tbuckley/cabot-search huggingface dataset:
A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1
Authors: G M F Wallace
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Pulmonary arteriovenous malformations (PAVMs) occur in over 25% of patients with the autosomal dominant disorder hereditary haemorrhagic telangiectasia (HHT). Mutations in two genes, <i>endoglin </i>and<i>ALK-1</i>, are known to cause HHT. Each encodes a protein expressed on vascular endothelial cells and involved in signalling by members of the transforming growth factor (TGF)-β superfamily. To date, PAVMs have not been detected in<i>ALK-1 </i>families. There is evidence from a single HHT family without pulmonary involvement that a third HHT gene may exist. To establish the existence of a further HHT gene responsible for PAVMs, linkage analyses were performed on an expanded PAVM-HHT family in which HHT did not result from<i>endoglin</i> mutations. <h3>METHODS</h3> Family members were assessed clinically to assign HHT disease status and were screened for PAVMs. DNA was extracted from blood obtained from 20 individuals of known disease status. Short tandem repeat polymorphic markers spanning the intervals containing the <i>endoglin </i>and<i>ALK-1</i> genes were amplified by the polymerase chain reaction using <sup>33</sup>P-labelled oligonucleotide primers, separated by denaturing polyacrylamide gel electrophoresis (PAGE), and the resultant autoradiographs were examined for allele sizes. Linkage analyses were performed using MLINK and GENEHUNTER. <h3>RESULTS</h3> Twelve members spanning four generations were affected with HHT. Two had proven PAVMs, one with a classical appearance, the other exhibiting microscopic PAVMs exacerbated by pregnancy. Two point lod and multipoint lod scores significantly excluded linkage to <i>endoglin</i>and <i>ALK-1</i> in this pedigree. <h3>CONCLUSIONS</h3> This study confirms the existence of a third HHT locus that accounts for disease in some HHT patients with pulmonary involvement.
Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study
Authors: Rowan T. Chlebowski, JoAnn E. Manson, Garnet L. Anderson, Jane A. Cauley, Aaron K. Aragaki, Marcia L. Stefanick, Dorothy S. Lane, Karen C. Johnson, Jean Wactawski-Wende, Chu Chen, Lihong Qi, Shagufta Yasmeen, Polly A. Newcomb, Ross L. Prentice
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundIn the Women's Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied.
Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis
Authors: J. A Kaye
Journal: BMJ (2001)

To estimate changes in the risk of autism and assess the relation of autism to the mumps, measles, and rubella (MMR) vaccine.Time trend analysis of data from the UK general practice research database (GPRD).General practices in the United Kingdom.Children aged 12 years or younger diagnosed with autism 1988-99, with further analysis of boys aged 2 to 5 years born 1988-93.Annual and age specific incidence for first recorded diagnoses of autism (that is, when the diagnosis of autism was first recorded) in the children aged 12 years or younger; annual, birth cohort specific risk of autism diagnosed in the 2 to 5 year old boys; coverage (prevalence) of MMR vaccination in the same birth cohorts.The incidence of newly diagnosed autism increased sevenfold, from 0.3 per 10 000 person years in 1988 to 2.1 per 10 000 person years in 1999. The peak incidence was among 3 and 4 year olds, and 83% (254/305) of cases were boys. In an annual birth cohort analysis of 114 boys born in 1988-93, the risk of autism in 2 to 5 year old boys increased nearly fourfold over time, from 8 (95% confidence interval 4 to 14) per 10 000 for boys born in 1988 to 29 (20 to 43) per 10 000 for boys born in 1993. For the same annual birth cohorts the prevalence of MMR vaccination was over 95%.Because the incidence of autism among 2 to 5 year olds increased markedly among boys born in each year separately from 1988 to 1993 while MMR vaccine coverage was over 95% for successive annual birth cohorts, the data provide evidence that no correlation exists between the prevalence of MMR vaccination and the rapid increase in the risk of autism over time. The explanation for the marked increase in risk of the diagnosis of autism in the past decade remains uncertain.
New evidence of inflammation in asthma
Authors: A. M Vignola
Journal: Thorax (2000)

