tbuckley/cabot-search huggingface dataset:
Candidate gene studies in respiratory disease: avoiding the pitfalls
Authors: I Hall
Journal: Thorax (2002)

Association studies of candidate gene polymorphisms in respiratory disease are easy to perform, but there are many pitfalls which have led to considerable criticism of these studies.

With the completion of a working draft of the human genome sequence, we are standing at the threshold of the most exciting period in biomedical research. It is now clear that the human genome contains around 32 000 genes,1 and information is rapidly accumulating on the degree of interindividual variability in the sequences of these genes through collaborations such as the single nucleotide polymorphism (SNP) consortium.2 Differences between individuals in their susceptibility to develop common diseases, the severity of their disease, and individual responses to treatment are all potentially predictable on the basis of the interaction of environmental factors with an individual's particular set of genotypes. Over the last few years this has led to a proliferation of association studies examining candidate gene polymorphisms for their potential role in respiratory disease. These studies are easy to perform—needing only a stored DNA sample and access to a relevant clinical data set—but there are many potential pitfalls to performing candidate gene association studies which have resulted in substantial criticism of this kind of study. This editorial provides guidance on some aspects of the design of such studies.

Some of the major issues which need to be considered in the design of candidate gene association studies are listed in table 1 and are briefly discussed below. It is estimated that SNPs occur at a rate of approximately 1 in 300 base pairs in non-coding DNA and 1 in 600 base pairs in coding DNA. Given that most genes are at least 1 kb in length (and many are much greater), it is immediately apparent that, even considering only the coding regions within the genome, …
Performance of high-risk human papillomavirus DNA testing as a primary screen for cervical cancer: a pooled analysis of individual patient data from 17 population-based studies from China
Authors: Fang-Hui Zhao, Margaret Jane Lin, Feng Chen, Shang-Ying Hu, Rong Zhang, Jerome L Belinson, John W Sellors, Silvia Franceschi, You-Lin Qiao, Philip E Castle
Journal: The Lancet Oncology (2010)
Carlos E Baena-Cagnani
Authors: G. W. C. J. Bousquet
Journal: BMJ (2015)

Carlos E Baena-Cagnani had a passion for basing medical practice on evidence and was instrumental in changing the public perception of allergy in Argentina, his home country, and throughout Latin America. For decades, allergic diseases were empirically managed, but Baena-Cagnani recognised early the importance of evidence based medicine and became a member of the executive committees of GINA (Global Initiative for Asthma) and of ARIA (Allergic Rhinitis and its Impact …
Her2/neu Expression Predicts the Response to Antiaromatase Neoadjuvant Therapy in Primary Breast Cancer
Authors: Li Zhu, Louis W. C. Chow, Wings T. Y. Loo, Xin-Yuan Guan, Mazakazu Toi
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Many studies suggest that Her2/neu play an important role in neoadjuvant endocrine therapy. This study aimed to determine whether the level of Her2/neu expression in advanced breast cancer changes after antiaromatase neoadjuvant treatment, as well as to identify the relationship between Her2/neu expression and response to this kind of therapy. Experimental Design: Thirty-six postmenopausal patients with hormonal receptor-positive primary breast cancer were included in a study of three monthly cycles of neoadjuvant endocrine therapy with either Aromasin (25 mg daily) or Femara (2.5 mg daily). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for Her2/neu were conducted both on pretreatment biopsies and surgical tumors. Results: Using IHC, 5 of 36 (13.9%) of the patients had a Her2/neu overexpression after treatment, as compared with 16 of 36 (44.4%) before. Meanwhile, there was no change in 21 (58.3%) patients, and through FISH, there was a change from amplification to no amplification in 15 (41.7%) patients. The response rate to the treatment was 75% for Her2/neu (+) tumors and 35% for Her2/neu (−) tumors (P = 0.017) while FISH was performed. The response rate was also significantly affected by the decrease in Her2/neu status after the treatment, with 73% of the tumors showing decreased Her2/neu expression and with 38% of the tumors showing no change of Her2/neu expression (P = 0.037). Conclusions: Using both IHC and FISH, advanced breast cancers show statistical evidence of decreasing incidence of Her2/neu expression after antiaromatase neoadjuvant treatment. Our data also suggest that Her2/neu expression and its change during the treatment might be predictive markers for this kind of therapy.
Profession of Medicine
Authors: Liam Donaldson
Journal: BMJ (2008)

The fundamental and consistent criterion that distinguishes a profession from other occupations is its autonomy, a condition that is not absolute but that depends for its existence on the tolerance and protection of the state. Eliot Freidson, a giant of medical sociology, drew this conclusion as the central theme of his comprehensive analysis of the nature of professions.

