tbuckley/cabot-search huggingface dataset:
Variant clinical courses of 2 patients with neonatal intrahepatic cholestasis who have a novel mutation of SLC25A13
Authors: Junji Takaya, Keiko Kobayashi, Atsushi Ohashi, Miharu Ushikai, Ayako Tabata, Sachiko Fujimoto, Fumiko Yamato, Takeyori Saheki, Yohnosuke Kobayashi
Journal: Metabolism (2005)
Leucocyte response and anti-inflammatory cytokines in community acquired pneumonia
Authors: U K Kolling
Journal: Thorax (2001)

In the host defence of the lung neutrophils (PMN) play a central role. Apart from antimicrobial properties, recent data indicate that PMN also exert anti-inflammatory effects by stimulation and release of cytokine antagonists such as interleukin-1 receptor antagonist (IL-1ra).Cytokine release from lipopolysaccharide stimulated whole blood was studied in 18 patients with community acquired pneumonia (CAP) and severe co-morbidities at admission and after 24 hours. Release of IL-1ra, interleukin-1beta (IL-1beta), tumour necrosis factor alpha (TNFalpha), soluble TNF receptor type I (sTNF-RI), and IL-8 was determined by ELISA.The mean (SD) leucocyte level at admission was 12.5 (4.1)/nl. There was a significant correlation between the release of anti-inflammatory cytokines such as IL-1ra and sTNF-RI and the leucocyte count at admission and after 24 hours. Additional in vitro experiments showed that co-incubation of peripheral blood mononuclear cells with autologous PMN led to a marked dose dependent increase in IL-1ra and sTNF-RI release.These results indicate that PMN may be responsible for the increase in anti-inflammatory cytokines in CAP. Strategies to increase neutrophil counts may exert beneficial effects, not only by augmenting the antimicrobial activity but also by modulating the inflammatory cytokine response.
Standard anti-tuberculosis treatment and hepatotoxicity: do dosing schedules matter?
Authors: K. C. Chang, C. C. Leung, W. W. Yew, C. M. Tam
Journal: European Respiratory Journal (2006)

A nested case–control study was conducted in order to examine whether dosing schedules of standard pyrazinamide-containing anti-tuberculosis (TB) treatment (standard treatment) might affect hepatotoxicity. The present authors retrospectively identified all patients with hepatitis using biochemical criteria from a cohort of 3,007 clinic patients who commenced anti-TB treatment from January 1 to June 30, 2001. Each case with hepatitis between 1–9 weeks post-TB treatment was compared using conditional logistic regression analysis with two controls selected randomly from patients without hepatitis in the same period and matched by sex, age and standard treatment. Impacts of sex and age were examined by logistic regression analysis of cases and patients without hepatitis. Hepatitis occurred in 167 patients, of whom 96 qualified as cases. A conditional logistic risk model identified hepatitis B surface antigen carriage as the only risk factor (odds ratio (95% confidence interval (CI)) 1.8 (1.1–3.1)). Logistic regression analysis showed that sex was nonsignificant but ageing increased the odds of hepatitis. The risk of hepatitis increased from 2.6% (1.9–3.5%) to 4.1% (3.2–5.3%) as age exceeded 49 yrs. Dosing schedules in the first 9 weeks have little impact on hepatotoxicity. If patients at risk of both hepatitis and relapse receive standard treatment, daily dosing is preferable.
ERYTHEMATA AS INDICATORS OF DISEASE
Authors: JAMES GALLOWAY
Journal: British Journal of Dermatology (1903)

AND GENTLEMEN,-I have chosen the subject of my address to the Society on account of the interest that it always has possessed for those interested in the study of Medicine, and to lay before you for your consideration certain recent observations.The subject is obviously too extensive to be dealt with in all its detailsin any single address, so that I have chosen a few special conditions only in illustration of my remarks, leaving indications given by erythematous eruptions in large groups of diseases quite undealt with.Early Ideas concerning the Relations of Erythernata.-Incertain diseases the occurrence of rashes forms such an important feature that they have been from early times recognised as indications of the disease, and sometimes appear almost to have overshadowed the disease itself,The macular and punctate rashes are so striking in what we now know as measles and scarlet fever that in the early classifications of skin eruptions rubeola and scarlatina took an equal place on account of their skin eruptions with purpura and erythema.That this classification was not satisfactory to the very logical mind of Yr.Robert Willan is quite clear on reading his chapter upon the Exanthemata.In his definition of a rash (Exanthema) he says it "consists of red patches on the skin, variously figured, in general confluent, and VOL.xv.U
Impaired Endothelium-Derived Hyperpolarizing Factor-Mediated Dilations and Increased Blood Pressure in Mice Deficient of the Intermediate-Conductance Ca <sup>2+</sup> -Activated K <sup>+</sup> Channel
Authors: Han Si, Willm-Thomas Heyken, Stephanie E. Wölfle, Marcin Tysiac, Rudolf Schubert, Ivica Grgic, Larisa Vilianovich, Günter Giebing, Tanja Maier, Volkmar Gross, Michael Bader, Cor de Wit, Joachim Hoyer, Ralf Köhler
Journal: Circulation Research (2006)

