tbuckley/cabot-search huggingface dataset:
Effects of intracellular acidosis on [Ca2+]i transients, transsarcolemmal Ca2+ fluxes, and contraction in ventricular myocytes.
Authors: O Kohmoto, K W Spitzer, M A Movsesian, W H Barry
Journal: Circulation Research (1990)

We examined the effects of intracellular acidosis produced by washout of NH4Cl on [Ca2+]i transients (indo-1 fluorescence), cell contraction (video motion detector), and 45Ca and 24Na fluxes in cultured chick embryo ventricular myocytes. Exposure of cells to 10 mM NH4Cl produced intracellular alkalosis (pH 7.6), and subsequent washout resulted in a transient acidosis (pH 6.5). Exposure to 10 mM NH4Cl slightly decreased [Ca2+]i transients but increased the amplitude of cell contraction. Subsequent washout of NH4Cl initially increased diastolic [Ca2+]i and decreased the peak positive and negative d[Ca2+]i/dt, while the amplitude of cell contraction was markedly decreased. Subsequently, peak systolic [Ca2+]i increased with partial recovery of contraction. A similar increase in [Ca2+]i and decrease in contraction after washout of NH4Cl was observed in single paced adult guinea pig ventricular cells. Acidosis decreased 45Ca uptake by sarcoplasmic reticulum vesicles isolated from chick embryo ventricle. However, the [Ca2+]i increase caused by intracellular acidosis was also observed in the presence of 10 mM caffeine, suggesting that altered sarcoplasmic reticulum handling of calcium is not the only mechanism involved. Intracellular acidosis only slightly increased total 24Na uptake under these conditions, an effect resulting from the combination of a stimulation of amiloride-sensitive sodium influx (Na(+)-H+ exchange) and inhibition of sodium influx via Na(+)-Ca2+ exchange, manifested by a significant decrease in 45Ca efflux. Further support for a lack of involvement of an increased [Na+]i in the observed increase in [Ca2+]i during acidosis was low-sodium, nominal 0-calcium extracellular solution, an experimental condition that minimizes the possible effects of Na(+)-H+ exchange and Na(+)-Ca2+ exchange. We conclude that the [Ca2+]i increase caused by intracellular acidosis in cultured ventricular cells is primarily due to changes in [Ca2+]i buffering and [Ca2+]i extrusion, rather than to an increase in transsarcolemmal calcium influx. Intracellular acidosis also markedly decreases the sensitivity of the contractile elements to [Ca2+]i in cultured chick embryonic and adult guinea pig ventricular myocytes.
Genetic disorders in premature ovarian failure
Authors: T. Laml
Journal: Human Reproduction Update (2002)

This review presents the genetic disorders associated with premature ovarian failure (POF), obtained by Medline, the Cochrane Library and hand searches of pertinent references of English literature on POF and genetic determinants cited between the year 1966 and February 2002. X monosomy or X deletions and translocations are known to be responsible for POF. Turner's syndrome, as a phenotype associated with complete or partial monosomy X, is linked to ovarian failure. Among heterozygous carriers of the fragile X mutation, POF was noted as an unexpected phenotype in the early 1990s. Autosomal disorders such as mutations of the phosphomannomutase 2 (PMM2) gene, the galactose-1-phosphate uridyltransferase (GALT) gene, the FSH receptor (FSHR) gene, chromosome 3q containing the Blepharophimosis gene and the autoimmune regulator (AIRE) gene, responsible for polyendocrinopathy-candidiasis-ectodermal dystrophy, have been identified in patients with POF. In conclusion, the relationship between genetic disorders and POF is clearly demonstrated in this review. Therefore, in the case of families affected by POF a thorough screening, including cytogenetic analysis, should be performed.
Immunocytochemical mapping of the phosphatase and tensin homolog (PTEN/MMAC1) tumor suppressor protein in human gliomas
Authors: Dan Fults, Carolyn Pedone
Journal: Neuro-Oncology (2000)

