tbuckley/cabot-search huggingface dataset:
The normal range and determinants of the intrinsic heart rate in man
Authors: T Opthof
Journal: Cardiovascular Research (2000)

Jose and Collison published a study on the normal range and the determinants of intrinsic heart rate in man in Cardiovascular Research in 1970 [Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970; 4: 160–167)]. The intrinsic heart rate is the heart rate under complete pharmacological blockade. They showed that (i) the resting heart rate is lower than the intrinsic heart rate and that (ii) the intrinsic heart rate declines with age. They also established that the variability in intrinsic heart rate between individuals of the same age is of the same order as the effect of ageing at the population level. This update discusses the relevance of these data with emphasis on sinus node function and autonomic balance. The paper of Jose and Collison was cited more than 200 times. The frequency of citation started to increase more than 10 years after publication.
Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women&lt;SUBTITLE&gt;Women's Health Initiative Memory Study&lt;/SUBTITLE&gt;
Authors: Sally A Shumaker, Claudine Legault, Lewis Kuller, Stephen R Rapp, Leon Thal, Dorothy S Lane, Howard Fillit, Marcia L Stefanick, Susan L Hendrix, Cora E Lewis, Kamal Masaki, Laura H Coker
Journal: JAMA (2004)

The Women's Health Initiative Memory Study (WHIMS) previously found increased risk for dementia and no effect on mild cognitive impairment (MCI) in women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA).To determine the effects of CEE alone and CEE plus MPA on incidence of probable dementia and MCI in older women.Randomized, double-blind, placebo-controlled clinical trials of CEE (estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004 (estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers.In the estrogen-alone trial, 1 daily tablet containing either 0.625 mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos.Probable dementia and MCI.In the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio [HR], 1.49; 95% confidence interval [CI], 0.83-2.66). Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years for CEE plus MPA vs placebo, respectively; P =.11). When data were pooled per the original WHIMS protocol, the overall HR for probable dementia was 1.76 (95% CI, 1.19-2.60; P =.005). After excluding participants with baseline Modified Mini-Mental State Examination scores at or below the screening cut point, the HR was 1.77 (95% CI, 0.74-4.23; P =.20) in the estrogen-alone trial and 2.19 (95% CI, 1.25-3.84; P =.006) in the pooled trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89). In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60). In the estrogen-alone trial, 93 participants receiving CEE were diagnosed with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95% CI, 1.01-1.89; P =.04).Estrogen therapy alone did not reduce dementia or MCI incidence and increased the risk for both end points combined. Pooling data for estrogen alone and estrogen plus progestin resulted in increased risks for both end points. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.
Intensive oil baths from six weeks of age reduce xerosis and possibly atopic eczema in infancy
Authors: Bente Krane Kvenshagen, Petter Mowinckel, Kai-Håkon Carlsen, Karin L. Carlsen
Journal: European Respiratory Journal (2012)

Background: Atopic eczema (AE) is often the first step of the allergic march, with onset early in life, followed by asthma and allergic rhinitis. AE affects up to 20 % of children, and is characterized by dry, itchy skin. AE is a complex genetic and environmental disease, with alteration of skin barrier. Restoration of the barrier by emollients and/or oil baths is an important part of AE treatment, but its role in preventing AE is not known. Theoretically reducing prevalence of AE could prevent later allergy and asthma development.  The present pilot study aimed to evaluate whether frequent oil baths of infants with dry skin could reduce xerosis and eczema at the age of six months.  Patients and methods: A randomized controlled intervention study of six weeks old infants with dry skin, followed to six months by monthly assessment. They were randomized by well baby clinics (1 vs 5, respectively) to either daily oil bath (0.5 dl) and fat cream in the face (n=24) or observation (normal procedures)(n=31). The outcome was skin quality at six months.  Results: Normal skin was observed at six months in 18 children (75%) with skin treatment, compared to 12 (38%) in the observation group (p  Conclusion: The present pilot study showed that regular oil baths of infants were feasible, reduced xerosis, and also possibly eczema. If verified in further studies, one might speculate if this would reduce development of allergy and asthma.
Autoimmunity Against the Second Extracellular Loop of β <sub>1</sub> -Adrenergic Receptors Induces β-Adrenergic Receptor Desensitization and Myocardial Hypertrophy In Vivo
Authors: Michikado Iwata, Tsutomu Yoshikawa, Akiyasu Baba, Toshihisa Anzai, Iwao Nakamura, Yumiko Wainai, Toshiyuki Takahashi, Satoshi Ogawa
Journal: Circulation Research (2001)

