tbuckley/cabot-search huggingface dataset:
Metabolome in schizophrenia and other psychotic disorders: a general population-based study
Authors: Matej Orešič, Jing Tang, Tuulikki Seppänen-Laakso, Ismo Mattila, Suoma E Saarni, Samuli I Saarni, Jouko Lönnqvist, Marko Sysi-Aho, Tuulia Hyötyläinen, Jonna Perälä, Jaana Suvisaari
Journal: Genome Medicine (2011)

Abstract Background Persons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, particularly hypertriglyceridemia and low high-density lipoprotein. More detailed molecular information on the metabolic abnormalities may reveal clues about the pathophysiology of these changes, as well as about disease specificity. Methods We applied comprehensive metabolomics in serum samples from a general population-based study in Finland. The study included all persons with DSM-IV primary psychotic disorder (schizophrenia, n = 45; other non-affective psychosis (ONAP), n = 57; affective psychosis, n = 37) and controls matched by age, sex, and region of residence. Two analytical platforms for metabolomics were applied to all serum samples: a global lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry, which covers molecular lipids such as phospholipids and neutral lipids; and a platform for small polar metabolites based on two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC-TOFMS). Results Compared with their matched controls, persons with schizophrenia had significantly higher metabolite levels in six lipid clusters containing mainly saturated triglycerides, and in two small-molecule clusters containing, among other metabolites, (1) branched chain amino acids, phenylalanine and tyrosine, and (2) proline, glutamic, lactic and pyruvic acids. Among these, serum glutamic acid was elevated in all psychoses ( P = 0.0020) compared to controls, while proline upregulation ( P = 0.000023) was specific to schizophrenia. After adjusting for medication and metabolic comorbidity in linear mixed models, schizophrenia remained independently associated with higher levels in seven of these eight clusters ( P &lt; 0.05 in each cluster). The metabolic abnormalities were less pronounced in persons with ONAP or affective psychosis. Conclusions Our findings suggest that specific metabolic abnormalities related to glucoregulatory processes and proline metabolism are specifically associated with schizophrenia and reflect two different disease-related pathways. Metabolomics, which is sensitive to both genetic and environmental variation, may become a powerful tool in psychiatric research to investigate disease susceptibility, clinical course, and treatment response.
A golden approach to ion channel inhibition
Authors: Gavin E. Jarvis, Andrew J. Thompson
Journal: Trends in Pharmacological Sciences (2013)

Drugs are often used in combination and, for pharmacologists, the manner of their interactions can cast light on drug mechanisms and biological processes. Here we provide simplified descriptions of commonly used analytical methods for analysing drug combinations and describe a new and practical experimental solution to address the mechanistic question: 'Do two channel-blocking drugs bind at the same site?' We define two simple mathematical models that describe the effects of two channel blockers acting simultaneously at either the same (Syntopic Model) or different (Allotopic Model) binding sites within a channel pore. We find that the optimum concentrations of two drugs for distinguishing between the two models are related to the mathematical Golden Ratio.
P93 A simulated bronchoscopy course for new specialist trainees
Authors: S. Mandal, A. R. C. Patel, J. J. P. Goldring
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> New trainees typically perform initial bronchoscopies on real patients under supervision. This model of training has safety and comfort implications relying on timely acquisition of skills, potentially compromised by a reduction in the number of bronchoscopies performed by trainees. Simulators have been validated in training novice practitioners. We present a model for initial bronchoscopy training by registrars for registrars. <h3>Methods</h3> We developed a course based on survey data from North-East Thames trainees. We provided first year trainees with precourse material consisting of BTS guidelines and a presentation of bronchial anatomy. The day involved 1 h of theory, including indications, contra-indications, sedation, local anaesthesia, consent and management of complications. This was followed by a practical session with specialist nurses including assembling a bronchoscopy stack, troubleshooting and effective team-working. Most of the day was divided into three stations: Use of two simulators (Accutouch, Immersion Corporation, USA), each trainee had 45 min of 1:1 tuition. Trainees were objectively scored using the validated Bronchoscopy Skills and Tasks Assessment Tool (Bronchoscopy International, USA). This score and freetext comments were sent to the trainees to discuss with consultants. A slideshow of airway anatomy and pathology followed by MCQs addressing pre-course material. Hands-on flexible bronchoscopy through a static bronchial tree model. Feedback was assessed using a questionnaire at the end of the day. <h3>Results</h3> 9/11 trainees were within 3 months of starting StR training, 2/11 were within 12 months, having performed a median of five bronchoscopies (interquartile range 5–30). All trainees felt the course was pitched at the right level. They would all recommend this course to others, giving a rating of 4.8/5. 90% thought the course should be carried out within the first 3 months of training. All participants would change their practice as a result of what had been learnt on the course. Suggestions for improvement included grey cases and even more hands-on simulation time. <h3>Conclusions</h3> This potential model for bronchoscopy training was: Pitched at the right level. Delivered at an appropriate time. Received overwhelmingly positive feedback. Can be effectively delivered by experienced peers.
Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride
Authors: Charles R. Roe, Lawrence Sweetman, Diane S. Roe, France David, Henri Brunengraber
Journal: Journal of Clinical Investigation (2002)