PTEN/MMAC1 (phosphatase and tensin homolog/mutated in multiple advanced cancers 1) is a tumor suppressor gene, the inactivation of which is an important step in the progression of gliomas to end-stage glioblastoma multiforme. We examined the distribution of PTEN protein in 49 primary human gliomas by immunocytochemistry using polyclonal antibodies that we raised against PTEN-glutathione S-transferase fusion proteins expressed in Escherichia coli. The study group consisted of 6 low-grade astrocytomas, 7 anaplastic astrocytomas, 21 glioblastomas multiforme, 4 low-grade oligodendrogliomas, 6 malignant oligodendrogliomas, and 5 malignant mixed oligoastrocytomas. For each tumor, we determined the percentage of tumor cells showing PTEN immunoreactivity in the most cellular regions of the tumor specimen. In both astrocytomas and oligodendrogliomas, there was an inverse relationship between the percentage of PTEN+ cells and malignancy grade, consistent with a role for PTEN as a tumor suppressor gene, the expression of which declines during glioma progression. In nonneoplastic tissue, PTEN was expressed in human fetal brain at 16, 23, and 27 weeks' gestation, but not in adult brain, indicating that PTEN is developmentally regulated in the CNS. In 21 glioblastomas multiforme, we correlated PTEN protein expression with PTEN gene sequence. Although PTEN-mutant tumors showed significantly diminished PTEN protein expression compared with wild-type cases, suppressed expression of PTEN is more prevalent than predicted from mutation frequencies.
Induction of Neoangiogenesis in Ischemic Myocardium by Human Growth Factors
Authors: B. Schumacher, P. Pecher, B. U. von Specht, Th. Stegmann
Journal: Circulation (1998)

Background —The present article is a report of our animal experiments and also of the first clinical results of a new treatment for coronary heart disease using the human growth factor FGF-I (basic fibroblast growth factor) to induce neoangiogenesis in the ischemic myocardium. Methods and Results —FGF-I was obtained from strains of Escherichia coli by genetic engineering, then isolated and highly purified. Several series of animal experiments demonstrated the apathogenic action and neoangiogenic potency of this factor. After successful conclusion of the animal experiments, it was used clinically for the first time. FGF-I (0.01 mg/kg body weight) was injected close to the vessels after the completion of internal mammary artery (IMA)/left anterior descending coronary artery (LAD) anastomosis in 20 patients with three-vessel coronary disease. All the patients had additional peripheral stenoses of the LAD or one of its diagonal branches. Twelve weeks later, the IMA bypasses were selectively imaged by intra-arterial digital subtraction angiography and quantitatively evaluated. In all the animal experiments, the development of new vessels in the ischemic myocardium could be demonstrated angiographically. The formation of capillaries could also be demonstrated in humans and was found in all cases around the site of injection. A capillary network sprouting from the proximal part of the coronary artery could be shown to have bypassed the stenoses and rejoined the distal parts of the vessel. Conclusions —We believe that the use of FGF-I for myocardial revascularization is in principle a new concept and that it may be particularly suitable for patients with additional peripheral stenoses that cannot be revascularized surgically.
Studying quality of life in PAH: Patient-reported outcome assessment and psychosocial evaluation in a 6 months follow-up
Authors: Laurence Halimi, Nicolas Molinari, Camille Briand, Anne Sophie Gamez, Nathalie Collin, Isabelle Vachier, Arnaud Bourdin
Journal: European Respiratory Journal (2014)

PAH is a rare and life-threatening disease, affecting preferentially young subjects. Very few data are available on  of life and psychosocial characteristics in PAH.

Aim: In non worsening patient's disease, we investigated associations between hemodynamic, functional parameters and QoL evolution, variability of QoL parameters over severity class changes and follow-up, and psychosocial factors.

Methods: Consecutive prevalent and incident outpatients aged between 18 and 80 years were recruited. SF-36 was filled at baseline, after 3 and 6 months of follow-up. Anxiety and depression were appreciated at entry (HAD and STAI-Y). Patients were assessed for NYHA functional class and performed 6-minute walk test (6MWT).

