tbuckley/cabot-search huggingface dataset:
New epidemiological studies. Oral contraceptives and venous thromboembolic disease. Analyses of the UK General Practice Research Database and the UK MediPlus Database
Authors: R. Farmer
Journal: Human Reproduction Update (1999)

The results of three independent studies of venous thromboembolic disease (VTE) and oral contraceptives are reviewed together with two further cohort/case-control studies which we conducted using the MediPlus and general practice Research Database (GPRD) databases. These latter studies jointly involved 395 cases and uniquely examined the association between VTE and individual combined oral contraceptive (COC) formulations. The two studies yielded very similar results. Crude incidence rates for idiopathic VTE of 4.6 and 3.8 were found per 10 000 exposed woman-years (EWY), in the MediPlus and GPRD studies respectively. Incidence rates increased markedly with age, and in both databases the rates amongst users of levonorgestrel products were lower than those amongst users of desogestrel and gestodene products. A case fatality rate of 3% and a mortality rate of 10 per million EWY were estimated. Odds ratios (OR) were calculated for confounding variables and different COC formulations. Both database studies indicated an excess of current smokers and women with high body mass indices amongst cases. There were significantly more cases with asthma in the GPRD study and cases who had been using their COC for less than a year. No statistically significant difference between COC formulations were found in the analyses where controls were matched to cases by practice and year of birth in both the MediPlus and GPRD studies. In the GPRD study we also ran a study where controls were matched by practice and within 5 year age bands. In this study the OR were consistently higher for the newer or 'third generation' products than when controls were matched by year of birth. However only the acne formulation/OC containing cyproterone acetate and 35 μg ethinyloestradiol yielded a significant OR of 2.3. It may be concluded that improvements in prescribing are paramount as the results strongly indicate that overweight women and those who smoke are at a greater risk of VTE. Further study is required to elucidate the possibility that asthma or its treatment may predispose to VTE, alone or in combination with other risk factors. However, neither the MediPlus nor GPRD studies indicate that any one COC formulation poses a greater risk of VTE than another.
Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen
Authors: Werner Schroth
Journal: JAMA (2009)

<h3>Context</h3>The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor–positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme.<h3>Objective</h3>To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen.<h3>Design, Setting, and Patients</h3>Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism.<h3>Main Outcome Measures</h3>Time to recurrence, event-free survival, disease-free survival, and overall survival.<h3>Results</h3>Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51).<h3>Conclusion</h3>Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.
Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man
Authors: Grégory Bouchaud, Samuel Gehrke, Carsten Krieg, Antonios Kolios, Jürg Hafner, Alexander A. Navarini, Lars E. French, Onur Boyman
Journal: The Journal of Experimental Medicine (2013)

Stromal cells at epithelial surfaces contribute to innate immunity by sensing environmental danger signals and producing proinflammatory cytokines. However, the role of stromal cells in controlling local inflammation is unknown. We show that endogenous soluble IL-15 receptor α (IL-15Rα) derived from epidermal stroma, notably keratinocytes, protects against dendritic cell/IL-15-mediated, T cell-driven skin inflammation in vivo, and is relevant to human psoriasis. Selective lack of IL-15Rα on stromal epidermal cells exacerbated psoriasiform inflammation in animals. Epidermal IL-15Rα was shed by keratinocytes via proteolytic cleavage by matrix metalloproteinases upon stimulation with proinflammatory cytokines to counteract IL-15–induced proliferation of IL-17+ αβ and γδ T cells and production of TNF, IL-23, IL-17, and IL-22 during skin inflammation. Notably, administration of soluble IL-15Rα was able to repress secretion of IL-1β, IL-6, and TNF by keratinocytes, dampen expansion of IL-17+ αβ and γδ T cells in vivo, and prevent psoriasis in two mouse models, including human xenograft AGR mice. Serum levels of soluble IL-15Rα negatively correlated with disease severity, and levels rose upon successful treatment of psoriasis in patients. Thus, stressed epidermal stromal cells use soluble IL-15Rα to dampen chronic inflammatory skin disease.
Recent advances in antimalarial drug development
Authors: Suryanaryana Vangapandu, Meenakshi Jain, Kirandeep Kaur, Premanand Patil, Sanjay R. Patel, Rahul Jain
Journal: Medicinal Research Reviews (2006)

Abstract Malaria caused by protozoa of the genus Plasmodium , because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re‐examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in‐depth look at the most significant progress made during the past 10 years in antimalarial drug development. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 1, 65–107, 2007
Lack of association between the protein tyrosine phosphatase non-receptor 22 (PTPN22)*620W allele and systemic sclerosis in the French Caucasian population
Authors: J Wipff, Y Allanore, A Kahan, O Meyer, L Mouthon, L Guillevin, C Pierlot, E Glikmans, T Bardin, C Boileau, F Cornelis, P Dieude
Journal: Annals of the Rheumatic Diseases (2006)