The endothelium plays a key role in the control of vascular tone and alteration in endothelial cell function contributes to several cardiovascular disease states. Endothelium-dependent dilation is mediated by NO, prostacyclin, and an endothelium-derived hyperpolarizing factor (EDHF). EDHF signaling is thought to be initiated by activation of endothelial Ca(2+)-activated K(+) channels (K(Ca)), leading to hyperpolarization of the endothelium and subsequently to hyperpolarization and relaxation of vascular smooth muscle. In the present study, we tested the functional role of the endothelial intermediate-conductance K(Ca) (IK(Ca)/K(Ca)3.1) in endothelial hyperpolarization, in EDHF-mediated dilation, and in the control of arterial pressure by targeted deletion of K(Ca)3.1. K(Ca)3.1-deficient mice (K(Ca)3.1(-/-)) were generated by conventional gene-targeting strategies. Endothelial K(Ca) currents and EDHF-mediated dilations were characterized by patch-clamp analysis, myography and intravital microscopy. Disruption of the K(Ca)3.1 gene abolished endothelial K(Ca)3.1 currents and significantly diminished overall current through K(Ca) channels. As a consequence, endothelial and smooth muscle hyperpolarization in response to acetylcholine was reduced in K(Ca)3.1(-/-) mice. Acetylcholine-induced dilations were impaired in the carotid artery and in resistance vessels because of a substantial reduction of EDHF-mediated dilation in K(Ca)3.1(-/-) mice. Moreover, the loss of K(Ca)3.1 led to a significant increase in arterial blood pressure and to mild left ventricular hypertrophy. These results indicate that the endothelial K(Ca)3.1 is a fundamental determinant of endothelial hyperpolarization and EDHF signaling and, thereby, a crucial determinant in the control of vascular tone and overall circulatory regulation.
Recruiting doctors from poor countries: the great brain robbery?
Authors: V. Patel
Journal: BMJ (2003)

An important impediment to achieving health for all in developing countries is the shortage of doctors and nurses. Can the NHS justify schemes to recruit staff from these countries? 

An enormous gap in health staffing exists between the United Kingdom and India. India has fewer than 3000 psychiatrists for its one billion population compared with one psychiatrist for every 9000 people in the United Kingdom, a 27-fold difference.1 Despite this inequality, the NHS has launched a scheme to recruit senior psychiatrists and other specialists from India and other developing countries. This scheme will worsen the brain drain and inequities in global health unless it is explicitly linked with measures to enable the flow of doctors back to developing countries.

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Waiting for treatment: shortage of medical staff is an important barrier to health in India

Credit: MARK HENLEY/PANOS PICTURES

Overseas recruitment schemes are marketed primarily as an opportunity for doctors to experience one of the world's best healthcare systems. Yet it is obvious that the NHS is trying to fill jobs in specialties where there is a shortage of staff. Although shortages are acknowledged in the promotional material for the new NHS international fellowship scheme, the difficulties that doctors will face when they attempt to return home are ignored. Experience with …

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Molecular Detection of Noninvasive and Invasive Bladder Tumor Tissues and Exfoliated Cells by Aberrant Promoter Methylation of Laminin-5 Encoding Genes
Authors: Ubaradka G. Sathyanarayana, Riichiroh Maruyama, Asha Padar, Makoto Suzuki, Jolanta Bondaruk, Arthur Sagalowsky, John D. Minna, Eugene P. Frenkel, H. Barton Grossman, Bogdan Czerniak, Adi F. Gazdar
Journal: Cancer Research (2004)