Results: 55 patients were enrolled, 44 stable, 12 men and 32 women, (75% with idiopathic PAH; mean age, 58.2 years ± 14.9; 6MWT, 400.52 m ± 132.7). At entry, profound deficiency in physical and mental composite QoL scores was reported as compared to patients with cancer or cardiac insufficiency. 47.7% had depressive symptoms. Anxiety was more prevalent in patients with PAH than in either patient with cancer or on the eve of surgical intervention (p<0.001). Men were significantly more anxious than women. At V1 and V2, SF-36 fluctuated overtime irrespectively of 6 MWT and NYHA trends.

Conclusions and perspectives: This study showed that most patients with PAH reported items likely gathered under the term quality of survival rather than  of life. Anxiety and depression were frequent and overtook other severe diseases. Ongoing longitudinal follow-up will properly investigate to which extent psychosocial factors might affect QoL in PAH.
D-4F, an Apolipoprotein A-I Mimetic Peptide, Inhibits the Inflammatory Response Induced by Influenza A Infection of Human Type II Pneumocytes
Authors: Brian J. Van Lenten, Alan C. Wagner, Mohamad Navab, G.M. Anantharamaiah, Eric Ka-Wai Hui, Debi P. Nayak, Alan M. Fogelman
Journal: Circulation (2004)

Evidence suggests that apolipoprotein A-I (apoA-I) and HDL play important roles in modulating inflammation. We previously reported that an apoA-I mimetic peptide, D-4F, reduced inflammatory responses to influenza virus in mice. To further define the antiinflammatory activity of D-4F, a human alveolar type II cell line, A549, was used.Cells were either uninfected or infected with influenza A in the presence or absence of D-4F. Cells treated with D-4F were more viable, and virus-induced cytokine production was suppressed by D-4F. Caspases associated with cytokine production were activated after infection but suppressed by D-4F treatment. Infected A549 cells showed dramatic increases in cellular phospholipid secretion into the media. When infected cells were incubated with D-4F, secretion of parent nonoxidized, noninflammatory phospholipids was unaltered, but production of proinflammatory oxidized phospholipids was inhibited.Type II pneumocytes respond to influenza A infection by activating caspases and secreting cytokines and cellular phospholipids into the extracellular environment, including oxidized phospholipids that evoke inflammatory responses. D-4F treatment inhibited these events. Our results suggest that apoA-I and apoA-I mimetic peptides such as D-4F are antiinflammatory agents that may have therapeutic potential.
Doctors react angrily to withdrawal of free copies of <i>BNF</i> for students
Authors: Adrian O'Dowd
Journal: BMJ (2007)

The safety of patients could be threatened by a government decision that will affect the quality of training of young doctors in the use of drugs, say leaders of the profession.

The Department of Health has decided to stop paying for a free copy of the British National Formulary ( BNF ) for all medical students in England. The move has been described as illogical, shortsighted, and against the current drive to reduce the number of prescribing errors.

The BNF provides up to date information on all drugs available on the NHS and is used daily by more than 200 000 health professionals in the United Kingdom to help them select the correct treatment for patients.

The BNF also helps students develop their …
Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): A comparison with NPMc+ AML
Authors: B Falini, B Bigerna, A Pucciarini, E Tiacci, C Mecucci, S W Morris, N Bolli, R Rosati, S Hanissian, Z Ma, Y Sun, E Colombo, D A Arber, R Pacini, R La Starza, B V Galletti, A Liso, M P Martelli, D Diverio, P-g Pelicci, F L Coco, M F Martelli
Journal: Leukemia (2005)
Complement Receptors CD21/35 Link Innate and Protective Immunity during Streptococcus pneumoniae Infection by Regulating IgG3 Antibody Responses
Authors: Karen M. Haas, Minoru Hasegawa, Douglas A. Steeber, Jonathan C. Poe, Mark D. Zabel, Cheryl B. Bock, David R. Karp, David E. Briles, John H. Weis, Thomas F. Tedder
Journal: Immunity (2002)
Insights into the swelling process and drug release mechanisms from cross-linked pectin/high amylose starch matrices
Authors: Fernanda M. Carbinatto, Ana Dóris de Castro, Raul C. Evangelista, Beatriz S.F. Cury
Journal: Asian Journal of Pharmaceutical Sciences (2013)