The current dietary treatment of long-chain fatty acid oxidation defects (high carbohydrate with medium-even-chain triglycerides and reduced amounts of long-chain fats) fails, in many cases, to prevent cardiomyopathy, rhabdomyolysis, and muscle weakness. We hypothesized that the apparent defect in energy production results from a depletion of the catalytic intermediates of the citric acid cycle via leakage through cell membranes (cataplerosis). We further hypothesized that replacing dietary medium-even-chain fatty acids (precursors of acetyl-CoA) by medium-odd-chain fatty acids (precursors of acetyl-CoA and anaplerotic propionyl-CoA) would restore energy production and improve cardiac and skeletal muscle function. We fed subjects with long-chain defects a controlled diet in which the fat component was switched from medium-even-chain triglycerides to triheptanoin. In three patients with very-long-chain acyl-CoA dehydrogenase deficiency, this treatment led rapidly to clinical improvement that included the permanent disappearance of chronic cardiomyopathy, rhabdomyolysis, and muscle weakness (for more than 2 years in one child), and of rhabdomyolysis and weakness in the others. There was no evidence of propionyl overload in these patients. The treatment has been well tolerated for up to 26 months and opens new avenues for the management of patients with mitochondrial fat oxidation disorders.
Doppler velocimetry in pregnant patients with sickle cell anemia
Authors: Henny H. Billett, Oded Langer, Owen T. Regan, Irwin Merkatz, Akolisa Anyaegbunam
Journal: American Journal of Hematology (1993)

Women with sickle cell anemia have an increased risk of bearing low-birth-weight (LBW) progeny. To establish prognostic indicators of neonatal outcome, 15 women with sickle cell anemia were followed through their pregnancies with the use of umbilical and uterine Doppler flow velocimetry. The systolic/diastolic ratios obtained were correlated with neonatal birth weight, gestational age, and birth weight percentile. Pregravid hemoglobin levels, reticulocyte counts, dense cell numbers, percentage hemoglobin F, and indirect bilirubin and lactate dehydrogenase levels were also determined, and statistical analysis was performed to assess whether any of these parameters would be useful in conjunction with velocimetry. We report here that, in sickle cell anemia, prenatal umbilical and uterine Doppler velocimetry ratios correlate inversely and significantly with neonatal birth weight (P < 0.005 and P < 0.002, respectively). In addition, prenatal maternal HbF levels also correlate significantly with Doppler velocimetry readings, an independent indicator of LBW progeny. Neither pregravid hemoglobin levels nor dense cell concentration correlates with Doppler umbilical and uterine flow velocimetry ratios determined during pregnancy. Pregravid high levels of HbF and velocimetry readings may serve to delineate a subset of sickle cell patients who may have different requirements for prenatal care. The possible mechanism for the detrimental effects of increased levels of fetal hemoglobin has not been clearly established, but it may involve increased propensity for vasoocclusion due to the unique rheology of the human placenta.
Sexual dimorphism, but not testosterone itself, is responsible for ankylosing enthesitis of the ankle in B10.BR (H-2k) male mice
Authors: J Capkova
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Ankylosing enthesopathy (ANKENT) with progressive stiffening of ankle and tarsal joints of the hind limbs is a naturally occurring arthropathy in B10.BR mice. Some features are similar to those of the spondyloarthropathies in humans. <b>Objective:</b> To study the role of sexual dimorphism and testosterone in the development of ANKENT. <b>Methods:</b> The incidence of ANKENT was observed in non-castrated, castrated, and testosterone substituted castrated male mice, and in control and testosterone treated female mice. <b>Results:</b> ANKENT occurred only in males; it did not develop in males castrated at age 2–3 months but occurred in castrated males injected with testosterone. Females injected with testosterone did not develop ANKENT. <b>Conclusion:</b> Testosterone can replace what castration eliminates, at least in the postpubertally castrated males, but is itself not sufficient to induce joint disease.
Preference elicitation approach for measuring the willingness to pay for liver cancer treatment in Korea
Authors: Donghun Cho, Changik Jo
Journal: Clinical and Molecular Hepatology (2015)

