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PubMed2000

Oral or topical nasal steroids for hearing loss associated with otitis media with effusion in children.

BACKGROUND: OME is common and may cause hearing loss with associated developmental delay. Treatment remains controversial. The effect of both systemic and intra-nasal steroids on effusions has been assessed by randomised controlled trials. OBJECTIVES: To examine evidence for or against treating children with hearing loss associated with OME with systemic or topical nasal steroids. SEARCH STRATEGY: Searches were conducted in February 2000. We searched the Cochrane Controlled Trials Register using the terms 'otitis-media', 'otitis media with effusion', 'glue ear', or 'OME', and 'steroids', 'glucocorticoids, synthetic', 'glucocorticoids, topical', 'anti-inflammatory agents, steroidal'. EMBASE and MEDLINE were also searched for additional information. SELECTION CRITERIA: Randomised controlled trials of oral and topical nasal steroids, either alone or in combination with another agent such as an antibiotic, were included. EXCLUSIONS: publications in abstract form only since adequate appraisal was not possible; uncontrolled, non-randomised or retrospective studies; studies reporting outcomes with ears (rather than children) as the unit of analysis. DATA COLLECTION AND ANALYSIS: Data were extracted from the published reports by the two authors independently (CCB and JH van der V) using standardised data extraction forms and methodology. The methodological quality of the included studies were independently assessed by the two authors using the scheme described in the Cochrane Handbook. Dichotomous results were expressed as an odds ratio using a fixed effects model together with the 95% confidence intervals. Continuous data were analysed using the weighted mean difference in a fixed effects model. Tests for heterogeneity between studies were performed using a Mantel-Haenszel approach. In trials with a cross over design, post-crossover treatment data were not used. MAIN RESULTS: No study prospectively documented hearing loss associated with OME prior to randomisation. Follow up was short term. No serious or lasting side effects were reported in the four studies that did mention side effects. Most comparisons involved small numbers of subjects. The odds ratio for OME persisting after short term follow up for children treated with oral steroids plus antibiotic compared to control plus antibiotic was 0.32 (95% CI 0.20 to 0.52). However there was significant heterogeneity between studies (p<0.01). Trends favoured steroids for most other comparisons, but confidence intervals included unity. There was no evidence of benefit for steroid treatment in the longer term, and no study assessed effect of steroid treatment on language development. REVIEWER'S CONCLUSIONS: There is evidence that steroids combined with an antibiotic lead to a quicker resolution of OME in the short term. However, there is not evidence for long term benefit from treating hearing loss associated with OME with either oral or topical nasal steroids. These treatments are therefore not recommended at the present time. Future studies should document hearing loss associated with OME before the start of study treatment. Follow up should be longer and ideally include symptom, audiometry and developmental outcomes. Data should not be presented with ears as the unit of analysis.

Administration, Intranasal↗
PubMed2002

-463 G/A myeloperoxidase promoter polymorphism is associated with clinical manifestations and the course of disease in MPO-ANCA-associated vasculitis.

Wegener's granulomatosis, microscopic polyangiitis, and Churg Strauss syndrome are forms of systemic vasculitides in which neutrophils and monocyte macrophages infiltrate the walls of small blood vessels, leading to destruction and occlusion. These diseases are associated with autoantibodies directed against granular components of neutrophils and monocytes, i.e., antineutrophil cytoplasmic antibodies (ANCA). The most common target antigens of ANCA in these vasculitides are myeloperoxidase (MPO) and proteinase 3 (PR3). ANCA-stimulated neutrophils injure endothelial cells, a process that is dependent upon the production of reactive oxygen radicals and the release of granular components such as MPO and PR3. Here we investigate whether a common functional MPO promoter polymorphism (-463 G/A) is associated with increased incidence and clinical aspects of ANCA-associated small vessel vasculitis. Genotyping was carried out for 142 patients with ANCA-associated small vessel vasculitis and 129 ethnically matched controls. The GG genotype was found to be associated with an increased risk for MPO-ANCA-associated vasculitis in females (86% GG, P = 0.045), but not males (64% GG, P = 1.0). Interestingly, the MPO A allele is associated with an increased incidence of relapses (P = 0.012) and an earlier age at diagnosis (P = 0.03) of MPO-ANCA-associated vasculitis. Both these associations are specific for MPO-ANCA and are not observed in patients with PR3-ANCA-associated vasculitis. These findings suggest that MPO expression levels influence the disease course of MPO-ANCA-associated vasculitis and further support the view that genetic factors are involved in the pathophysiology of this autoimmune disease.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2001