Abstract —Although immunoapheresis removing autoantibodies against the second extracellular domain of β 1 -adrenergic receptors (ARs) improves cardiac function in patients with cardiomyopathy, the underlying mechanisms have not been defined. We examined the role of autoimmunity against the domain in the development of cardiac dysfunction in vivo. Japanese white rabbits were immunized with a synthetic peptide corresponding to the second extracellular loop of β 1 -AR once a month with (β+biso rabbits, n=10) or without (β rabbits, n=13) bisoprolol treatment (2 mg/kg per day). Control rabbits received vehicle without bisoprolol treatment (n=13). Autoantibodies of IgG isotype against the domain were persistently detected in β and β+biso rabbits. Purified IgG from sera of β and β+biso rabbits increased cAMP production in a rabbit cardiac membrane preparation, which was blocked by bisoprolol. At 3 months, β-AR uncoupling with increased G protein–coupled receptor kinase 5 (GRK5) expression was found in β rabbits. At 6 months, left ventricular hypertrophy was noted with hemodynamic derangements in β rabbits. This was accompanied by decreased β 1 -AR density and increased inhibitory G protein and GRK5 expression, which were related to marked decrease in membrane cAMP production. These changes in β rabbits at 6 months were prevented in β+biso rabbits. There was no difference in the plasma norepinephrine concentration in the 3 groups over the observation period. Thus, autoimmunity against the second extracellular loop of β 1 -ARs induced profound β-AR desensitization and myocardial hypertrophy in vivo, associated with cardiac dysfunction. Sustained sympathomimetic-like actions of autoantibodies against the domain may be partly responsible for these changes.
Prevention of occupational skin disease: a workplace intervention study in geriatric nurses
Authors: M. Dulon, U. Pohrt, C. Skudlik, A. Nienhaus
Journal: British Journal of Dermatology (2009)

Health care workers have an increased risk of occupational dermatosis.To determine whether a skin care programme reduces skin disease on the hands of geriatric nurses and increases protective behaviour and the provision of skin care products at the workplace. The intervention was based on a 2-h skin care training session and an occupational advisory service.The study design was a randomized intervention study with a control group. Three hundred and eighty-eight geriatric nurses were included in the intervention group exposed to a skin care programme (IG; n = 146) and in the control group (CG; n = 242). Both groups completed questionnaires on exposure and underwent clinical examinations of their hands at the beginning and after a 12-month period. Preventive measures initiated by the employer at the workplace were documented at baseline and at 3 months after the intervention.At baseline, no difference between the IG and the CG was found with respect to skin changes or work-related behaviour. At follow-up, the frequency of skin disease was significantly reduced in the IG, from 26% at baseline to 17% at follow-up, whereas the frequency remained almost unchanged in the CG. Effects on behaviour in the IG included significant increases in the use of moisturizers and hand disinfection instead of hand washing. The provision of cotton gloves and barrier cream products increased at intervention workplaces.Effective implementation of an occupational skin care programme for geriatric nurses should include both the training of the nurses and an occupational advisory service for management.
Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation
Authors: Stefan H. Hohnloser, Harry J.G.M. Crijns, Martin van Eickels, Christophe Gaudin, Richard L. Page, Christian Torp-Pedersen, Stuart J. Connolly
Journal: New England Journal of Medicine (2009)

Dronedarone is a new antiarrhythmic drug that is being developed for the treatment of patients with atrial fibrillation.
CIRCADIAN AND SEASONAL VARIATIONS IN APPROPRIATE SHOCKS FOR IMPLANTABLE CARDIAC DEFIBRILLATORS
Authors: Alireza Nazeri, Alireza Heshmat, Vei Vei Lee, MacArthur A. Elayda, Mohammad Saeed, Abdi Rasekh, Christopher M. Frank, Ali Massumi, Mehdi Razavi
Journal: Journal of the American College of Cardiology (2011)
Unusual trihydroxy bile acids in the urine of patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and those with cirrhosis
Authors: Toshiaki Nakashima, Atsushi Sano, Yoshifumi Seto, Toshikazu Nakajima, Toshihide Shima, Yoshikuni Sakamoto, Tadao Okuno, Kei Kashima, Takeshi Hasegawa
Journal: Hepatology (1990)