For those who work regularly with medical professional bodies or with doctors in managed care environments, Freidson’s monograph, now nearly 40 years old, rings so many bells as to be positively …
The conscious roots of selfless, unconscious goals
Authors: Gordon B. Moskowitz, Emily Balcetis
Journal: Behavioral and Brain Sciences (2014)

Abstract We counter Huang &amp; Bargh's (H&amp;B's) metaphoric description of the unconscious, selfish goal on three points. First, we argue, unconscious goals are rooted in conscious choices related to well-being. Second, unconscious goal pursuit occurs through early-stage orienting mechanisms that promote individuals' well-being. Third, unconscious goals work selflessly, resulting in their own demise.
Characterisation of asthma among adults with and without childhood farm contact
Authors: A. Schulze, R. T. van Strien, G. Praml, D. Nowak, K. Radon
Journal: European Respiratory Journal (2007)

Childhood farm contact is associated with a lower prevalence of sensitisation and allergic rhinitis. Findings have been contradictory for asthma. The aim of the present study was to investigate the differences between farm and nonfarm subjects using objective measurements. A cross-sectional questionnaire study was performed among rural adults aged 18-44 yrs, of which 37% lived on a farm during the first 3 yrs of life and were thus referred to as "farm subjects". Lung function, bronchial hyperresponsiveness (BHR) to methacholine and sensitisation were measured in a random sample. A total of 1,595 subjects were included in the analyses. Among farm subjects, sensitisation against inhalant allergens (odds ratio (OR) 0.7; 95% confidence interval 0.6-0.9), allergic rhinitis (0.5 (0.4-0.8)) and asthma diagnosis (0.7(0.4-1.1)) were less common than among nonfarm subjects. For BHR and lung function, no statistically significant differences were found between the two groups. Stratifying for sensitisation, farm subjects had a lower OR of asthma diagnosis (0.5 (0.3-1.0)) and a nonsignificantly reduced OR of BHR with sensitisation (0.8 (0.5-1.1)). The present study confirmed, using objective measurements, that farm subjects have a lower prevalence of symptoms and asthma diagnosis, while the prevalence of bronchial hyperresponsiveness does not differ.
Lumbar Supports and Education for the Prevention of Low Back Pain in Industry
Authors: Mireille N. M. van Poppel, Bart W. Koes, Trudy van der Ploeg, Tjabe Smid, Lex M. Bouter
Journal: JAMA (1998)

Context.-Low back pain is a frequent and costly health problem.Prevention of low back pain is important both for the individual patient and from an economic perspective.Objective.-Toassess the efficacy of lumbar supports and education in the prevention of low back pain in industry.Design.-A randomized controlled trial with a factorial design.Setting.-The cargo department of an airline company in the Netherlands.Participants.-A total of 312 workers were randomized, of whom 282 were available for the 6-month follow-up.Interventions.-Subjects were randomly assigned to 4 groups: (1) education (lifting instructions) and lumbar support, (2) education, (3) lumbar support, and (4) no intervention.Education consisted of 3 group sessions on lifting techniques with a total duration of 5 hours.Lumbar supports were recommended to be used during working hours for 6 months.Main Outcome Measures.-Lowback pain incidence and sick leave because of back pain during the 6-month intervention period.Results.-Compliance with wearing the lumbar support at least half the time was 43%.In the 282 subjects for whom data were available, no statistically significant differences in back pain incidence (48 [36%] of 134 with lumbar support vs 51 [34%] of 148 without, P = .81)or in sick leave because of low back pain (mean, 0.4 days per month with lumbar support vs 0.4 days without, P = .52)were found among the intervention groups.In a subgroup of subjects with low back pain at baseline, lumbar supports reduced the number of days with low back pain per month (median, 1.2 vs 6.5 days per month; P = .03).Conclusions.-Overall,lumbar supports or education did not lead to a reduction in low back pain incidence or sick leave.The results of the subgroup analysis need to be confirmed by future research.Based on our results, the use of education or lumbar supports cannot be recommended in the prevention of low back pain in industry.
C-reactive protein and microalbuminuria are associated with atrial fibrillation
Authors: Folkert W. Asselbergs, Gilles F. Diercks, Maarten P. van den Berg, Ad J. van Boven, Isabelle C. van Gelder, Dirk J. van Veldhuisen, Wiek H. van Gilst
Journal: Journal of the American College of Cardiology (2003)
Association of the ABCB1 gene polymorphisms 2677G&gt;T/A and 3435C&gt;T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients
Authors: H. Chang, S.Y. Rha, H.-C. Jeung, C.-K. Im, J.B. Ahn, W.S. Kwon, N.C. Yoo, J.K. Roh, H.C. Chung
Journal: Annals of Oncology (2008)
A1C and Diabetes Diagnosis: The Rancho Bernardo Study
Authors: Caroline K. Kramer, Maria Rosario G. Araneta, Elizabeth Barrett-Connor
Journal: Diabetes Care (2009)