Background/Aims The Korean government has expanded the coverage of the national insurance scheme for four major diseases: cancers, cardiovascular diseases, cerebrovascular diseases, and rare diseases. This policy may have a detrimental effect on the budget of the national health insurance agency. Like taxes, national insurance premiums are levied on the basis of the income or wealth of the insured. Methods Using a preference elicitation method, we attempted to estimate how much people are willing to pay for insurance premiums that would expand their coverage for liver cancer treatment. Results We calculated the marginal willingness to pay (MWTP) through the marginal rate of substitution between the two attributes of the insurance premium and the total annual treatment cost by adopting conditional logit and mixed logit models. Conclusions The effects of various other terms that could interact with socioeconomic status were also estimated, such as gender, income level, educational attainment, age, employment status, and marital status. The estimated MWTP values of the monthly insurance premium for liver cancer treatment range from 4,130 KRW to 9,090 KRW. Keywords: Preference elicitation; Marginal willingness to pay; Marginal rate of substitution; Conditional logit; Mixed logit
Serum thioredoxin levels as an indicator of oxidative stress in patients with hepatitis C virus infection
Authors: Yoshio Sumida, Toshiaki Nakashima, Takaharu Yoh, Yoshiki Nakajima, Hiroki Ishikawa, Hironori Mitsuyoshi, Yoshikuni Sakamoto, Takeshi Okanoue, Kei Kashima, Hajime Nakamura, Junji Yodoi
Journal: Journal of Hepatology (2000)
Biphasic contractions induced by milrinone at low temperature in ferret ventricular muscle: role of the sarcoplasmic reticulum and transmembrane calcium influx.
Authors: C O Malecot, D M Bers, B G Katzung
Journal: Circulation Research (1986)

The effects of milrinone were studied in ferret papillary muscle stimulated at various rates and temperatures from 23 degrees to 36 degrees C. In voltage-clamp experiments, 50 micrograms/ml (0.237 mM) milrinone induced a 2.1-fold increase in calcium current at 28 degrees or 36 degrees C. At 50 micrograms/ml, milrinone transiently increased contractility in all muscles at 28 degrees C, but its steady-state effect was either increased (+50%) or decreased (-24.7%) steady-state twitch amplitude. A negative inotropic effect always occurred below 27 degrees C. Milrinone decreased the total twitch duration and split the twitch into two components (P1 and P2) in the absence of any evidence of aberrant conduction. Increasing milrinone concentration from 50 to 300 micrograms/ml decreased P1 and increased P2. Ryanodine (100 mM) or caffeine (10 mM) suppressed P1. Contractions elicited after 30 seconds of rest were also biphasic in the presence of milrinone, but not in its absence. P2 of post-rest contraction was increased by caffeine or calcium (10 mM) and decreased by cobalt (2 mM) when drugs were applied at the beginning of the rest. Ryanodine and caffeine also suppressed P1 of post-rest contraction. The evidence suggests that P1 may be caused by Ca release from the sarcoplasmic reticulum and P2 by increased Ca influx during the action potential via the calcium channel. It is also suggested that P2 may be present under control conditions, but to a lesser extent, and masked by a large P1.
Prorenin Receptor Is Essential for Podocyte Autophagy and Survival
Authors: Fabian Riediger, Ivo Quack, Fatimunnisa Qadri, Björn Hartleben, Joon-Keun Park, Sebastian A. Potthoff, Dennis Sohn, Gabin Sihn, Anthony Rousselle, Verena Fokuhl, Ulrike Maschke, Bettina Purfürst, Wolfgang Schneider, Lars C. Rump, Friedrich C. Luft, Ralf Dechend, Michael Bader, Tobias B. Huber, Genevieve Nguyen, Dominik N. Muller
Journal: Journal of the American Society of Nephrology (2011)

The prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found that these animals died between 2 to 3 wk after birth. Within 14 d, PRR-knockout mice developed nephrotic syndrome, albuminuria with podocyte foot-process fusion, and cytoskeletal changes. Podocyte-specific PRR deletion also led to disturbed processing of multivesicular bodies and enrichment of autophagosomal (LC3) and lysosomal (LAMP2) markers, indicating a functional block in autophagosome-lysosome fusion and an overload of the proteasomal protein-degradation machinery. In vitro, PRR knockdown and pharmacologic blockade of vacuolar H+-ATPases, which associate with the PRR, increased vesicular pH, led to accumulation of LC3-positive and LAMP2-positive vesicles and altered the cytoskeleton. Taken together, these results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein-turnover machinery. Furthermore, PRR contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity.
Azathioprine-Induced Carcinogenesis in Mice According to Msh2 Genotype
Authors: Alexandra Chalastanis, Virginie Penard-Lacronique, Magali Svrcek, Valérie Defaweux, Nadine Antoine, Olivier Buhard, Sylvie Dumont, Bettina Fabiani, Isabelle Renault, Emmanuel Tubacher, Jean-François Fléjou, Hein te Riele, Alex Duval, Martine Muleris
Journal: JNCI Journal of the National Cancer Institute (2010)

The thiopurine prodrug azathioprine is used extensively in cancer therapy. Exposure to this drug results in the selection of DNA mismatch repair–deficient cell clones in vitro. It has also been suggested that thiopurine drugs might constitute a risk factor for the emergence of human neoplasms displaying microsatellite instability (MSI) because of deficient DNA mismatch repair. Azathioprine was administered via drinking water (6–20 mg/kg body weight per day) to mice that were null (Msh2−/−; n = 27), heterozygous (Msh2+/−; n = 22), or wild type (Msh2WT; n = 18) for the DNA mismatch repair gene Msh2. Control mice (45 Msh2−/−, 38 Msh2+/−, and 12 Msh2WT) received drinking water lacking azathioprine. The effect of azathioprine on tumorigenesis and survival of the mice was evaluated by Kaplan–Meier curves using log-rank and Gehan–Breslow–Wilcoxon tests. Mouse tumor samples were characterized by histology and immunophenotyping, and their MSI status was determined by polymerase chain reaction analysis of three noncoding microsatellite markers and by immunohistochemistry. Msh2 status of tumor samples was assessed by loss of heterozygosity analyses and sequencing after reverse transcription–polymerase chain reaction of the entire Msh2 coding sequence. All statistical tests were two-sided. Most untreated Msh2WT and Msh2+/- mice remained asymptomatic and alive at 250 days of age, whereas azathioprine-treated Msh2WT and Msh2+/− mice developed lymphomas and died prematurely (median survival of 71 and 165 days of age, respectively). Azathioprine-treated Msh2+/− mice developed diffuse lymphomas lacking Msh2 expression and displaying MSI due to somatic inactivation of the functional Msh2 allele by loss of heterozygosity or mutation. By contrast, azathioprine-treated Msh2WT mice displayed no obvious tumor phenotype, but histological examination showed microscopic splenic foci of neoplastic lymphoid cells that retained Msh2 expression and did not display MSI. Both untreated and azathioprine-treated Msh2−/− mice had a reduced lifespan compared with untreated Msh2WT mice (median survival of 127 and 107 days of age, respectively) and developed lymphomas with MSI. Azathioprine-induced carcinogenesis in mice depends on the number of functional copies of the Msh2 gene.
Determinants of Fetal Growth at Different Periods of Pregnancies Complicated by Gestational Diabetes Mellitus or Impaired Glucose Tolerance
Authors: Ute M. Schaefer-Graf, Siri L. Kjos, Ömer Kilavuz, Andreas Plagemann, Martin Brauer, Joachim W. Dudenhausen, Klaus Vetter
Journal: Diabetes Care (2003)