Urinary bile acids from 20 patients treated with chenodeoxycholate, 18 treated with ursodeoxycholate, 15 treated with rifampicin and 8 patients with advanced cirrhosis were analyzed by gas-liquid chromatography and gas-liquid chromatography-mass spectrometry. Occurrence rates and amounts of three so-called unusual trihydroxy bile acids, hyocholate, ursocholate and omega-muricholate, were increased in patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and decreased in cirrhotic patients as compared with those in untreated healthy adults. These data suggest that chenodeoxycholate and ursodeoxycholate are hydroxylated to produce unusual trihydroxy bile acids in bile acid-loaded humans and that this metabolism may be related to the induction of hepatic microsomal enzymes by rifampicin. In contrast, the hydroxylation of chenodeoxycholate and ursodeoxycholate may be impaired by severe hepatic damage. Because the urine is a secretory pathway for internal bile acids, the occurrence of unusual trihydroxy bile acids in the urine may be used as an indicator of hepatic ability to metabolize "hydrophobic" dihydroxy bile acids to their secretory forms.
A Gene Expression Signature from Human Breast Cancer Cells with Acquired Hormone Independence Identifies MYC as a Mediator of Antiestrogen Resistance
Authors: Todd W. Miller, Justin M. Balko, Zara Ghazoui, Anita Dunbier, Helen Anderson, Mitch Dowsett, Ana M. González-Angulo, Gordon B. Mills, William R. Miller, Huiyun Wu, Yu Shyr, Carlos L. Arteaga
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Although most patients with estrogen receptor α (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped. Experimental Design: We adapted four ER+ human breast cancer cell lines to grow in an estrogen-depleted medium. A gene signature of estrogen independence was developed by comparing expression profiles of long-term estrogen-deprived (LTED) cells to their parental counterparts. We evaluated the ability of the LTED signature to predict tumor response to neoadjuvant therapy with an aromatase inhibitor and disease outcome following adjuvant tamoxifen. We utilized Gene Set Analysis (GSA) of LTED cell gene expression profiles and a loss-of-function approach to identify pathways causally associated with resistance to endocrine therapy. Results: The LTED gene expression signature was predictive of high tumor cell proliferation following neoadjuvant therapy with anastrozole and letrozole, each in different patient cohorts. This signature was also predictive of poor recurrence-free survival in two studies of patients treated with adjuvant tamoxifen. Bioinformatic interrogation of expression profiles in LTED cells revealed a signature of MYC activation. The MYC activation signature and high MYC protein levels were both predictive of poor outcome following tamoxifen therapy. Finally, knockdown of MYC inhibited LTED cell growth. Conclusions: A gene expression signature derived from ER+ breast cancer cells with acquired hormone independence predicted tumor response to aromatase inhibitors and associated with clinical markers of resistance to tamoxifen. Activation of the MYC pathway was associated with this resistance. Clin Cancer Res; 17(7); 2024–34. ©2011 AACR.
GITR modulates innate and adaptive mucosal immunity during the development of experimental colitis in mice
Authors: L Santucci, M Agostini, S Bruscoli, A Mencarelli, S Ronchetti, E Ayroldi, A Morelli, M Baldoni, C Riccardi
Journal: Gut (2006)

<b>Background:</b> Uncontrolled T cell activation and abnormal function of the innate immune system against normal enteric bacterial flora play a critical part in the pathogenesis of inflammatory bowel disease (IBD). Therefore, pharmacological strategies directed to restore the normal responsiveness of the immune system could be efficacious in the treatment of these pathological conditions. Glucocorticoid-induced tumour necrosis factor receptor (GITR)-related gene is a member of the tumour necrosis factor receptor superfamily that is constitutively expressed at high levels on regulatory T cells and at low levels on unstimulated T cells, B cells and macrophages. GITR triggering leads to activation of T effectors and reversal of suppressive function of regulatory T cells. <b>Aim:</b> To investigate the role of GITR in the development of experimental colitis in mice. <b>Results:</b> Using GITR<sup>−/−</sup> mice, GITR deletion protected against 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis by reducing innate immune responses and effector T cell activity. Effector T cells isolated from GITR<sup>−/−</sup> mice were less effective than T cells isolated from GITR<sup>+/+</sup> mice to transfer colitis in immunodeficient mice. Blocking the GITR/ligand for GITR (GITRL) signal by giving soluble GITR prevented TNBS-induced colitis in normal GITR<sup>+/+</sup> and also in lymphocyte-deficient SCID mice. <b>Conclusions:</b> Collectively, these data suggest that GITR plays a critical part in regulating both acquired and innate mucosal immune responses during the development of experimental colitis in mice. Therefore, targeting the GITR/GITRL system signalling may represent a potential pharmacological tool for the treatment of IBD.
Synovial macrophage-osteoclast differentiation in inflammatory arthritis
Authors: L Danks
Journal: Annals of the Rheumatic Diseases (2002)

