tbuckley/cabot-search huggingface dataset:
Does the adenosine A2A receptor stimulate the ryanodine receptor?
Authors: L VENETUCCI, S ONEILL, D EISNER
Journal: Cardiovascular Research (2006)

A recent paper in Cardiovascular Research from Hove-Madsen and colleagues [1] has investigated the role of the adenosine A2A receptor in human atrial myocytes. Elegant confocal images show that this receptor is localized at the level of the Z line in the myocyte. Their paper then proceeds to address an important physiological question; the role of this receptor. No effect was found on the amplitude or voltage-dependence of the L-type Ca current. However agonists of the adenosine A2A receptor increased the frequency of both Ca sparks and Ca waves, phenomena that result from Ca induced Ca release (CICR) from the sarcoplasmic reticulum (SR). There was no change in either the amount of Ca extruded from the cell during each Ca wave or the SR Ca content (as assessed by the integral of the caffeine evoked Na–Ca exchange, NCX, current). Based on these …
The value of radiology in predicting gallstone type when selecting patients for medical treatment.
Authors: G D Bell, R H Dowling, B Whitney, D J Sutor
Journal: Gut (1975)

Since medical treatment of gallstones is confined to cholesterol-rich stones, the ability of clinical radiographs to predict gallstone type was tested prospectively by comparing the preoperative radiological appearance of gallstones from 57 unselected patients with cholelithiasis coming to cholecystectomy with the subsequent analysis of the stones both by X-ray diffraction and by chemical techniques. Fifty-two per cent of the patients had 9non-functioning9 gallbladders which failed to opacify after at least two contrast examinations and 25 out of 50 had radioopaque stones. Of the 25 patients with radiolucent stones, the stones in 20 ((80%) were predominantly cholesterol in type but radiology was misleading in five; three contained 40-55% calcium salts but were still radiolucent while two were amorphous and contained less than 10% cholesterol by weight on chemical analysis. While radiology was sometimes misleading when the stones were small and irregular, large radiolucent stones with a smooth profile were invariably cholesterol-rich stones. The results also show that in men calcified stones were commoner than in women and that in older women the gallstones contained more calcium salts and less cholesterol than in younger women less than 50 yr). This paper analyses critically the value and limitations of clinical radiology in predicting gallstone type.
The Cincinnati Obstetrical and Gynecological Society 1876-1976
Authors: Lester S. King
Journal: JAMA (1977)

Those who keep records may not appreciate their value, but a good set of records can pay enormous dividends for historians. This is splendidly shown in a small but significant volume describing the centennial of the Cincinnati Obstetrical and Gynecological Society. The author made skillful use of an almost unbroken set of minutes, extending for a hundred years, with information pieced out from published sources. The record, as he analyzed it, shows the microcosm of medical practice. It indicates personalities, professional conflicts, and jealousies; pictures the struggle toward stricter professionalization and increased standards of competence; describes professional, social, and socioeconomic viewpoints and details. We can glimpse the changing status of medicine and the progress in medical science as it affected the specialty of obstetrics and gynecology. However, as we come closer to the present day, we see the same old problems reemerging in modern dress, and we realize that the
Selection at Linked Sites in the Partial Selfer Caenorhabditis elegans
Authors: A. D. Cutter
Journal: Molecular Biology and Evolution (2003)

Natural selection can produce a correlation between local recombination rates and levels of neutral DNA polymorphism as a consequence of genetic hitchhiking and background selection. Theory suggests that selection at linked sites should affect patterns of neutral variation in partially selfing populations more dramatically than in outcrossing populations. However, empirical investigations of selection at linked sites have focused primarily on outcrossing species. To assess the potential role of selection as a determinant of neutral polymorphism in the context of partial self-fertilization, we conducted a multivariate analysis of single-nucleotide polymorphism (SNP) density throughout the genome of the nematode Caenorhabditis elegans. We based the analysis on a published SNP data set and partitioned the genome into windows to calculate SNP densities, recombination rates, and gene densities across all six chromosomes. Our analyses identify a strong, positive correlation between recombination rate and neutral polymorphism (as estimated by noncoding SNP density) across the genome of C. elegans. Furthermore, we find that levels of neutral polymorphism are lower in gene-dense regions than in gene-poor regions in some analyses. Analyses incorporating local estimates of divergence between C. elegans and C. briggsae indicate that a mutational explanation alone is unlikely to explain the observed patterns. Consequently, we interpret these findings as evidence that natural selection shapes genome-wide patterns of neutral polymorphism in C. elegans. Our study provides the first demonstration of such an effect in a partially selfing animal. Explicit models of genetic hitchhiking and background selection can each adequately describe the relationship between recombination rate and SNP density, but only when they incorporate selfing rate. Clarification of the relative roles of genetic hitchhiking and background selection in C. elegans awaits the development of specific theoretical predictions that account for partial self-fertilization and biased sex ratios.
Effect of Metformin in Pediatric Patients With Type 2 Diabetes
Authors: Kenneth Lee Jones, Silva Arslanian, Valentina A. Peterokova, Jong-Soon Park, Mark J. Tomlinson
Journal: Diabetes Care (2002)