Abstract Laminin-5 (LN5) anchors epithelial cells to the underlying basement membrane, and it is encoded by three distinct genes: LAMA3, LAMB3, and LAMC2. To metastasize and grow, cancer cells must invade and destroy the basement membrane. Our previous work has shown that epigenetic inactivation is a major mechanism of silencing LN5 genes in lung cancers. We extended our methylation studies to resected bladder tumors (n = 128) and exfoliated cell samples (bladder washes and voided urine; n = 71) and correlated the data with clinicopathologic findings. Nonmalignant urothelium had uniform expression of LN5 genes and lacked methylation. The methylation frequencies for LN5 genes in tumors were 21–45%, and there was excellent concordance between methylation in tumors and corresponding exfoliated cells. Methylation of LAMA3 and LAMB3 and the methylation index were correlated significantly with several parameters of poor prognosis (tumor grade, growth pattern, muscle invasion, tumor stage, and ploidy pattern), whereas methylation of LAMC2 and methylation index were associated with shortened patient survival. Of particular interest, methylation frequencies of LAMA3 helped to distinguish invasive (72%) from noninvasive (12%) tumors. These results suggest that methylation of LN5 genes has potential clinical applications in bladder cancers.
Hypermethylation and Transcriptional Downregulation of the Carboxyl-Terminal Modulator Protein Gene in Glioblastomas
Authors: C. B. Knobbe, J. Reifenberger, B. Blaschke, G. Reifenberger
Journal: JNCI Journal of the National Cancer Institute (2004)

The carboxyl-terminal modulator protein (CTMP) has been identified as a negative regulator of protein kinase B/Akt. Aberrant Akt signaling is frequently observed in glioblastomas, the most common and most malignant glial brain tumors. Because loss of CTMP function and/or expression may remove the inhibitory effects on Akt and promote tumorigenesis, we studied 93 primary glioblastomas and nine glioblastoma cell lines for CTMP deletion, mutation, promoter hypermethylation, and mRNA expression. None of the tumors or cell lines had CTMP-homozygous deletions or coding sequence mutations. However, CTMP mRNA expression was lower by at least 50% relative to non-neoplastic brain tissue in 37 (40%) glioblastomas and six (67%) glioma cell lines. Reduced CTMP mRNA levels were closely associated with hypermethylation of the CTMP promoter. Furthermore, treatment of CTMP-hypermethylated A172 glioma cells with the demethylating agent 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor trichostatin A resulted in partial demethylation of the CTMP promoter and increased CTMP mRNA expression. Thus, epigenetic downregulation of CTMP transcription is a common aberration in glioblastomas.
Early-Adulthood Cardiovascular Disease Risk Factor Profiles Among Individuals With and Without Diabetes in the Framingham Heart Study
Authors: Sarah Rosner Preis, Michael J. Pencina, Devin M. Mann, Ralph B. D’Agostino, Peter J. Savage, Caroline S. Fox
Journal: Diabetes Care (2013)

Many studies of diabetes have examined risk factors at the time of diabetes diagnosis instead of considering the lifetime burden of adverse risk factor levels. We examined the 30-year cardiovascular disease (CVD) risk factor burden that participants have up to the time of diabetes diagnosis.Among participants free of CVD, incident diabetes cases (fasting plasma glucose ≥ 126 mg/dL or treatment) occurring at examinations 2 through 8 (1979-2008) of the Framingham Heart Study Offspring cohort were age- and sex-matched 1:2 to controls. CVD risk factors (hypertension, high LDL cholesterol, low HDL cholesterol, high triglycerides, obesity) were measured at the time of diabetes diagnosis and at time points 10, 20, and 30 years prior. Conditional logistic regression was used to compare risk factor levels at each time point between diabetes cases and controls.We identified 525 participants with new-onset diabetes who were matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who eventually developed diabetes had higher levels of hypertension (odds ratio [OR], 2.2; P = 0.003), high LDL (OR, 1.5; P = 0.04), low HDL (OR, 2.1; P = 0.0001), high triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P < 0.0001) at time points 30 years before diabetes diagnosis. After further adjustment for BMI, the ORs for hypertension (OR, 1.9; P = 0.02) and low HDL (OR, 1.7; P = 0.01) remained statistically significant.CVD risk factors are increased up to 30 years before diagnosis of diabetes. These findings highlight the importance of a life course approach to CVD risk factor identification among individuals at risk for diabetes.
Dilated Cardiomyopathy Mutant Tropomyosin Mice Develop Cardiac Dysfunction With Significantly Decreased Fractional Shortening and Myofilament Calcium Sensitivity
Authors: Sudarsan Rajan, Rafeeq P.H. Ahmed, Ganapathy Jagatheesan, Natalia Petrashevskaya, Greg P. Boivin, Dalia Urboniene, Grace M. Arteaga, Beata M. Wolska, R. John Solaro, Stephen B. Liggett, David F. Wieczorek
Journal: Circulation Research (2007)