The minor allele of the <i>R620W</i> missense single-nucleotide polymorphism (SNP; <i>rs2476601</i>) in the <i>PTPN22</i> (protein tyrosine phosphatase non-receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo. Systemic sclerosis (SSc) is a connective tissue disease with some autoimmune abnormalities. The aim of our study was to test for association of the <i>PTPN22*620W</i> allele with SSc in a French Caucasian cohort with a case–control study of 121 patients with SSc and 103 controls. All patients and controls were genotyped for the <i>PTPN22*R620W</i> SNP. No association was found between the <i>PTPN22*620W</i> allele and SSc (7% <i>v</i> 9.2%, p = 0.39). The frequency of genotypes carrying at least one <i>620W</i> allele was similar in both groups (13% <i>v</i> 17%, p = 0.38). The <i>PTPN22*620W</i> allele was also not associated with autoantibody patterns. Thus, the <i>PTPN22*R620W</i> polymorphism cannot be regarded as a genetic susceptibility factor for SSc in the French Caucasian population.
A controlled double blind study of azathioprine in the management of Crohn's disease.
Authors: S Candy, J Wright, M Gerber, G Adams, M Gerig, R Goodman
Journal: Gut (1995)

While immunosuppressive agents are used widely in the management of Crohn9s disease, their efficacy has not been well established in randomised controlled trials. This study was designed to examine whether azathioprine increases remission rate when used in conjunction with a diminishing dose regimen of prednisolone over a period of 12 weeks. It further examined whether azathioprine offers any therapeutic advantage over placebo in the maintenance of remission in Crohn9s disease over a period of 15 months. Sixty three patients with active Crohn9s disease were treated with a 12 weeks diminishing dose of prednisolone and at the same time entered into a randomised, double blind 15 month trial of either azathioprine (2.5 mg/kg) or placebo. Remission rates between the two groups were compared at 12 weeks and at 15 months. There was no significant difference in the proportion of patients who had achieved and maintained remission by week 12 but at 15 months there was a highly significant difference in the proportion of patients in remission (42% receiving azathioprine v 7% receiving placebo), p = 0.001. Using life tables this beneficial effect was reflected as the difference in the median number of days on the trial (p = 0.02). There were significantly greater decreases over the trial period in the median erythrocyte sedimentation rate, C reactive protein, and leucocyte count in the azathioprine group. There were no cases of severe bone marrow suppression or clinical pancreatitis. In conclusion, azathioprine offers a therapeutic advantage over placebo in the maintenance of remission in Crohn9s disease.
Sporadic and TSC-related lymphangioleiomyomatosis (LAM): The experience of Ospedale San Paolo of Milan (preliminary data)
Authors: Gianluca Imeri, Fabiano Di Marco, Gisella Palumbo, Silvia Terraneo, Stefano Centanni, Fulvia Ribolla, Giuseppe Francesco Sferrazza Papa, Giulia Pellegrino, Emanuela Rancati, Elena Maria Parazzini
Journal: European Respiratory Journal (2014)