Pathological bone resorption (marginal erosions and juxta-articular osteoporosis) by osteoclasts commonly occurs in rheumatoid arthritis (RA).To define the nature of the mononuclear precursor cells from which osteoclasts are formed in inflamed synovial tissues and to determine the cellular and humoral factors which influence osteoclast differentiation.Macrophage (CD14+), non-macrophage (CD14-), and unsorted (CD14+/CD14-) synovial cell populations from RA and inflammatory/non-inflammatory osteoarthritis (OA) synovium were cultured in the presence of receptor activator for nuclear factor kappaB ligand (RANKL) and monocyte-colony stimulating factor (M-CSF; in the presence/absence of prostaglandin E(2) (PGE(2)), interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), and IL6). Osteoclast differentiation was assessed by expression of tartrate resistant acid phosphatase (TRAP), vitronectin receptor (VNR), and lacunar resorption.TRAP+ and VNR+ multinucleated cells capable of lacunar resorption were only formed in cultures of CD14+-containing synovial cell populations (that is, CD14+ and CD14+/CD14- cells). No difference in the extent of osteoclast formation was noted in cultures of CD14+ cells isolated from RA, inflammatory OA, and non-inflammatory OA synovium. However, more TRAP+/VNR+ cells and more lacunar resorption was noted in CD14+/CD14- cells from RA and inflammatory OA synovial tissues. The addition of PGE(2), IL1beta, TNFalpha, and IL6 did not increase RANKL/M-CSF-induced osteoclast formation and lacunar resorption of both CD14+/CD14- and CD14+ synovial cell populations.Osteoclast precursors in synovial tissues are CD14+ monocyte/macrophages. The increase in osteoclast formation in cultures of CD14+/CD14- compared with CD14+ synovial cells in RA and inflammatory OA points to a role for CD14- cells in promoting osteoclast differentiation and bone resorption in inflamed synovial tissues by a mechanism which does not involve a direct effect of proinflammatory cytokines/prostaglandins on RANKL-induced macrophage-osteoclast differentiation.
Inhibition of p38 MAPK Activation via Induction of MKP-1
Authors: Alexandra K. Kiemer, Nina C. Weber, Robert Fürst, Nicole Bildner, Stefanie Kulhanek-Heinze, Angelika M. Vollmar
Journal: Circulation Research (2002)

The atrial natriuretic peptide (ANP) is a cardiovascular hormone possessing antiinflammatory potential due to its inhibitory action on the production of inflammatory mediators, such as tumor necrosis factor-α (TNF-α). The aim of this study was to determine whether ANP is able to attenuate inflammatory effects of TNF-α on target cells. Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α in the presence or absence of ANP. Changes in permeability, cytoskeletal alterations, phosphorylation of p38 MAPK and HSP27, and expression of MKP-1 were determined by macromolecule permeability assay, fluorescence labeling, RT-PCR, and immunoblotting. Antisense studies were done by transfecting cells with MKP-1 antisense oligonucleotides. Activation of HUVECs with TNF-α lead to a significant increase of macromolecule permeability and formation of stress fibers. Treatment of cells with ANP (10 −8 to 10 −6 mol/L) significantly reduced the formation of stress fibers and elevated permeability. Both TNF-α–induced effects were shown to be mediated via the activation of p38 using SB203580, a specific inhibitor of p38. ANP significantly reduced the TNF-α–induced activation of p38 and attenuated the phosphorylation of HSP27, a central target downstream of p38. ANP showed no effect on p38 upstream kinases MKK3/6. However, a significant induction of the MAPK phosphatase MKP-1 mRNA and protein could be observed in ANP-treated cells. Antisense experiments proved a causal role for MKP-1 induction in the ANP-mediated inhibition of p38. These data show the inhibitory action of ANP on TNF-α–induced changes in endothelial cytoskeleton and macromolecule permeability involving an MKP-1–induced inactivation of p38 MAPK. These effects point to an antiinflammatory and antiatherogenic potential of this cardiovascular hormone.
Screening for Founder Mutations in <i>BRCA1</i> and <i>BRCA2</i> in Unselected Jewish Women
Authors: Kelly A. Metcalfe, Aletta Poll, Robert Royer, Marcia Llacuachaqui, Anna Tulman, Ping Sun, Steven A. Narod
Journal: Journal of Clinical Oncology (2009)