<b>Background:</b> Patients with interferon-γ receptor 1 (IFNγR1) deficiency show selective susceptibility to intracellular pathogens such as mycobacteria. IFNγR1 deficiency is an inherited immunodeficiency disorder, which can be either recessive or dominant. Dominant forms of IFNγR1 deficiency are known to be associated with mutations that introduce a premature stop codon in the intracellular domain of IFNγR1. One such mutation, 818del4, is believed to be the most common type. Although these mutations are presumed to exert a dominant-negative effect on IFNγ signal transduction, the underlying molecular mechanism is unresolved. <b>Objective:</b> We characterised the 774del4 mutant of IFNγR1 using a gene-expression system to examine the effects of this mutation on IFNγ signal transduction. <b>Results:</b> We identified a novel dominant mutation in <i>IFNGR1</i>, designated 774del4, which produced a truncated form of IFNγR1 in a patient with recurrent mycobacterial infections. IFNγR1 was overexpressed on the surfaces of CD14-positive cells from the peripheral blood of this patient, and STAT1 phosphorylation in response to high doses of IFNγ was partially deficient. We expressed two truncated forms of IFNγR1, 774del4 and 818del4, in HEK 293 cells using transient transfection and found that these mutants overexpressed IFNγR1 on the cell surface because of impaired receptor stability, which resulted in a dominant-negative effect on IFNγ signal transduction. <b>Conclusion:</b> Like the 818del4 mutation, 774del4 produces a truncated form of IFNγR1, which has a dominant-negative effect on IFNγ signal transduction through altered receptor stability.
Measurement of human hair growth by optical microscopy and image analysis
Authors: S. HAYASHI, I. MIYAMOTO, K. TAKEDA
Journal: British Journal of Dermatology (1991)

We have developed a quantitative method for measuring hair growth using optical microscopy and image analysis, and have used this to investigate the rate of growth in subjects with and without alopecia. The hairs were cut from an area 7–8 mm in diameter and 24 h and 72 h later, images of the areas were obtained using an optical microscope and were recorded on a video disc. Measurements of the regrowing hairs, placed parallel to the scalp using a glass slide attached to the front of the microscope, were made using the image analyser. In subjects with little or no baldness there was a clear difference between fast‐growing hairs and resting or slow‐growing hairs. However, in subjects with alopecia there was no such difference and the growth rate of all the hairs showed a continuous distribution. Using this method other parameters such as the number of hairs per unit area and hair diameter as well as grouping of the hairs could be measured.
The Number, Quality, and Coverage of Randomized Controlled Trials in Nephrology
Authors: Giovanni F M Strippoli, Jonathan C Craig, Francesco P Schena
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Randomized controlled trials (RCT) are the optimal study design to answer intervention questions. The authors evaluated the number, quality, and coverage of RCT in nephrology. MEDLINE was searched using the relevant medical subject headings for nephrology and 12 major specialties in internal medicine, limited by “randomized controlled trial” as a publication type. A random selection of 160 RCT in nephrology (40 for each decade) published since 1966 and an additional 270 RCT from ongoing or published Cochrane systematic reviews in various areas of nephrology, dialysis, and transplantation were evaluated for quality of reporting using standard criteria. The number of RCT published in nephrology from 1966 to 2002 (2779) is fewer than all other specialties of internal medicine (range: 5335 in hematology to 27109 in cardiology) with the proportion of all citations which are RCT being the third lowest (1.15%). There has been an increase in both indices from 1966 to 1996, but not at a greater rate than other specialties, and there has been no increase over the past 5 yr. Some areas of nephrology, in particular glomerulonephritis, are clear outliers with very low numbers of RCT to guide clinical decision-making. Overall the quality of RCT reporting in nephrology is low and has not improved over the past 30 yr with unclear allocation concealment (89%), lack of reported blinding of outcome assessors (92%), and failure to perform “intention-to-treat analysis” (50%) particularly frequent. The challenges of improving the quality and quantity of trials in nephrology are substantial, but they can be overcome by using standard guidelines and checklists for trial reporting, greater attention to the trial methods and not just the results, involving experts in trial design and reporting, multicenter collaboration, and larger and simpler trials.
Family history and risk of kidney stones.
Authors: G C Curhan, W C Willett, E B Rimm, M J Stampfer
Journal: Journal of the American Society of Nephrology (1997)