LAM is a rare pulmonary cystic disease that may be sporadic (S-LAM) or associated with Tuberous Sclerosis Complex (TSC-LAM). This study was aimed at evaluating potential differences between TSC patients with or without LAM and between S-LAM and TSC-LAM patients. We analyzed 89 women (37±12 years, mean±DS), 11 affected by S-LAM and 78 by TSC. Among women affected by TSC (38±12 years), 27 had LAM (35%). These patients had a mild ventilatory defect, with a mean FEV1 almost normal (96±26% vs. 98±11%in TSC patients without LAM). TSC women with LAM were older (44±11 years) than those without (34±11 years, pl0.001). The MRC score (Medical Research Council) was 0.5±1.0 vs. 0.3±0.7 for TSC patients, with and without LAM, respectively (p=0.176). Patients affected by TSC-LAM had more air trapping and reduction of DLCO, but the difference was not statistically significant (p=0.404 and 0.068, respectively). In patients affected by TSC-LAM we found a higher rate of hepatic angiomyolipomas, compared with TSC patients without LAM (48% vs. 22%, p=0.032). No other differences associated with LAM emerged in TSC patients, such as genetic mutations, renal angiomyolipomas, skin lesions, epilepsy, encephalic lesions. S-LAM patients had a mean age of 42±9 years and 50% of these had a clinical history of at least a pneumothorax. Mean FEV1, DLCO/VA and RV/TLC were 76±27%, 61±19% and 151±29%, respectively. Dyspnea assessed with MRC scale was 2.3±1.6. As a whole, our TSC-LAM patients showed milder respiratory manifestations than S-LAM patients, probably because in TSC a screening to detect LAM is usually performed.
Abstract 412: Expression of cancer stem cell markers in pancreatic ductal adenocarcinomas and pancreatic intraepithelial neoplasias
Authors: Shoko Kure, Yoko Matsuda, Masahito Hagio, Taeko Suzuki, Junji Ueda, Kazuya Yamahatsu, Tetsushi Yamamoto, Zenya Naito, Toshiyuki Ishiwata
Journal: Cancer Research (2012)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high incidence of distant metastasis. Recent studies have shown that cancer stem cells (CSCs) are important in cancer cell growth, invasion, metastasis, and recurrence. Several studies have revealed some CSC-specific markers for PDAC, such as CD133, CD24, CD44, CXCR4, ESA, and nestin. Some evidence also suggests that PDAC progresses through a multistep process comprised of noninvasive precursor lesions known as pancreatic intraepithelial neoplasias (PanINs). The reports of CSCs in PanINs are limited. We performed a comprehensive analysis of the expression of CSC markers in PDACs, PanINs, and normal pancreatic tissues. Materials &amp; Methods: CD24, CD44, ESA, CD133, CXCR4, and nestin were used as CSC markers. Human PDACs (n=67), PanIN-1 (n=35), PanIN-2 (n=52), PanIN-3 (n=18), and normal pancreatic tissues (n=54), which were obtained from patients who underwent surgical operations in the surgical department of Nippon Medical School, were used for immunohistochemical analysis. Human PDAC cell lines, PANC-1, KLM-1, and MIA PaCa-2, were used for flow cytometric assays and quantitative RT-PCR analysis. Results: Regarding the clinicopathological features, the positivity of CD44 and CD133 showed significant correlations for UICC classifications and histological features In the survival analysis, CD133-positive PDACs led to a significantly poorer prognosis. In the immunohistochemical analysis, CD24, CD44, ESA, CXCR4, and nestin showed a gradual increase of positivity along with the grades of PanINs. Flow cytometric assays and RT-PCR analysis confirmed the expression profile in PDAC. Conclusion: CSC markers were expressed to various extents in PDAC, and the expression of CD133 and CD44 was correlated with the prognosis and stage. Furthermore, CSC markers showed a gradual increase along with the grades of PanINs; therefore, CSC may be involved in the carcinogenesis of PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 412. doi:1538-7445.AM2012-412
Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation
Authors: M. Waeber, M. Castiglione-Gertsch, D. Dietrich, B. Thürlimann, A. Goldhirsch, K.W. Brunner, M.M. Borner
Journal: Annals of Oncology (2003)
Disparities in Diabetes Care Between Smokers and Nonsmokers
Authors: Akiko S. Hosler, Theresa M. Hinman, Harlan R. Juster
Journal: Diabetes Care (2007)

Smoking is a known risk factor for both macro- and microvascular complications of diabetes, contributing to higher medical costs, lower quality of life, and premature deaths in adults with diabetes who smoke (1–3). Although the prevalence of smoking has decreased over the last decade in the U.S., (4,5) one in six adults with diabetes still smokes (6). Diabetes experts recommend that diabetic smokers be advised about smoking cessation and closely monitored for signs of complications by health care professionals, (7) but diabetic smokers are reportedly less likely to receive the recommended care. A survey of health plan members reported that diabetic smokers were likely to have fewer diabetes care visits and receive less frequent preventive care than diabetic nonsmokers (8). Using data from community-based, statewide diabetes intervention programs, the present study compares five major diabetes care indicators between diabetic smokers and age-, sex-, and race-matched diabetic nonsmokers while controlling for the effects of insurance status.

The data were collected from participants of the New York State Diabetes Coalitions community-based intervention programs, 1999–2004, which were designed to reach the medically underserved (9). All participants were required to complete standardized forms at program registration. The data contained self-reported health status, smoking behavior, diabetes care, and insurance status of >16,000 adults (aged ≥18 years) with diagnosed diabetes. Participants with <13 months of duration since diagnosis of diabetes were excluded from the study. Then, all current …
Interaction between a normoxic and a hypoxic region of guinea pig and ferret papillary muscles.
Authors: H Hofmann
Journal: Circulation Research (1985)