Protein-protein association: investigation of factors influencing association rates by brownian dynamics simulations.

The rate of protein-protein association limits the response time due to protein-protein interactions. The bimolecular association rate may be diffusion-controlled or influenced, and in such cases, Brownian dynamics simulations of protein-protein diffusional association may be used to compute association rates. Here, we report Brownian dynamics simulations of the diffusional association of five different protein-protein pairs: barnase and barstar, acetylcholinesterase and fasciculin-2, cytochrome c peroxidase and cytochrome c, the HyHEL-5 antibody and hen egg lysozyme (HEL), and the HyHEL-10 antibody and HEL. The same protocol was used to compute the diffusional association rates for all the protein pairs in order to assess, by comparison to experimentally measured rates, whether the association of these proteins can be explained solely on the basis of diffusional encounter. The simulation protocol is similar to those previously derived for simulation of the association of barnase and barstar, and of acetylcholinesterase and fasciculin-2; these produced results in excellent agreement with experimental data for these protein pairs, with changes in association rate due to mutations reproduced within the limits of expected computational and modeling errors. Here, we find that for all protein pairs, the effects of mutations can be well reproduced by the simulations, even though the degree of the electrostatic translational and orientational steering varies widely between the cases. However, the absolute values of association rates for the acetylcholinesterase: fasciculin-2 and HyHEL-10 antibody: HEL pairs are overestimated. Comparison of bound and unbound protein structures shows that this may be due to gating resulting from protein flexibility in some of the proteins. This may lower the association rates compared to their bimolecular diffusional encounter rates.

Acetylcholinesterase↗
PubMed2005

Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.

Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P=.001) and PADI4 (PADI4_94, OR 1.24; P=.001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P=.0006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P=.004) and that PTPN22 has a stronger effect in males than in females (P=.03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.

Adult↗
PubMed2005

ADH4 gene variation is associated with alcohol and drug dependence: results from family controlled and population-structured association studies.

We found strong associations between ADH4 gene variation and alcohol and drug dependence by the Hardy-Weinberg Disequilibrium (HWD) test and case-control association analysis in an initial study. The present study aimed to confirm these findings by controlling for population stratification and admixture effects to which the HWD test and case-control association methods may be vulnerable. In addition to 365 unrelated healthy controls and 560 unrelated cases in the initial study, we evaluated 104 small nuclear families with affected offspring who had diagnoses of alcohol and/or drug dependence. Seven single nucleotide polymorphisms (SNPs) at the ADH4 gene locus were genotyped in all subjects, and 38 unlinked ancestry-informative markers were also genotyped in unrelated cases and controls. Structured association analysis demonstrated that the genotypes of six ADH4 markers were associated with alcohol dependence, and all seven ADH4 markers were associated with drug dependence (P=10-0.047). Logistic regression analysis showed that: (i) the genotypes of SNP2 (rs1042363) were significantly associated with alcohol dependence and drug dependence (mainly cocaine dependence), and the genotypes of SNP3 (rs1126671) were also significantly associated with alcohol dependence and (ii) one seven-variant haplotype and one diplotype were significantly associated with alcohol dependence and other seven-variant diplotypes were significantly associated with drug dependence (including cocaine and opioid dependence). Transmission disequilibrium test, haplotype-based haplotype relative risk and genotype-based haplotype relative risk analyses all confirmed the association of the ADH4 markers with alcohol dependence and drug dependence. Using rigorous study designs that account for possible population stratification, these findings confirm and extend our original observations indicating that variation at ADH4 predisposes to alcohol and drug dependence.