Kidney stones develop more frequently in individuals with a family history of kidney stones than in those without a family history; however, little information is available regarding whether the increased risk is attributable to genetic factors, environmental exposures, or some combination. In this report, the relation between family history and risk of kidney stone formation was studied in a cohort of 37,999 male participants in the Health Professionals Follow-up Study. Information on family history, kidney stone formation, and other exposures of interest, including dietary intake, was obtained by mailed questionnaires. A family history of kidney stones was much more common in men with a personal history of stones at baseline in 1986 than in those without a history of stones (age-adjusted prevalence odds ratio, 3.16; 95% confidence interval [CI], 2.90 to 3.45). During 8 yr of follow-up, 795 incident cases of stones were documented. After adjusting for a variety of risk factors, the relative risk of incident stone formation in men with a positive family history, compared with those without, was 2.57 (95% CI, 2.19 to 3.02). Family history did not modify the inverse association between dietary calcium intake and the risk of stone formation. These results suggest that a family history of kidney stones substantially increases the risk of stone formation. In addition, these data suggest that dietary calcium restriction may increase the risk of stone formation, even among individuals with a family history of kidney stones.
Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses
Authors: Akihiro Kimura, Tetsuji Naka, Taisuke Nakahama, Ichino Chinen, Kazuya Masuda, Keiko Nohara, Yoshiaki Fujii-Kuriyama, Tadamitsu Kishimoto
Journal: The Journal of Experimental Medicine (2009)

Toll-like receptor (TLR) signals perform a crucial role in innate immune responses to pathogens. In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated by LPS, but not by transforming growth factor (TGF)-β plus interleukin (IL)-6, which can induce Ahr in naive T cells. The production of IL-6 and tumor necrosis factor (TNF)-α by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-κB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6. Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1.
EPSTEIN-BARR VIRUS ANTIBODY LEVELS IN CHILDREN FROM THE WEST NILE DISTRICT OF UGANDA
Authors: G.W. Kafuko, B.G. Kirya, B.E. Henderson, G.M.R. Munube, P.M. Tukei, N.E. Day, G. Henle, W. Henle, R.H. Morrow, M.C. Pike, P.G. Smith, E.H. Williams
Journal: The Lancet (1972)
New Currents in Electrical Stimulation of Excitable Tissues
Authors: Peter J. Basser, Bradley J. Roth
Journal: Annual Review of Biomedical Engineering (2000)

▪ Abstract Electric fields can stimulate excitable tissue by a number of mechanisms. A uniform long, straight peripheral axon is activated by the gradient of the electric field that is oriented parallel to the fiber axis. Cortical neurons in the brain are excited when the electric field, which is applied along the axon-dendrite axis, reaches a particular threshold value. Cardiac tissue is thought to be depolarized in a uniform electric field by the curved trajectories of its fiber tracts. The bidomain model provides a coherent conceptual framework for analyzing and understanding these apparently disparate phenomena. Concepts such as the activating function and virtual anode and cathode, as well as anode and cathode break and make stimulation, are presented to help explain these excitation events in a unified manner. This modeling approach can also be used to describe the response of excitable tissues to electric fields that arise from charge redistribution (electrical stimulation) and from time-varying magnetic fields (magnetic stimulation) in a self-consistent manner. It has also proved useful to predict the behavior of excitable tissues, to test hypotheses about possible excitation mechanisms, to design novel electrophysiological experiments, and to interpret their findings.
Differences among the coloured, white, black, and other South African populations in smoking-attributed mortality at ages 35–74 years: a case-control study of 481 640 deaths
Authors: Freddy Sitas, Sam Egger, Debbie Bradshaw, Pam Groenewald, Ria Laubscher, Danuta Kielkowski, Richard Peto
Journal: The Lancet (2013)
Peptide-Mediated Disruption of Calmodulin–Cyclin E Interactions Inhibits Proliferation of Vascular Smooth Muscle Cells and Neointima Formation
Authors: Sonya Hui, Jaehyun Choi, Syed Zaidi, Abdul Momen, Sarah K. Steinbach, Al-Muktafi Sadi, Kiwon Ban, Mansoor Husain
Journal: Circulation Research (2011)