Papillary muscles were mounted in a three-compartment bath. The tip of the muscle was exposed to hypoxic and glucose-free solution. The other parts of the preparation were superfused with Tyrode's solution, building a free-flow border between hypoxic and normoxic superfusates. The normoxic part of the bath was subdivided by a rubber membrane so that current pulses could be applied between segments of the preparation. Signs of electrotonic interaction between normoxic and hypoxic parts were observed a few minutes after the onset of hypoxia. Transmembrane action potentials in the normoxic part retained their plateau, but progressively shortened. Those in the hypoxic tip showed an early phase of rapid repolarization followed by a plateau phase near the resting potential. Terminal repolarization in the two parts coincided for many minutes. After 35 minutes, fast propagated activity ceased in the tip and was replaced first by conducted slow responses, then by decremental conduction. At 50 minutes, cells near the borderline had resting potentials of either -76 +/- 7 mV (SD, n = 9) in normoxic tissue or -16 +/- 3 mV (SD, n = 9) in hypoxic tissue. Concurrently, subthreshold potentials no longer appeared to spread into the tip. Unipolar electrograms remained diphasic over the normoxic part but lost their negative deflection near the borderline, implying the absence of axial current flow into the hypoxic part. Furthermore, electrotonic potentials generated by current flow across the rubber membrane did not spread beyond a line of demarcation. Reduced nicotinamide adenine dinucleotide fluorescence increased in the hypoxic part, and appeared to correlate with the development of electrical decoupling.(ABSTRACT TRUNCATED AT 250 WORDS)
Treatment of Children and Adolescents With Stage II Testicular and Stages I and II Ovarian Malignant Germ Cell Tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9048 and Children's Cancer Group 8891
Authors: Paul C. Rogers, Thomas A. Olson, John W. Cullen, Deborah F. Billmire, Neyssa Marina, Frederick Rescorla, Mary M. Davis, Wendy B. London, Stephen J. Lauer, Roger H. Giller, Barbara Cushing
Journal: Journal of Clinical Oncology (2004)

To determine whether children with localized gonadal malignant germ cell tumors (MGCT) stage II testicular and stages I and II ovarian treated with four cycles of standard-dose cisplatin combined with etoposide and low-dose bleomycin (PEB) have an event-free survival (EFS) of at least 85% without significant toxicity.Between May 1990 and July 1995, eligible pediatric patients with stage II or recurrent from stage I (as a stage II) testicular MGCT and stages I and II ovarian MGCT were enrolled onto this Pediatric Oncology Group and Children's Cancer Group study. PEB chemotherapy consisted of bleomycin 15 U/m2 on day 1, cisplatin 20 mg/m2/d on days 1 to 5, and etoposide 100 mg/m2/d on days 1 to 5. Patients received four cycles of therapy at 21-day intervals.Seventy-four patients with a median age of 10.5 years (range, 8.7 months to 16.7 years) were enrolled. Primary sites included: stage II testicular (n = 17), stage I ovarian (n = 41), and stage II ovarian MGCT (n = 16). Treatment with standard PEB resulted in 6-year EFS of 95% and overall survival (OS) of 95.7%. EFS and OS by primary site were as follows: stage II testicular, 100% and 100%; stage I ovarian, 95.1% and 95.1%; and stage II ovarian, 87.5% and 93.8%, respectively. Two patients died from recurrent disease, and one patient died of secondary acute myelocytic leukemia. Infrequent grade 3 to 4 hematologic toxicity was reported. No grade 3 to 4 renal, pulmonary, or ototoxicity was observed.Combination chemotherapy with PEB results in excellent EFS and OS with minimal toxicity in children and adolescents with localized gonadal MGCT.
Common Carotid Arterial Wall Thickness in NIDDM Subjects
Authors: Arturo Pujia, Agostino Gnasso, Concetta Irace, Alfredo Colonna, Pier Luigi Mattioli
Journal: Diabetes Care (1994)

To verify whether carotid arterial intimal plus media thickness (IMT) is greater in non-insulin-dependent diabetes mellitus (NIDDM) subjects, known to be at high risk for atherosclerosis. Evidence is growing that IMT is increased in subjects with coronary heart disease (CHD) risk factors like hypercholesterolemia and cigarette smoking.Fifty-four NIDDM subjects and 54 sex- and age-matched control subjects underwent CHD risk factors assessment and echo-Doppler examination of carotid arteries. IMT was measured by computer technique in the common carotid artery (CCA). Presence of plaques and/or stenosis (carotid atherosclerosis [CA]) was also evaluated by a single-blinded reader.NIDDM subjects had larger IMT, higher levels of triglycerides, and lower concentrations of high-density lipoprotein (HDL) cholesterol compared with control subjects. IMT was positively correlated to age and systolic blood pressure and inversely to HDL cholesterol in both groups. The prevalence of CA was 46% in NIDDM subjects and 18% in control subjects. In multiple regression analysis, IMT was the only variable significantly associated to CA.IMT of CCA is enlarged in NIDDM subjects compared with control subjects. Its association with carotid plaques and/or stenosis might be of importance to detect early atherosclerotic lesions in the carotid arteries.