Purpose There are two mutations in BRCA1 and one mutation in BRCA2 that are present in up to 2.5% of Ashkenazi Jewish women. Current guidelines for testing stipulate that a personal or family history of cancer be present to be eligible for testing. To date, population screening in this population has not been suggested. However, this may be rational. Little is known about the appropriateness of testing guidelines for the Jewish population or the level of interest in testing. Methods Eligible subjects were women who self-identified as Jewish, who were between the ages of 25 and 80 years, and who resided in Ontario. Subjects were recruited through an article in a national newspaper. Women were asked to complete a study questionnaire and a family history questionnaire and to provide a blood or saliva sample. The risk of carrying a BRCA mutation was estimated for each woman. Results A total of 2,080 women were enrolled onto the study. The overall mutation prevalence was 1.1% (0.5% for BRCA1 and 0.6% for BRCA2). Among the 22 mutation carriers, the mean estimate of carrying a BRCA mutation was 3.9%. Ten (45%) of the 22 women met the current Ontario Ministry of Health Guidelines criteria for testing. Conclusion There is considerable interest for genetic testing among Jewish women at low risk of carrying a mutation. However, many women with mutations are ineligible for genetic testing under current guidelines. Approximately 1% of Jewish women carry a BRCA mutation, and these women should be considered to be candidates for genetic testing.
Endotoxin exposure, wheezing, and rash in infancy in a New Zealand birth cohort
Authors: J GILLESPIE, K WICKENS, R SIEBERS, P HOWDENCHAPMAN, I TOWN, M EPTON, P FITZHARRIS, D FISHWICK, J CRANE, None THENEWZEALANDASTHMAANDALLERG
Journal: Journal of Allergy and Clinical Immunology (2006)
Impaired flow-mediated vasodilation of the brachial artery in patients with primary hyperparathyroidism improves after parathyroidectomy
Authors: M Kosch
Journal: Cardiovascular Research (2000)

Objective: The endothelium is a newly recognised target tissue of parathyroid hormone (PTH). It is not clear whether hyperparathyroidism affects endothelial function and whether parathyroidectomy (Ptx) has an influence on arterial vessel wall properties. We studied brachial flow-mediated vasodilation (FMD) and brachial and carotid intima-media thickness (IMT) in patients with primary hyperparathyroidism (pHPT) before and after Ptx and in healthy controls. Methods: 19 patients with pHPT (mean+SEM, age 45±4.7 years, PTH 238±52 ng/l) were studied. Diabetes, hypertension and vascular disease were excluded. Twenty healthy volunteers matched for age, sex and blood pressure served as controls. Enddiastolic diameter, FMD and nitroglycerine-induced (NMD) dilation of the brachial artery were measured by a multigate pulsed doppler system (echo-tracking), IMT was determined using automatic analysis of the M-line signal. Healthy volunteers where studied on one occasion, patients were studied at baseline and 6 months after Ptx. Results: Six months after Ptx PTH had decreased to normal, blood pressure levels remained unchanged. Endothelium dependent FMD at baseline was impaired in patients compared to controls (4.7±1.2 vs. 18.2±3.7%, P<0.01), however, FMD improved significantly after Ptx (16.7±3.0%, P<0.01). Nitroglycerine-induced dilation, IMT and artery diameter were not different between groups and did not change after Ptx. Conclusions: Impaired endothelium dependent vasodilation in patients with primary hyperparathyroidism improves after successful parathyroidectomy. Endothelial dysfunction associated with primary hyperparathyroidism occurs without detectable structural wall alterations of the brachial artery and appears therefore to be an early and reversible arterial alteration.