OBJECTIVE—Metformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes. RESEARCH DESIGN AND METHODS—This study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10–16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels ≥7.0 and ≤13.3 mmol/l (≥126 and ≤240 mg/dl), HbA1c ≥7.0%, stimulated C-peptide ≥0.5 nmol/l (≥1.5 ng/ml), and a BMI &amp;gt;50th percentile for age. RESULTS—Metformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was −2.4 mmol/l (−42.9 mg/dl) for metformin compared with +1.2 mmol/l (+21.4 mg/dl) for placebo (P &amp;lt; 0.001). Mean HbA1c values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P &amp;lt; 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin. CONCLUSION—Metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients.
Methodological Issues in Cohort Studies That Relate Sodium Intake to Cardiovascular Disease Outcomes
Authors: Laura K. Cobb, Cheryl A.M. Anderson, Paul Elliott, Frank B. Hu, Kiang Liu, James D. Neaton, Paul K. Whelton, Mark Woodward, Lawrence J. Appel
Journal: Circulation (2014)

Background— The results of cohort studies relating sodium (Na) intake to blood pressure–related cardiovascular disease (CVD) are inconsistent. To understand whether methodological issues account for the inconsistency, we reviewed the quality of these studies. Methods and Results— We reviewed cohort studies that examined the association between Na and CVD. We then identified methodological issues with greatest potential to alter the direction of association (reverse causality, systematic error in Na assessment), some potential to alter the direction of association (residual confounding, inadequate follow-up), and the potential to yield false null results (random error in Na assessment, insufficient power). We included 26 studies with 31 independent analyses. Of these, 13 found direct associations between Na and CVD, 8 found inverse associations, 2 found J-shaped associations, and 8 found null associations only. On average there were 3 to 4 methodological issues per study. Issues with greater potential to alter the direction of association were present in all but 1 of the 26 studies (systematic error, 22; reverse causality, 16). Issues with lesser potential to alter the direction of association were present in 18 studies, whereas those with potential to yield false null results were present in 23. Conclusions— Methodological issues may account for the inconsistent findings in currently available observational studies relating Na to CVD. Until well-designed cohort studies in the general population are available, it remains appropriate to base Na guidelines on the robust body of evidence linking Na with elevated blood pressure and the few existing general population trials of the effects of Na reduction on CVD.
Differential Antiproliferative Effects of Calcitriol on Tumor-Derived and Matrigel-Derived Endothelial Cells
Authors: Ivy Chung, Michael K. Wong, Geraldine Flynn, Wei-dong Yu, Candace S. Johnson, Donald L. Trump
Journal: Cancer Research (2006)

Abstract The most active metabolite of vitamin D, calcitriol, is growth inhibitory for various tumor types in vitro and in vivo and inhibits the growth of endothelial cells freshly isolated from tumors [tumor-derived endothelial cells (TDEC)]. We compared the effects of calcitriol on Matrigel-derived endothelial cells (MDEC) and TDEC isolated from Matrigel plugs and squamous cell carcinoma tumors, respectively. TDEC and MDEC expressed vitamin D receptor (VDR) and responded to calcitriol by increasing VDR protein expression. Although no mutations were found in VDR from either cell type, Scatchard plot analysis revealed a higher ligand-binding affinity in TDEC (Kd, 0.26 nmol/L) than MDEC (Kd, 0.65 nmol/L). The VDR signaling axis in both cells was intact as shown using nuclear translocation and 24-hydroxylase promoter-luciferase reporter assays. However, unlike TDEC, MDEC were resistant to calcitriol-induced growth inhibition. Calcitriol (10 nmol/L) resulted in a 12.3% growth inhibition of MDEC compared with 47% in TDEC. In TDEC, calcitriol resulted in induction of G0/G1 arrest (10.75%) and reduction of S-phase cells (6.8%) with induction of p27 and down-regulation of p21 protein expression. Apoptotic effects, determined by Annexin V staining were also observed in calcitriol-treated TDEC (38.6%). Calcitriol caused reduced expression of p-Erk and p-Akt and an increase of poly(ADP-ribose) polymerase and caspase-3 cleavage in TDEC. By contrast, none of these effects on cell cycle or apoptosis were seen in calcitriol-treated MDEC. These results show that TDEC were more sensitive than MDEC to the antiproliferative effects of calcitriol despite apparently normal VDR content and structure of signaling axis in both cell types. (Cancer Res 2006; 66(17): 8565-73)
Tumor cell metabolism: the marriage of molecular genetics and proteomics with cellular intermediary metabolism; proceed with caution!
Authors: Leslie C Costello, Renty B Franklin
Journal: Molecular Cancer (2006)

