The intercellular adhesion molecule-1 K469E polymorphism in type 1 diabetes

Type 1 (insulin-dependent) diabetes is a complex trait. The region harboring the ICAM1 gene on 19p13 links to type 1 diabetes, and a growing body of evidence indicates that intercellular adhesion molecule-1 (ICAM-1) could play a role in type 1 diabetes development. Recently, association studies of an ICAM-1 K469E polymorphism in type 1 diabetes populations have reported conflicting results. Hence, we performed a transmission disequilibrium test analysis of the ICAM-1 K469E variations in 253 Danish type 1 diabetes families. Linkage and association was not found between the ICAM-1 K469E variation and type 1 diabetes in Danish patients (P(tdt)> or =0.48), and our data did not indicate an interaction between ICAM1 and IDDM1 in predisposition to type 1 diabetes in Danes (P=0.78). We did not observe significant association with late-onset type 1 diabetes (P(tdt)> or =0.12) or differences in transmission patterns between groups of affected offspring stratified for age at onset (P> or =0.19), as suggested in Japanese patients. Combined analysis of the present and previously reported transmission data comprising 728 affected offspring of Romanian, Finnish, and Danish ancestry suggested association between the ICAM-1 E469 allele and type 1 diabetes (P(tdt)=0.013), but association was not found in the combined Scandinavian material. In conclusion, we found no association of the ICAM-1 K469E polymorphism with type 1 diabetes or its subsets stratified for age at onset and HLA risk in Danish patients. Analysis of ICAM-1 K469E transmissions reported in three populations suggested association to type 1 diabetes, but also demonstrated heterogeneity between populations.     

海洋生物制药现状及展望

现代生物技术在制药产业中发挥了重要作用,海洋生物技术的出现和发展推动了海洋生 物药物的研究,是今后生物技术药物的发展方向。综述了生物技术在海洋药物开发中的应用,并 展望了新世纪海洋生物制药的前景。     

Candidate Luminal B Breast Cancer Genes Identified by Genome,Gene Expression and DNA Methylation Profiling

Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.     

Search for the possible role of ‘immunotherapy’ in operable bronchial non-small cell carcinoma (stage I and II): A phase I study with Corynebacterium parvum intrapleurally

Summary The possibility of giving C. parvum intrapleurally (i.p.) was investigated. C. parvum was given post-operatively either i.p. only or i.p. and intravenously (i.v.) simultaneously. The dose varied from 0.1–10 mg i.p. All patients had been operated for a bronchial carcinoma. Results: (1) Subjective complaints of either dyspnoea, thoracic pain, chills or nausea occured in 31 of 63 patients. No clear dose relation was found. A feeling of discomfort and fever could occur for another 3–4 days after the above more acute symptoms had disappeared. (2) Increased fever (0.5° C) occurred in 71% of the patients injected i.p. only. (3) No anaphylactic reaction was observed. (4) Increased total white blood cell counts (<20%) occurred in 38 patients. The WBC increase was mainly due to higher number of neutrocytes and granulocytes. Total lymphocyte, monocyte, eosinophilic, and basophilic granulocytes values per mm³ circulating blood remained unchanged, except at the dose of 7 mg C. parvum i.p. when monocyte values were increased significantly from 576±247 to 1100±578/mm³. (5) Moderate to severe effusions were observed radiologically in three patients after C. parvum intrapleurally.The study group is: M. Kaufmann, J. Stjernswärd (Ludwig Institut for Cancer Research, Lausanne Branch, Switzerland), M. Zelen, K. Stanley (Frontier Science and Technology Research Foundation, Inc. Amherst, New York, USA), D. S. Freestone, R. Bomford, M. T. Scott, T. Priestman (The Wellcome Research Laboratory, Beckenham, England), C. Mouritzen, G. Ahlbom (Dept. of Thoracic and Cardiovascular Surgery, Aarhus Kommunehospital, Aarhus, Denmark), N. Konietzko, D. Greschuchna (Ruhrland Klinic, Essen-Haidhausen, Germany), P. Hilgard (Innere Klinik und Poliklinik [Tumorforschung] Essen, Germany), J. Vogt-Moykopf, D. Zeidler, H. Toomes (Thoraxchirurgische Spezial-Klinik, Heidelberg-Rohrbach, Germany), F. Krause, R. Rios (Thoraxchirurgische Abt., Fachkrankenhaus für Lungen- und Bronchialerkrankungen, Löwenstein, Germany), J. Orel, M. Benedik, B. Hrabar (Clinical Center, Dept. of Thoracic Surgery, Ljubljana, Yugoslavia), S. Plesnicar (The Institute of Oncology, Ljubljana, Yugoslavia), H. A. Rostad, J. R. Vale (Rikshospital, Oslo, Norway), S. Hagen, S. Birkeland, (Ulleval Hospital, Oslo, Norway), T. Harbitz, R. Nissen-Meyer (Aker Hospital, Oslo, Norway), L. Rodriguez, V. O. Björk, K. Böök (Karolinska Sjukhuset, Thoracic Clinic, Stockholm, Sweden), E. Gradel, J. Hasse, P. Holbro (Kantonsspital, Thoraxchirurgische Klinik, Basel, Switzerland), L. Eckmann (Tiefenauspital, Chir. Univ.-Klinik, Bern, Switzerland), B. Nachbur, T. Liechti (Inselspital, Dept. of Thoracic and Cardiovascular Surgery, Bern, Switzerland), H. Cottier (Inst. of Pathology, Inselspital, Bern, Switzerland), W. Maurer, M. Kaufmann, P. Froelicher (Bürgerspital, Surgical Dept., Solothurn, Switzerland), H. Denck, N. Pridun (Krankenhaus der Stadt Wien-Lainz, Chir. Abt., Vienna, Austria), K. Karrer (Institute for Cancer Research, University of Vienna, Austria) Reprint requests should be addressed to any of the members listed above, or to the Ludwig Lung Cancer Trial, Operation Office, LICR, CH-1066 Epalinges, Switzerland. (For Current Contents, etc., please use above address)     