OBJECTIVE To examine the sensitivity and specificity of A1C as a diagnostic test for type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS Cross-sectional study of community-dwelling adults without known diabetes who had an oral glucose tolerance test and A1C measured on the same day. RESULTS Mean age of the 2,107 participants was 69.4 ± 11.1 years; 43% were men. Based on the American Diabetes Association (ADA) criteria, 198 had previously undiagnosed type 2 diabetes. The sensitivity/specificity of A1C cut point of 6.5% was 44/79%. Results were similar in age- and sex-stratified analyses. Given the A1C cut point of 6.5%, 85% of participants were classified as nondiabetic by ADA criteria. CONCLUSIONS The limited sensitivity of the A1C test may result in delayed diagnosis of type 2 diabetes, while the strict use of ADA criteria may fail to identify a high proportion of individuals with diabetes by A1C ≥6.5% or retinopathy.
A STUDY ON THE MECHANISM OF INVASIVENESS OF STREPTOCOCCI
Authors: Emery Westervelt Dennis, Dicran Berberian
Journal: The Journal of Experimental Medicine (1934)

1. Menkin's observations of the failure of inflammatory fixation in areas of acute inflammation due to Streptococcus haemolyticus have been confirmed. 2. The lack of inflammatory fixation in the presence of streptococci is not due to the passive nature of the streptococcus, but may be attributed to the production of (1) fibrinolytic, and (2) antifibrinogenic substances which dissolve the fibrin barrier, or prevent its formation, thus maintaining the patency of the lymphatics and capillaries and facilitating the dissemination of the organisms. 3. The production of fibrinolytic or antifibrinogenic substances, and the invasiveness of a given strain of streptococcus are correlative. 4. Both substances are relatively thermostable. Fibrinolysin is destroyed if held at 100 degrees C. for 1 hour. The antifibrinogenic substance is weakened but is not destroyed under the same conditions. 5. There is evidence that both substances are antigenic, and exhibit some degree of type specificity. 6. The role of fibrinolysin and the antifibrinogenic factor in the invasion of the tissues by streptococci is discussed.
Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study
Authors: A Delannoy, E Delabesse, V Lhéritier, S Castaigne, F Rigal-Huguet, E Raffoux, F Garban, O Legrand, S Bologna, V Dubruille, P Turlure, O Reman, M Delain, F Isnard, D Coso, P Raby, A Buzyn, S Caillères, S Darre, C Fohrer, A Sonet, C Bilhou-Nabera, M-C Béné, H Dombret, P Berthaud, X Thomas
Journal: Leukemia (2006)
Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome.
Authors: M Sata, M Ikebe
Journal: Journal of Clinical Investigation (1996)

More than 30 missense mutations in the beta-cardiac myosin heavy chain gene have been shown to be responsible for familial hypertrophic cardiomyopathy. To clarify the effects of these point mutations on myosin motor function, we expressed wild-type and mutant human beta-cardiac myosin heavy chains in insect cells with human cardiac light chains. The wild-type myosin was well purified with similar enzymatic and motor activities to those of the naturally isolated V3 cardiac myosin. Arg249-->Gln and Arg453-->Cys mutations resulted in decreased actin translocating activity (61 and 23% of the wild-type, respectively) with decreased intrinsic ATPase activity. Arg403-->Gln mutation greatly decreased actin translocating activity (27% of wild type) with a 3.3-fold increased dissociation constant for actin, while intrinsic ATPase activity was unchanged. Val606-->Met mutation only mildly affected the actin translocating activity as well as ATPase activity of myosin. The degree of deterioration by each mutation was closely correlated with the prognosis of the affected kindreds, indicating that myosin dysfunction caused by the point mutations is responsible for the pathogenesis of the disease. Structure/function relationship of myosin is discussed.
Is There Clinical Value to Prognostic Signatures in Early-Stage NSCLC?
Authors: Paul A. Bunn, Fred R. Hirsch, Dara L. Aisner
Journal: Clinical Cancer Research (2014)