Mutations in striated muscle alpha-tropomyosin (alpha-TM), an essential thin filament protein, cause both dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy. Two distinct point mutations within alpha-tropomyosin are associated with the development of DCM in humans: Glu40Lys and Glu54Lys. To investigate the functional consequences of alpha-TM mutations associated with DCM, we generated transgenic mice that express mutant alpha-TM (Glu54Lys) in the adult heart. Results showed that an increase in transgenic protein expression led to a reciprocal decrease in endogenous alpha-TM levels, with total myofilament TM protein levels remaining unaltered. Histological and morphological analyses revealed development of DCM with progression to heart failure and frequently death by 6 months. Echocardiographic analyses confirmed the dilated phenotype of the heart with a significant decrease in the left ventricular fractional shortening. Work-performing heart analyses showed significantly impaired systolic, and diastolic functions and the force measurements of cardiac myofibers revealed that the myofilaments had significantly decreased Ca(2+) sensitivity and tension generation. Real-time RT-PCR quantification demonstrated an increased expression of beta-myosin heavy chain, brain natriuretic peptide, and skeletal actin and a decreased expression of the Ca(2+) handling proteins sarcoplasmic reticulum Ca(2+)-ATPase and ryanodine receptor. Furthermore, our study also indicates that the alpha-TM54 mutation decreases tropomyosin flexibility, which may influence actin binding and myofilament Ca(2+) sensitivity. The pathological and physiological phenotypes exhibited by these mice are consistent with those seen in human DCM and heart failure. As such, this is the first mouse model in which a mutation in a sarcomeric thin filament protein, specifically TM, leads to DCM.
Testing for irritation with a multifactorial approach: comparison of eight non-invasive measuring techniques on five different irritation types
Authors: J.W. Fluhr, O. Kuss, T. Diepgen, S. Lazzerini, A. Pelosi, M. Gloor, E. Berardesca
Journal: British Journal of Dermatology (2001)

Journal Article Testing for irritation with a multifactorial approach: comparison of eight non‐invasive measuring techniques on five different irritation types Get access J.W. Fluhr, J.W. Fluhr Department of Dermatology, University of Pavia, IRCCS Policlinico San Mateo, 27100 Pavia, Italy Department of Clinical Social Medicine, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany Joachim Fluhr, Dermatology Service and Research Unit (190), Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, U.S.A. E‐mail: joachim.fluhr@gmx.net Search for other works by this author on: Oxford Academic Google Scholar O. Kuss, O. Kuss Department of Dermatology, University of Pavia, IRCCS Policlinico San Mateo, 27100 Pavia, Italy Department of Clinical Social Medicine, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany Search for other works by this author on: Oxford Academic Google Scholar T. Diepgen, T. Diepgen Department of Dermatology, University of Pavia, IRCCS Policlinico San Mateo, 27100 Pavia, Italy Department of Clinical Social Medicine, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany Search for other works by this author on: Oxford Academic Google Scholar S. Lazzerini, S. Lazzerini Department of Dermatology, University of Pavia, IRCCS Policlinico San Mateo, 27100 Pavia, Italy Department of Clinical Social Medicine, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany Search for other works by this author on: Oxford Academic Google Scholar A. Pelosi, A. Pelosi Department of Dermatology, University of Pavia, IRCCS Policlinico San Mateo, 27100 Pavia, Italy Department of Clinical Social Medicine, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany Search for other works by this author on: Oxford Academic Google Scholar M. Gloor, M. Gloor Department of Dermatology, Klinikum Karlsruhe, Mottkestr. 120, 76133, Karlsruhe, Germany Search for other works by this author on: Oxford Academic Google Scholar E. Berardesca E. Berardesca Department of Dermatology, University of Pavia, IRCCS Policlinico San Mateo, 27100 Pavia, Italy Department of Clinical Social Medicine, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 145, Issue 5, 1 November 2001, Pages 696–703, https://doi.org/10.1046/j.1365-2133.2001.04431.x Published: 01 November 2001
Three sensitive assays do not provide evidence for circulating HuD-specific T cells in the blood of patients with paraneoplastic neurological syndromes with anti-Hu antibodies
Authors: A. H. C. de Jongste, M. T. de Graaf, E. Martinuzzi, P. D. M. van den Broek, J. Kraan, C. H. J. Lamers, R. Mallone, J. W. Gratama, P. A. E. Sillevis Smitt
Journal: Neuro-Oncology (2012)