Human Leukocyte Antigen Class I Supertypes and HIV-1 Control in African Americans

The role of human leukocyte antigen (HLA) class I supertypes in controlling human immunodeficiency virus type 1 (HIV-1) infection in African Americans has not been established. We examined the effects of the HLA-A and HLA-B alleles and supertypes on the outcomes of HIV-1 clade B infection among 338 African American women and adolescents. HLA-B58 and -B62 supertypes (B58s and B62s) were associated with favorable HIV-1 disease control (proportional odds ratio [POR] of 0.33 and 95% confidence interval [95% CI] of 0.21 to 0.52 for the former and POR of 0.26 and 95% CI of 0.09 to 0.73 for the latter); B7s and B44s were associated with unfavorable disease control (POR of 2.39 and 95% CI of 1.54 to 3.73 for the former and POR of 1.63 and 95% CI of 1.08 to 2.47 for the latter). In general, individual alleles within specific B supertypes exerted relatively homogeneous effects. A notable exception was B27s, whose protective influence (POR, 0.58; 95% CI, 0.35 to 0.94) was masked by the opposing effect of its member allele B*1510. The associations of most B supertypes (e.g., B58s and B7s) were largely explained either by well-known effects of constituent B alleles or by effects of previously unimplicated B alleles aggregated into a particular supertype (e.g., B44s and B62s). A higher frequency of HLA-B genotypic supertypes correlated with a higher mean viral load (VL) and lower mean CD4 count (Pearson''s r = 0.63 and 0.62, respectively; P = 0.03). Among the genotypic supertypes, B58s and its member allele B*57 contributed disproportionately to the explainable VL variation. The study demonstrated the dominant role of HLA-B supertypes in HIV-1 clade B-infected African Americans and further dissected the contributions of individual class I alleles and their population frequencies to the supertype effects.African Americans in the United States have been affected disproportionately by the human immunodeficiency virus type 1 (HIV-1) epidemic. They accounted for only 13% of the U.S. population but for 47% of AIDS cases diagnosed in the United States in 2006 (14, 17). An HIV-1 vaccine would be of enormous benefit to this subpopulation. One strategy for HIV-1 vaccine development seeks to capitalize on the recognition and destruction of HIV-1-infected cells by cytotoxic T lymphocytes (CTLs) (32, 33, 35).CTL recognition is critically dependent on binding, presentation, and cell surface display of a variety of antigenic peptides (epitopes) by extremely polymorphic human leukocyte antigen (HLA) molecules. As the relative importance of increasing numbers of HIV-1 epitopes for individual HLA class I molecules has been recognized (9, 16), the feasibility of developing a vaccine tailored to every epitope and HLA specificity has come to seem more remote. Conceptualization of epitope specificity in terms of broad groupings (supertypes) of HLA molecules may provide a rational but simpler approach to this challenge.Several efforts have succeeded at consolidating the huge spectrum of individual HLA class I alleles into four HLA-A and five HLA-B supertype categories (37-39), based on the ability of different HLA class I molecules to present similar epitopes. Unlike individual allele frequencies, which vary greatly across ethnic groups, all nine supertypes (comprising most, but not all, HLA-A and HLA-B alleles) are present in all human populations. This more uniform representation of allele groups may confer an advantage in the form of balancing selection (38).HLA alleles within one supertype that share epitope binding specificities might be expected to demonstrate similar associations with HIV-1 outcomes or vaccine response; conversely, alleles within a supertype that differ substantially in function might be expected to show differential responses to natural infection or vaccines designed on the basis of supertype (2). Functional heterogeneity of alleles within the supertypes could be due to differences in the class I alleles themselves (e.g., variable epitope avidity or tolerance to viral mutations), in host background (genetic epistasis), or in the virus (e.g., clade-related epitope specificities or viral escape).Previous work has detected associations between the HLA class I supertypes and HIV-1 outcomes for Caucasians with clade B infections (34, 44) and for native Africans with clade A or C infections (23, 28). We are unaware of studies among African Americans in the context of clade B HIV-1 infection or of any systematic attempt to tease apart the independent contributions of supertypes and their individual class I alleles to HIV-1 outcomes. Here we document the frequencies of the HLA class I alleles and supertypes in the Reaching for Excellence in Adolescent Care and Health (REACH) and HIV Epidemiologic Research Study (HERS) cohorts, and we report the relative effects of those alleles and supertypes on the degree of HIV-1 disease control.     