Cell cycle progression in vascular smooth muscle cells (VSMCs) is a therapeutic target for restenosis.Having discovered that calmodulin (CaM)-dependent cyclin E/CDK2 activity underlies Ca(2+)-sensitive G(1)-to-S phase transitions in VSMCs, we sought to explore the physiological importance of the CaM-cyclin E interaction.A peptide based on the CaM binding sequence (CBS) of cyclin E was designed to interfere with CaM-cyclin E binding. Compared with control peptides, CBS blocked activating Thr160 phosphorylation of CDK2, decreased basal cyclin E/CDK2 activity, and eliminated Ca(2+)-sensitive cyclin E/CDK2 activity in nuclear extracts from mouse VSMCs. Nucleofection with CBS, or treatment with CBS conjugated to the HIV-1 TAT protein transduction domain to improve bioavailability, inhibited G(1)-to-S cell cycle progression in a dose-dependent manner. These effects were not observed with control peptides. TAT-CBS inhibited (3)H-thymidine incorporation in primary human aortic SMCs (HA-SMCs) in vitro, manifested greater transduction into HA-SMCs compared with endothelial cells in vitro, and limited decreased SM22α expression, neointima formation, and medial thickening without affecting collagen deposition or reendothelialization in a mouse model of carotid artery injury in vivo. The antiproliferative effects of CBS remained evident in mouse embryonic fibroblasts derived from wild-type mice but not cyclin E1/E2 double knockout mice.A synthetic peptide designed to disrupt CaM-cyclin E binding inhibits Ca(2+)/CaM-dependent CDK2 activity, cell cycle progression, and proliferation in VSMCs and limits arterial remodeling following injury. Importantly, this effect appears to be cyclin E-dependent and may form the basis of a potentially novel therapeutic approach for restenosis.
Coaerosolization of Phosphodiesterase Inhibitors Markedly Enhances the Pulmonary Vasodilatory Response to Inhaled Iloprost in Experimental Pulmonary Hypertension
Authors: RALPH THEO SCHERMULY, ELENA KRUPNIK, HERRMANN TENOR, CHRISTIAN SCHUDT, NORBERT WEISSMANN, FRANK ROSE, FRIEDRICH GRIMMINGER, WERNER SEEGER, DIETER WALMRATH, HOSSEIN ARDESCHIR GHOFRANI
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Inhalation of aerosolized iloprost, a stable prostacyclin analog, has been suggested for treatment of primary and secondary pulmonary hypertension, but demands multiple daily inhalation maneuvers because of the short-term effect of this approach. In intact rabbits, pulmonary hypertension was induced by continuous infusion of the stable thromboxane mimetic U46619. Thereafter, the influence of aerosolized iloprost on pulmonary and systemic hemodynamics and gas exchange was investigated in the presence and absence of phosphodiesterase (PDE) inhibitors for stabilization of the second-messenger cAMP. First, dose–effect curves for pulmonary artery pressure (Ppa) decline were established for the nonspecific PDE inhibitors pentoxifylline and dipyridamole and for the dual-selective PDE3/4 inhibitor tolafentrine when being applied as sole agent, either via the intravenous or the inhalative route. Subthreshold doses for each agent and each route of administration were then combined with a standardized iloprost aerosolization maneuver, which resulted in a substantial prolongation, but not augmentation, of the lung vasodilatory response for the prostanoid. Next, higher doses of each PDE inhibitor were employed for nebulization, causing per se some pulmonary vasodilative effect, in the absence of arterial pressure decrease or impairment of gas exchange. Coaerosolization of these PDE inhibitor doses with standardized iloprost caused approximate doubling of the immediate pulmonary vasodilator response, marked prolongation of the pressure relief overtime, and a 2- to 4-fold increase in the area under the curve of pulmonary vasodilation (efficacy tolafentrine > dipyridamole > pentoxifylline). Still, systemic arterial pressure was not suppressed and gas exchange was fully maintained. We conclude that coadministration of PDE inhibitors with inhaled iloprost markedly enhances the prostanoid-induced pulmonary artery pressure decrease while maintaining the lung selectivity of the vasodilatory response, and that coaerosolization is a particularly suitable route of administration. Even nonselective clinically approved PDE inhibitors may be employed for this purpose.
Allele polymorphisms of tumor integrins correlate with peritoneal carcinosis capability of gastric cancer cells in radically resected patients
Authors: M. Scartozzi, C. Loretelli, I. Bearzi, A. Mandolesi, E. Galizia, A. Onofri, M. Pistelli, A. Bittoni, R. Berardi, S. Cascinu
Journal: Annals of Oncology (2010)
p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs
Authors: Martina Müller, Sylvia Wilder, Detlev Bannasch, David Israeli, Katrin Lehlbach, Min Li-Weber, Scott L. Friedman, Peter R. Galle, Wolfgang Stremmel, Moshe Oren, Peter H. Krammer
Journal: The Journal of Experimental Medicine (1998)