pAMPK and pmTOR favorably predicted outcome in early non-small cell lung cancer (NSCLC). The differences were small. Phosphoprotein lability makes routine clinical use and validation difficult. Protein immunohistochemistry is unlikely to be clinically useful, and numerous efforts to create predictive models to select resected patients for therapy have been unsuccessful.
Mutations in the genes for hepatocyte nuclear factor (HNF)-1alpha, -4alpha, -1beta, and -3beta; the dimerization cofactor of HNF-1; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians.
Authors: L J Baier, P A Permana, M Traurig, A Dobberfuhl, C Wiedrich, J Sutherland, P Thuillez, G Luczy-Bachman, M Hara, Y Horikawa, Y Hinokio, R L Hanson, C Bogardus
Journal: Diabetes Care (2000)

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of type 2 diabetes characterized by an early age at onset and autosomal dominant inheritance. MODY can result from heterozygous mutations in at least five genes. The purpose of this study was to determine whether alterations in known MODY genes and two MODY candidate genes contribute to the development of early-onset type 2 diabetes in Pima Indians.The coding regions of the known MODY genes hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, HNF-1beta, and insulin promoter factor 1 and the coding regions of two MODY candidate genes, HNF-3beta and the dimerization cofactor of HNF-1, were sequenced in genomic DNA from Pima Indians. The primary "affected" study population consisted of 46 Pima Indians whose age at onset of type 2 diabetes was < or =20 years. DNA sequence variants identified in the affected group were then analyzed in a group of 80 "unaffected" Pima Indians who were at least 40 years old and had normal glucose tolerance.A total of 11 polymorphisms were detected in these genes. However, none of the polymorphisms differed in frequency among Pima Indians with an early age at onset of diabetes compared with older Pima Indians with normal glucose tolerance.Mutations in these known MODY or MODY candidate genes are not a common cause of early-onset diabetes in Pima Indians.
Hepatic transmethylation reactions in micropigs with alcoholic liver disease
Authors: Jesus A. Villanueva, Charles H. Halsted
Journal: Hepatology (2004)

Alcoholic liver disease is associated with abnormal hepatic methionine metabolism, including increased levels of homocysteine and S-adenosylhomocysteine (SAH) and reduced levels of S-adenosylmethionine (SAM) and glutathione (GSH). The concept that abnormal methionine metabolism is involved in the pathogenesis of alcoholic liver disease was strengthened by our previous findings in a micropig model where combining dietary folate deficiency with chronic ethanol feeding produced maximal changes in these metabolites together with early onset of microscopic steatohepatitis and an eightfold increase in plasma aspartate aminotransferase. The goal of the present study was to determine potential mechanisms for abnormal levels of these methionine metabolites by analyzing the transcripts and activities of transmethylation enzymes in the livers of the same micropigs. Ethanol feeding or folate deficiency, separately or in combination, decreased transcript levels of methylenetetrahydrofolate reductase (MTHFR), methionine adenosyltransferase (MAT1A), glycine-N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase (SAHH). Ethanol feeding alone reduced the activities of methionine synthase (MS) and MATIII and increased the activity of GNMT. Each diet, separately or in combination, decreased the activities of MTHFR and SAHH. In conclusion, the observed abnormal levels of methionine metabolites in this animal model of accelerated alcoholic liver injury can be ascribed to specific effects of ethanol with or without folate deficiency on the expressions and activities of hepatic enzymes that regulate transmethylation reactions. These novel effects on transmethylation reactions may be implicated in the pathogenesis of alcoholic liver disease.
Impact of Classification of Hilar Cholangiocarcinomas (Klatskin Tumors) on the Incidence of Intra- and Extrahepatic Cholangiocarcinoma in the United States
Authors: Tania M. Welzel, Katherine A. McGlynn, Ann W. Hsing, Thomas R. O'Brien, Ruth M. Pfeiffer
Journal: JNCI Journal of the National Cancer Institute (2006)