Trends in Expanded-Spectrum Cephalosporin-Resistant Escherichia coli and Klebsiella pneumoniae among Dutch Clinical Isolates,from 2008 to 2012

We investigated time trends in extended-spectrum cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates from different patient settings in The Netherlands from 2008–2012. E. coli and K. pneumoniae isolates from blood and urine samples of patients > = 18 years were selected from the Dutch Infectious Disease Surveillance System-Antimicrobial Resistance (ISIS-AR) database. We used multivariable Poisson regression to study the rate per year of blood stream infections by susceptible and resistant isolates, and generalized estimating equation (GEE) log-binomial regression for trends in the proportion of extended-spectrum cephalosporin-resistant isolates. Susceptibility data of 197,513 E. coli and 38,244 K. pneumoniae isolates were included. The proportion of extended-spectrum cephalosporin-resistant E. coli and K. pneumoniae isolates from urine and blood samples increased in all patient settings, except for K. pneumoniae isolates from patients admitted to intensive care units. For K. pneumoniae, there was a different time trend between various patient groups (p<0.01), with a significantly higher increase in extended-spectrum cephalosporin-resistant isolates from patients attending a general practitioner than in isolates from hospitalized patients. For E. coli, the increasing time trends did not differ among different patient groups. This nationwide study shows a general increase in extended-spectrum cephalosporin-resistant E. coli and K. pneumoniae isolates. However, differences in trends between E. coli en K. pneumoniae underline the importance of E. coli as a community-pathogen and its subsequent influence on hospital resistance level, while for K. pneumoniae the level of resistance within the hospital seems less influenced by the resistance trends in the community.     

Withholding the artificial administration of fluids and food from elderly patients with dementia: ethnographic study

ObjectiveTo clarify the practice of withholding the artificial administration of fluids and food from elderly patients with dementia in nursing homes.DesignQualitative, ethnographic study in two phases.Setting10 wards in two nursing homes in the Netherlands.Participants35 patients with dementia, eight doctors, 43 nurses, and 32 families.ResultsThe clinical course of dementia was considered normal and was rarely reason to begin the artificial administration of fluids and food in advanced disease. Fluids and food seemed to be given mainly when there was an acute illness or a condition that needed medical treatment and which required hydration to be effective. The medical condition of the patient, the wishes of the family, and the interpretations of the patients'' quality of life by their care providers were considered more important than living wills and policy agreements.ConclusionsDoctors'' decisions about withholding the artificial administration of fluids and food from elderly patients with dementia are influenced more by the clinical course of the illness, the presumed quality of life of the patient, and the patient''s medical condition than they are by advanced planning of care. In an attempt to understand the wishes of the patient doctors try to create the broadest possible basis for the decision making process and its outcome, mainly by involving the family.

What is already known on this topic

Debate has focused on whether it is beneficial to withhold the artificial administration of fluids and food from patients with advanced dementia

What this study adds

The course of dementia, the patient''s quality of life, and the patient''s current medical condition influence doctors'' decision making more than advanced planning of careDoctors try to create the broadest possible basis for the decision making process and its outcome, mainly by involving the family