Cross-linked pectin/high amylose mixtures were evaluated as a new excipient for matrix tablets formulations, since the mixing of polymers and cross-linking reaction represent rational tools to reach materials with modulated and specific properties that meet specific therapeutic needs. Objective: In this work the influence of polymer ratio and cross-linking process on the swelling and the mechanism driving the drug release from swellable matrix tablets prepared with this excipient was investigated. Methods: Cross-linked samples were characterized by their micromeritic properties (size and shape, density, angle of repose and flow rate) and liquid uptake ability. Matrix tablets were evaluated according their physical properties and the drug release rates and mechanisms were also investigated. Results: Cross-linked samples demonstrated size homogeneity and irregular shape, with liquid uptake ability insensible to pH. Cross-linking process of samples allowed the control of drug release rates and the drug release mechanism was influenced by both polymer ratio and cross-linking process. The drug release of samples with minor proportion of pectin was driven by an anomalous transport and the increase of the pectin proportion contributed to the erosion of the matrix. Conclusion: The cross-linked mixtures of high amylose and pectin showed a suitable excipient for slowing the drug release rates.
Biallelic <i>ATM</i> Inactivation Significantly Reduces Survival in Patients Treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial
Authors: Anna Skowronska, Anton Parker, Gulshanara Ahmed, Ceri Oldreive, Zadie Davis, Sue Richards, Martin Dyer, Estella Matutes, David Gonzalez, A. Malcolm R. Taylor, Paul Moss, Peter Thomas, David Oscier, Tatjana Stankovic
Journal: Journal of Clinical Oncology (2012)

Purpose The prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial. Patients and Methods We analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort. Results We identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively). Conclusion The combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first-line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy.
Impact of sleep-disordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction
Authors: Michael Arzt, Anna Satzl, Andrea Hetzenecker, Kurt Debl, Andreas Luchner, Oliver Husser, Okka Hamer, Florian Poschenrieder, Claudia Fellner, Florian Zeman, Günter Riegger, Michael Pfeifer, Stefan Buchner
Journal: European Respiratory Journal (2013)

Background: SDB may be a risk factor for expansion of infarct size early after acute MI by exposing the heart to repetitive oxygen desaturations and increased cardiac afterload.

Objectives: The objective of this study was to assess the impact of sleep-disordered breathing (SDB) on myocardial salvage and infarct size within three months after acute myocardial infarction (MI).

Methods: Patients with acute MI and percutaneous coronary intervention were enrolled in this prospective observational study. All patients underwent cardiovascular magnetic resonance (CMR) to define salvaged myocardium and infarct size within 5 days and at three months after acute MI. Patients were stratified according to apnea-hypopnea-index (AHI) assessed by polysomnography at baseline into those with (AHI ≥15/h) and without (AHI <15/h) SDB.

Results: Of the 56 patients included, 29 (52%) had SDB. The area at risk between both groups was similar (40±12% vs 40±14%, p=0• 925). Patients with SDB had significantly less salvaged myocardium (myocardial salvage index 52% vs 77%, p<0• 001), smaller reduction in infarct size (0• 3% vs 6• 5%, p<0• 001) within three months after acute MI, a larger final infarct size (23% vs 12%, p<0• 001) and a lower final left ventricular ejection fraction (48% vs 54%, p=0• 023). In a multivariate analysis including established risk factors for large MI, AHI was independently associated with less myocardial salvage and a larger infarct size three months after acute MI.