To determine maternal parameters with the strongest influence on fetal growth in different periods of pregnancies complicated by an abnormal glucose tolerance test (GTT).Retrospective study of 368 women with gestational diabetes mellitus (GDM; > or = 2 abnormal GTT values, n = 280) and impaired glucose tolerance (IGT; one abnormal value, n = 88) with 869 ultrasound examinations at entry to and during diabetic care. Both groups were managed comparably. Abdominal circumference (AC) > or = 90th percentile defined fetal macrosomia. Maternal historical and clinical parameters, and diagnostic and glycemic values of glucose profiles divided into five categories of 4 weeks of gestational age (GA; <24 weeks, 24 weeks/0 days to 27 weeks/6 days, 28/0-31/6, 32/0-35/6, and 36/0-40/0 [referred to as <24 GA, 24 GA, 28 GA, 32 GA, and 36 GA categories, respectively]) were tested by univariate and multiple logistic regression analysis for their ability to predict an AC > or = 90th percentile at each GA group and large-for-gestational-age (LGA) newborn. Data obtained at entry were also analyzed separately irrespective of the GA.Maternal weight, glycemia after therapy, rates of fetal macrosomia, and LGA were not significantly different between GDM and IGT; thus, both groups were analyzed together. LGA in a previous pregnancy, (odds ratio [OR] 3.6; 95% CI 1.8-7.3) and prepregnancy obesity (BMI > or = 30 kg/m(2); 2.1; 1.2-3.7) independently predicted AC > or = 90th percentile at entry. When data for each GA category were analyzed, no predictors were found for <24 GA. Independent predictors for each subsequent GA category were as follows: at 24 GA, LGA history (OR 9.8); at 28 GA, LGA history (OR 4.2), and obesity (OR 3.3); at 32 GA, fasting glucose of 32 GA (OR 1.6 per 5-mg/dl increase); at 36 GA, fasting glucose of 32 GA (OR 1.6); and for LGA at birth, LGA history (OR 2.7), and obesity (OR 2.4).In the late second and early third trimester, maternal BMI and LGA in a previous pregnancy appear to have the strongest influence on fetal growth, while later in the third trimester coincident with the period of maximum growth described in diabetic pregnancies, maternal glycemia predominates.
Crossed Immunoelectrophoresis Analysis of Bee Venom
Authors: R. Einarsson, A. Annerhed, R. Karlsson, B. Olsson, B. Renck
Journal: Allergy (1982)

Bee venom obtained by electrical stimulation has been analysed by crossed immunoelectrophoresis against high-titer rabbit antibodies. The antigenic analysis of bee venom revealed that the extract contained 17 antigens, which were detected in the crossed immunoelectrophoresis pattern after staining with Coomassie Brilliant Blue. The crossed immunoelectrophoresis pattern indicated heterogeneity in several of the antigens, as most of the precipitates (exhibiting enzyme and hemolytic activities) represented multiple forms of phospholipase A, hyaluronidase, acid phosphatase and melittin.
Role for Interactions Between IP-10/Mig and CXCR3 in Proliferative Glomerulonephritis
Authors: PAOLA ROMAGNANI, CHIARA BELTRAME, FRANCESCO ANNUNZIATO, LAURA LASAGNI, MICHAELA LUCONI, GRAZIA GALLI, LORENZO COSMI, ENRICO MAGGI, MAURIZIO SALVADORI, CINZIA PUPILLI, MARIO SERIO
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The mechanisms responsible for mesangial cell proliferation in proliferative glomerulonephritis are only partially understood. This article reports the results of an immunohistochemical study showing high expression of the chemokine receptor CXCR3 by mesangial cells of patients with IgA nephropathy, membranoproliferative glomerulonephritis, or rapidly progressive glomerulonephritis. CXCR3 was also detectable by flow cytometry in cultured human mesangial cells, in which it appeared to be functionally active, as determined by the ability of its ligand, the (interferon-γ)-inducible protein of 10 kD (IP-10) to induce intracellular Ca 2+ influx. Both IP-10 and the monokine induced by interferon-γ (Mig) were also effective in inducing proliferation of human mesangial cells. These data suggest that in patients with proliferative glomerulonephritis, the chemokines IP-10 and/or Mig not only may act as chemoattractants for infiltrating mononuclear cells in the inflamed tissue, but also may directly induce the proliferation of mesangial cells.
The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis
Authors: Florian Sparber, Julia M. Scheffler, Nicole Amberg, Christoph H. Tripp, Valeska Heib, Martin Hermann, Sonja P. Zahner, Björn E. Clausen, Boris Reizis, Lukas A. Huber, Patrizia Stoitzner, Nikolaus Romani
Journal: Blood (2013)