Metabolic transformations of malignant cells are essential to the development and progression of all cancers. The understanding of the pathogenesis and progression of cancer requires the establishment of the altered genetic/metabolic factors that are essential to the development, growth, and proliferation of the malignant cells. Recognition of this important relationship has resulted in a resurgence of interest in the intermediary metabolism of tumor cells. The role of molecular genetics and proteomics and the application of molecular technology in assessing altered cellular metabolism has become a major area of biomedical research. The contemporary generation of biomedical scientists is exceptionally well trained in all areas of molecular biology and molecular technology, which are now important tools to be applied to the regulation of cellular intermediary metabolism. Simultaneously, the didactic and methodological training associated with the principles and operation of metabolic pathways, enzymology, cellular enzyme activity, and associated biochemical implications has been diminished and often eliminated from the pre- and post-doctoral programs. Interpretations and conclusions of alterations in cellular enzyme activity and associated metabolic pathways based on genetic/proteomic changes can and will result in misrepresentation of important metabolic implications in malignancy and other diseases. It is essential that the genetic/proteomic studies be coupled to biochemical/metabolic cellular events to satisfy the axiom: "genetic transformations and proteomic alterations will have little relevancy to disease processes if the genetic/proteomic alterations are not manifested in altered and impaired cellular and metabolic function". The appropriate marriage of molecular genetics/proteomics with the regulation of cellular intermediary metabolism will provide new revelations and understanding of malignancy that could not be achieved in earlier generations.
Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
Authors: James R. Lupski, Jeffrey G. Reid, Claudia Gonzaga-Jauregui, David Rio Deiros, David C.Y. Chen, Lynne Nazareth, Matthew Bainbridge, Huyen Dinh, Chyn Jing, David A. Wheeler, Amy L. McGuire, Feng Zhang, Pawel Stankiewicz, John J. Halperin, Chengyong Yang, Curtis Gehman, Danwei Guo, Rola K. Irikat, Warren Tom, Nick J. Fantin, Donna M. Muzny, Richard A. Gibbs
Journal: New England Journal of Medicine (2010)

Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot-Marie-Tooth disease.We identified a family with a recessive form of Charcot-Marie-Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members.We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot-Marie-Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome.As shown in this study of a family with Charcot-Marie-Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.
Thorax 2009: another great year!
Authors: J A Wedzicha, S L Johnston
Journal: Thorax (2009)

lowest (10%) within patients presenting co-morbidities and lower than the overall mortality.This finding reopens the debate about the low acute mortality of patients with COPD presenting with CAP.In fact COPD was a protective factor for treatment failure in one study. 15Although the rate of acute treatment with steroids in patients with COPD is not reported in the study of Ewig et al, it is highly likely that a high percentage of them could have received such treatment, which could have attenuated the lung and systemic inflammatory response leading to a lower mortality. 16On the other hand, recent information suggests that despite the fact that previous inhaled steroid treatment may increase the risk of hospitalised CAP 17 it may be associated with lower CAP severity and consequently lower mortality. 18 The number of patients requiring mechanical ventilation was lower compared with other studies, particularly in advanced ages.As recognised by the authors, this could be due to treatment limitations such as ''do not resuscitate'' orders, or avoiding intensive care unit admission in older ages and severely disabled strata.This issue could not be analysed in detail by the authors.These are factors that might have influenced the high mortality of German hospitalised patients with CAP in this large study.This is a common error in most retrospective studies of CAP.For future studies it is highly recommended to record these two variables in order to interpret reliable data on mortality more precisely.Finally, this study confirms in a large population the good performance of CRB-65 to predict mortality in CAP in a threeclass pattern, a score much easier and less tedious to calculate than the PSI 19 and which further simplifies similar scores such as CURB and CURB-65.The data presented by Ewig et al 4 are currently the most solid and informative data available about hospitalisation rates in patients with CAP.The information reported in this study reminds us that this is an acute illness which occurs particularly in the elderly, a population which is going to increase in the next decades.CAP in this population currently represents an enormous economic and healthcare burden, and this burden will increase substantially in future years.Programmes of prevention are the only effective way to decrease the magnitude of this problem.
Stimulated arachidonate metabolism during foam cell transformation of mouse peritoneal macrophages with oxidized low density lipoprotein.
Authors: M Yokode, T Kita, Y Kikawa, T Ogorochi, S Narumiya, C Kawai
Journal: Journal of Clinical Investigation (1988)