Conclusions: SDB was associated with less myocardial salvage and a smaller reduction in infarct size. These findings suggest a contribution of SDB to impaired healing of MI.
Genetic determinants of hair, eye and skin pigmentation in Europeans
Authors: Patrick Sulem, Daniel F Gudbjartsson, Simon N Stacey, Agnar Helgason, Thorunn Rafnar, Kristinn P Magnusson, Andrei Manolescu, Ari Karason, Arnar Palsson, Gudmar Thorleifsson, Margret Jakobsdottir, Stacy Steinberg, Snæbjörn Pálsson, Fridbert Jonasson, Bardur Sigurgeirsson, Kristin Thorisdottir, Rafn Ragnarsson, Kristrun R Benediktsdottir, Katja K Aben, Lambertus A Kiemeney, Jon H Olafsson, Jeffrey Gulcher, Augie Kong, Unnur Thorsteinsdottir, Kari Stefansson
Journal: Nature Genetics (2007)
Impact of HbA1c, Followed From Onset of Type 1 Diabetes, on the Development of Severe Retinopathy and Nephropathy: The VISS Study (Vascular Diabetic Complications in Southeast Sweden)
Authors: Maria Nordwall, Mariann Abrahamsson, Meryl Dhir, Mats Fredrikson, Johnny Ludvigsson, Hans J. Arnqvist
Journal: Diabetes Care (2014)

OBJECTIVE HbA1c is strongly related to the development of diabetes complications, but it is still controversial which HbA1c level to strive for in the treatment of type 1 diabetes. The aim of the current study was to evaluate HbA1c, followed from diagnosis, as a predictor of severe microvascular complications and to formulate HbA1c target levels for treatment. RESEARCH DESIGN AND METHODS A longitudinal observation study followed an unselected population of 451 patients diagnosed with type 1 diabetes during 1983–1987 before the age of 35 years in a region of Southeast Sweden. Retinopathy was evaluated by fundus photography and nephropathy data collected from medical records. HbA1c was measured starting from diagnosis and during the whole follow-up period of 20–24 years. Long-term weighted mean HbA1c was then calculated. Complications were analyzed in relation to HbA1c levels. RESULTS The incidence of proliferative retinopathy and persistent macroalbuminuria increased sharply and occurred earlier with increasing long-term mean HbA1c. None of the 451 patients developed proliferative retinopathy or persistent macroalbuminuria below long-term weighted mean HbA1c 7.6% (60 mmol/mol); 51% of the patients with long-term mean HbA1c above 9.5% (80 mmol/mol) developed proliferative retinopathy and 23% persistent macroalbuminuria. CONCLUSIONS Long-term weighted mean HbA1c, measured from diagnosis, is closely associated with the development of severe complications in type 1 diabetes. Keeping HbA1c below 7.6% (60 mmol/mol) as a treatment target seems to prevent proliferative retinopathy and persistent macroalbuminuria for up to 20 years.
Severe chronic constipation of young women: 'idiopathic slow transit constipation'.
Authors: D M Preston, J E Lennard-Jones
Journal: Gut (1986)

A series of 64 women complaining of severe constipation is described, in each of whom delayed elimination of markers from the colon was demonstrated but a barium enema was normal. All completed a detailed questionnaire and the responses are compared with those obtained in an age-matched series of healthy women with no bowel complaint. In each group 40 women also recorded in a manner suitable for analysis all food eaten over a period of seven days. The patients passed about one stool weekly with the aid of laxatives, and were greatly troubled by abdominal pain, bloating, malaise and nausea, to the extent that the symptoms were a major social disability and many lost time from work. Decreased bowel frequency and other symptoms were often first noticed around the age of puberty and slowly became worse until they were severe by the third decade. In a few, the symptoms began suddenly after an abdominal operation c-accident. Comparison with the control group showed no evidence that the patients had been underweight at any time or that they took less fibre; treatment with a bran supplement did not usually help them. The patients experienced rectal sensation before defaecation less often than the control subjects and they used digital pressure to assist defaecation more frequently. The women with constipation tended to have more painful and irregular menstrual periods, and there was an increased incidence of ovarian cystectomy and hysterectomy. Hesitancy in starting to pass urine was more common, as were some somatic symptoms such as cold hands or blackouts. Attention is drawn to this distinctive combination in young women of slow total gut transit time and a colon of normal width on barium enema, associated with abdominal, anorectal, gynaecological and somatic symptoms, as a disorder which can be disabling and particularly difficult to treat.