Anti-Hu antibody–associated paraneoplastic neurological syndromes (Hu-PNSs) are severe and often precede the detection of a malignancy, usually small-cell lung cancer. In Hu-PNS, it is hypothesized that neuronal cells are destroyed by T cells targeted against HuD, a protein expressed by small-cell lung cancer cells and neurons. There is only limited evidence for the existence of HuD-specific T cells. To detect these T cells in the blood of Hu-PNS patients, we employed 3 highly sensitive assays that included T cell stimulation with dendritic cells (DCs) to specifically expand the number of any HuD-specific T cells. A total of 17 Hu-PNS patients were tested with 1 or more of the following 3 assays: (1) tetramer staining after stimulation of T cells with conventionally generated DCs (n = 9), (2) interleukin (IL)-13 enzyme-linked immunosorbent spot (ELISpot; n = 3), IL-4 and IL-5 and interferon (IFN)–γ multiplex cytokine bead array (n = 2) to assay cytokine production by T cells after stimulation with conventionally generated DCs, and (iii) IFN-γ ELISpot and tetramer staining after T cell stimulation with accelerated co-cultured DCs (n = 11). No circulating HuD-specific T cells were found. We suggest that either autoaggressive T cells in Hu-PNS are not targeted against HuD or that their numbers in the blood are too low for detection by highly sensitive techniques.
Alpha-1 antitrypsin deficiency alleles and severe cystic fibrosis lung disease
Authors: R Mahadeva, S Stewart, D Bilton, D A Lomas
Journal: Thorax (1998)

Alpha-1 antitrypsin (alpha 1-AT) is the most abundant proteinase inhibitor within the lung. We have recently reported the surprising observation that cystic fibrosis patients with mild to moderate deficiency of alpha 1-antitrypsin have significantly better pulmonary function than non-deficient patients. This study may have been biased as it did not include the most severely affected patients who have died in childhood or those who have undergone orthotopic lung transplantation. The prevalence of alpha 1-antitrypsin deficiency alleles in this most severely affected group of patients with cystic fibrosis was therefore assessed.DNA was obtained from neonatal blood spots from children with cystic fibrosis who had died from pulmonary disease and from formalin fixed lung tissue from transplanted cystic fibrosis patients. The common S and Z deficiency alleles of alpha 1-AT were sought by amplification mutagenesis of the appropriate region of the alpha 1-AT gene followed by restriction enzyme digestion with Xmn I and Taq I, respectively.Seventy-nine patients were identified (seven dead, 72 transplanted). Two patients (2.5%) were heterozygous for the Z allele of alpha 1-AT and four (5.1%) were heterozygous for the S allele. This is not significantly different from the incidence in the normal population of 4% and 8% for the S and Z alleles, respectively.These data support previous findings that deficiency of alpha 1-AT is not associated with more severe pulmonary disease in cystic fibrosis and may be associated with milder lung disease. Further work is needed to clarify the mechanisms underlying the progressive lung damage in cystic fibrosis.
Gastric Acid Secretion is Abnormally Sensitive to Endogenous Gastrin Released after Peptone Test Meals in Duodenal Ulcer Patients
Authors: Shiu Kum Lam, Jon I. Isenberg, Morton I. Grossman, Will H. Lane, John H. Walsh
Journal: Journal of Clinical Investigation (1980)

We studied 25 duodenal ulcer patients and 14 age- and sex-matched normal controls to determine whether gastric acid secretion in duodenal ulcer patients is abnormally sensitive to stimulation by gastrin endogenously released in response to meals. Acid response to saline and to 0.5, 1.0, 2.0, 4.0, and 8.0% peptone infused into the stomach was measured by 30 min intragastric titration. Total serum gastrin (G-total) and serum heptadecapeptide gastrin (G17), fasting and 30 min after each test meal, were measured by specific radioimmunoassays. In 19 ulcer patients and 11 normal subjects (controls), acid response to graded doses (11, 33, 100, and 300 pmol kg−1 h−1) of G17-I were also measured.