Chemotherapeutic drugs cause DNA damage and kill cancer cells mainly by apoptosis. p53 mediates apoptosis after DNA damage. To explore the pathway of p53-dependent cell death, we investigated if p53-dependent apoptosis after DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated hepatoma, gastric cancer, colon cancer, and breast cancer cell lines upon treatment with different anticancer agents known to act via p53 accumulation. Cisplatin, mitomycin, methotrexate, mitoxantrone, doxorubicin, and bleomycin at concentrations present in the sera of patients during therapy led to an upregulation of both CD95 receptor and CD95 ligand. Induction of the CD95 ligand occurred in p53 wild-type (wt), p53 mutant (mt), and p53 deficient (p53−/−) cell lines and at wt and mt conformation of temperature-sensitive p53 mutants. In contrast, upregulation of the CD95 receptor was observed only in cells with wt p53, not in cells with mt or without any p53. Restitution of inducible wt p53 function restored the ability of p53−/− Hep3B cells to upregulate the CD95 receptor in response to anticancer drugs. This rendered the cells sensitive to CD95-mediated apoptosis. In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, whereas mt p53 failed to induce apoptosis via activation of the CD95 gene. These observations provide a mechanistic explanation for the ability of p53 to contribute to tumor progression and to resistance of cancer cells to chemotherapy.
Role of the Autonomic Nervous System in the Renal Vasoconstriction Response to Hemorrhage in the Rabbit
Authors: PAUL I. KORNER, GORDON S. STOKES, SAXON W. WHITE, JOHN P. CHALMERS
Journal: Circulation Research (1967)

In normal unanesthetized rabbits with intact autonomic effectors, rapid removal of 26% of the blood volume resulted in prolonged renal vasoconstriction. This response was completely absent in rabbits without functioning autonomic effectors (after guanethidine treatment + adrenalectomy + atropine), despite the greater arterial hypotension in this group. The effects of removing 26% and 32% of the blood volume were compared in the normal innervated and chronically surgically denervated kidney of the same animal. After 26% hemorrhage, the vessels of both kidneys constricted, but the response was significantly greater on the innervated side; reduction in GFR was the same in both kidneys. After 32% hemorrhage the renal constrictor response was greater than after 26% hemorrhage, the difference largely resulting from additional humoral effects, as estimated by the greater vasoconstriction observed in the hypersensitive surgically denervated kidney at this level of hemorrhage; GFR also fell more on the denervated side. The results indicate that sympatho-adrenal activity is essential in the production of renal vasoconstriction after hemorrhage, and suggest that this response is normally produced by the synergistic action of increased sympathetic nerve activity and humoral effects, including those of the adrenal catecholamines.