Changes in arachidonate metabolism were examined in mouse peritoneal macrophages incubated with various types of lipoproteins. Oxidized low density lipoprotein (LDL) was incorporated by macrophages and stimulated macrophage prostaglandin E2 (PGE2) and leukotriene C4 syntheses, respectively, 10.8- and 10.7-fold higher than by the control. Production of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin, was also stimulated. No stimulation was found with native LDL, which was minimally incorporated by the cells. Acetylated LDL and beta-migrating very low density lipoprotein (beta-VLDL), though incorporated more efficiently than oxidized LDL, also had no stimulatory effect. When oxidized LDL was separated into the lipoprotein-lipid peroxide complex and free lipid peroxides, most of the stimulatory activity was found in the former fraction, indicating that stimulation of arachidonate metabolism in the cell is associated with uptake of the lipoprotein-lipid peroxide complex. These results suggest that peroxidative modification of LDL could contribute to the progression of atheroma by stimulating arachidonate metabolism during incorporation into macrophages.
Air flow at different temperatures increases sodium lauryl sulphate-induced barrier disruption and irritation in vivo
Authors: J.W. Fluhr, J. Praessler, A. Akengin, S.M. Fuchs, P. Kleesz, R. Grieshaber, P. Elsner
Journal: British Journal of Dermatology (2005)

Background Combined exposure to dry climatic conditions and local heat sources together with detergents represents a common workplace situation. These conditions may support the induction of chronic barrier disruption leading subsequently to irritant contact dermatitis (ICD). Objectives To test the irritant and barrier disrupting properties of air flow at different temperatures and velocities. Methods Using noninvasive biophysical measurements such as transepidermal water loss (TEWL) (TM 210; Courage & Khazaka, Cologne, Germany) we assessed the effects of short‐term exposure to air flow at different temperatures (24 °C and 43 °C) in combination with sodium lauryl sulphate (SLS) 0·5% on the skin of 20 healthy volunteers in a tandem repeated irritation test. Chromametry was used to control the accuracy of the SLS irritation model. Results In our study air flow alone did not lead to a significant increase in TEWL values. Sequential treatment with air flow and SLS led to an impairment of barrier function and irritation stronger than that produced by SLS alone. The two different air flow temperatures led to different skin temperatures but had no influence on permeability barrier function. Conclusions Warm air flow has an additional effect on the SLS‐induced barrier disruption in a tandem irritation test with sequential exposure to SLS/air flow. This combination is suspected to promote ICD in workplace and household situations, especially in short‐term applications as tested in our model.
Hemochromatosis, Multiorgan Hemosiderosis, and Coronary Artery Disease
Authors: Michael Miller
Journal: JAMA (1994)

To examine the prevalence of coronary artery disease (CAD) in autopsies of patients with iron-overload syndromes.Retrospective autopsy study of CAD in cases of hemochromatosis and multiorgan hemosiderosis.Registry of nearly 48,000 autopsies performed at The Johns Hopkins Hospital between 1889 and 1992.One hundred twenty-three subjects were studied. In a 2:1 control-case ratio, 82 controls matched by age, race, and sex were compared with 41 cases with iron overload.Severity of CAD.Pathological description of the coronary arteries were recorded as advanced or severe in 12% of iron-overload cases (n = 41) (mean age, 57.6 +/- 13.2 years) compared with 38% of controls (n = 82) (mean age, 57.0 +/- 13.8 years) (P = .01). The prevalence of three-vessel disease assessed by postmortem coronary arteriography was 11.1% in iron-overload cases (n = 18) (mean age, 61.7 +/- 12.2 years) compared with 33.3% in controls (n = 36) (mean age, 61.1 +/- 12.5 years) (P = .04). The odds ratio of CAD with iron overload was 0.18 (95% confidence interval, 0.04 to 0.73).Iron overload resulting from hemochromatosis or multiorgan hemosiderosis is not associated with an increased prevalence of CAD.