Cholangiocarcinomas are topographically categorized as intrahepatic or extrahepatic by the International Classification of Diseases for Oncology (ICD-O). Although hilar cholangiocarcinomas (Klatskin tumors) are extrahepatic cholangiocarcinomas, the second edition of the ICD-O (ICD-O-2) assigned them a histology code 8162/3, Klatskin, which was cross-referenced to intrahepatic cholangiocarcinoma. Recent studies in the United States that included this code (8162/3, Klatskin) with intrahepatic cholangiocarcinoma reported an increasing incidence of intrahepatic cholangiocarcinoma and a decreasing incidence of extrahepatic cholangiocarcinoma. To investigate the impact of this misclassification on site-specific cholangiocarcinoma incidence rates, we calculated annual percent changes (APCs) with data from the Surveillance, Epidemiology, and End Results (SEER) program using a Poisson regression model that was age-adjusted to the year 2000 U.S. population. All statistical tests were two-sided. During 1992-2000, when SEER used ICD-O-2, 1710 intrahepatic cholangiocarcinomas, 1371 extrahepatic cholangiocarcinomas, and 269 hilar cholangiocarcinomas identified by code 8162/3, Klatskin were diagnosed. Ninety-one percent (246 of 269) of the hilar cholangiocarcinomas were incorrectly coded as intrahepatic cholangiocarcinomas, resulting in an overestimation of intrahepatic cholangiocarcinoma incidence by 13% and underestimation of extrahepatic cholangiocarcinomas incidence by 15%. However, even after the exclusion of tumors that were coded to the histology code 8162/3, Klatskin, age-adjusted annual intrahepatic cholangiocarcinoma incidence increased during this period (APC = 4%, 95% confidence interval = 2% to 6%, P<.001).
Protecting endothelial function: A novel therapeutic target of ATP-sensitive potassium channel openers
Authors: T MINAMINO, M HORI
Journal: Cardiovascular Research (2006)

See article by Wang et al.  [7]  (pages 497–503) in this issue .

Endothelial dysfunction is commonly observed in patients with hypertension, type II diabetes mellitus, and hypercholesteremia and is considered to be an early event in the changes accompanying atherosclerosis [1,2]. Disruption of normal endothelial function leads to loss of vasomotor control, reduced production of nitric oxide (NO), formation of a procoagulant surface, and promotion of inflammation [1,2]. These events may lead to destabilization of atherosclerotic plaques and could cause acute coronary syndrome. Indeed, recent clinical studies have demonstrated that endothelial dysfunction is a predictor for the development of cardiovascular events [3,4].

Endothelial cells express a diverse array of ion channels which play important roles in modulating cell function [5]. Since Noma first identified ATP-sensitive potassium (KATP) channels in cardiac myocytes, the physiological roles of KATP channels have been extensively studied in cardiac muscle and other tissues [5,6]. Endothelial KATP channels contribute to maintaining the resting membrane potential. In addition, they also regulate intracellular Ca2+ levels that affect the production and release of endothelial autacoids, … 

*Corresponding author. Tel.: +81 6 6879 3635; fax: +81 6 6879 3634. Email address: mhori{at}medone.med.osaka-u.ac.jp
H-2-controlled suppression of T cell response to lactate dehydrogenase B. Characterization of the lactate dehydrogenase B suppressor pathway.
Authors: C N Baxevanis, N Ishii, Z A Nagy, J Klein
Journal: The Journal of Experimental Medicine (1982)

We characterized the cell types involved in the H-2-controlled suppression of T cell response to lactate dehydrogenase B (LDHB). The suppressor effector (Tse) was found to be an Lyt-1+2+, J+ cell that recognizes antigen together with Ek molecules of antigen-presenting cells (APC). To become functional, the Tse cell requires a second signal from a nonspecific, Lyt-1+2-, J+ suppressor-inducer (Tsi) cell. The Tsi-Tse interaction is not subject to any genetic restriction. The target cell of suppression is an Lyt-1+2-, J- (most likely T helper [Th]) cell that recognizes LDHB in the context of A molecules on APC. The suppression is manifested in inhibition of the antigen-specific, A-restricted proliferation of Th cells. The interaction between Tse and Th is restricted by the A region of the H-2 complex. Because this restriction is determined by the receptor of Th cells, the mechanism of Th-Tse interaction most likely involves a concomitant recognition of LDHB and A region-controlled molecules by Th cells on the surface of Tse cells.