and carboxyl termini were linked and new ones created elsewhere. It has been well-documented that circular permutants usually retain native structures and biological functions. Here we report CPSARST (Circular Permutation Search Aided by Ramachandran Sequential Transformation) to be an efficient database search tool. In this post-genomics era, when the amount of protein structural data is increasing exponentially, it provides a new way to rapidly detect novel relationships among proteins.
Association between Polymorphisms in the DNA Repair Genes, <i>XRCC1, APE1</i>, and <i>XPD</i> and Acute Side Effects of Radiotherapy in Breast Cancer Patients
Authors: Jenny Chang-Claude, Odilia Popanda, Xiang-Lin Tan, Silke Kropp, Irmgard Helmbold, Dietrich von Fournier, Wulf Haase, Marie Luise Sautter-Bihl, Frederik Wenz, Peter Schmezer, Christine B. Ambrosone
Journal: Clinical Cancer Research (2005)

Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), APE1 (Asp148Glu), and XPD (Lys751Gln and Asp312Asn), with the risk of acute skin reactions following radiotherapy.We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose.Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; Pinteraction = 0.009).The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.