Adult↗
PubMed2006

Incidence and risk factors of rash associated with efavirenz in HIV-infected patients with preceding nevirapine-associated rash.

OBJECTIVE: To determine the incidence and risk factors of rash associated with efavirenz in HIV-infected patients with preceding nevirapine-associated rash. METHODS: A retrospective cohort study was conducted in HIV-infected patients diagnosed with nevirapine-associated rash who subsequently received efavirenz between July 2003 and January 2005. Patients were followed up for 3 months after receiving efavirenz. Possible risk factors, including demographics, previous opportunistic infections, CD4 cell count, viral load, severity of nevirapine-associated rash and concurrent drugs, were studied and compared between those who had (group A) and did not have (group B) rash associated with efavirenz. RESULTS: A total of 122 patients (52.5% male) were included in the study, with a mean age of 38.2 years. Median (and interquartile range) CD4 cell count and viral load were 55 (20-167) cells/microL and 86,150 (35,321-700,750) HIV-1 RNA copies/mL, respectively. Of the 122 patients, 10 (8.2%) developed rash associated with efavirenz and all required discontinuation of efavirenz. The baseline characteristics of group A (10 patients) and group B (112 patients) were similar. Median (and interquartile range) time from nevirapine discontinuation to efavirenz initiation was 12 (9-21) days in group A and 11 (7-21) days in group B (P=0.765). None of the risk factors investigated was associated with developing rash associated with efavirenz. The preceding development of severe nevirapine-associated rash had a trend towards a higher rate in group A than in group B (20.0% vs 10.7%; odds ratio=2.08; 95% confidence interval 0.39-10.97; P=0.322). CONCLUSIONS: The majority (>90%) of HIV-infected patients with CD4 counts <200 cells/muL who had preceding nevirapine-associated rash could tolerate efavirenz well. Efavirenz may be an option for subsequent use in these patients, particularly in those who had preceding nevirapine-associated rash.

Adult↗
PubMed2003

Comparison of Shiga toxin production by hemolytic-uremic syndrome-associated and bovine-associated Shiga toxin-producing Escherichia coli isolates.

There is considerable diversity among Shiga toxin (Stx)-producing Escherichia coli (STEC) bacteria, and only a subset of these organisms are thought to be human pathogens. The characteristics that distinguish STEC bacteria that give rise to human disease are not well understood. Stxs, the principal virulence determinants of STEC, are thought to account for hemolytic-uremic syndrome (HUS), a severe clinical consequence of STEC infection. Stxs are typically bacteriophage encoded, and their production has been shown to be enhanced by prophage-inducing agents such as mitomycin C in a limited number of clinical STEC isolates. Low iron concentrations also enhance Stx production by some clinical isolates; however, little is known regarding whether and to what extent these stimuli regulate Stx production by STEC associated with cattle, the principal environmental reservoir of STEC. In this study, we investigated whether toxin production differed between HUS- and bovine-associated STEC strains. Basal production of Stx by HUS-associated STEC exceeded that of bovine-associated STEC. In addition, following mitomycin C treatment, Stx2 production by HUS-associated STEC was significantly greater than that by bovine-associated STEC. Unexpectedly, mitomycin C treatment had a minimal effect on Stx1 production by both HUS- and bovine-associated STEC. However, Stx1 production was induced by growth in low-iron medium, and induction was more marked for HUS-associated STEC than for bovine-associated STEC. These observations reveal that disease-associated and bovine-associated STEC bacteria differ in their basal and inducible Stx production characteristics.

Animals↗
PubMed1999

Priming in a free association task as a function of association directionality.

Two experiments investigated priming in free association, a conceptual implicit memory task. The stimuli consisted of bidirectionally associated word pairs (e.g., BEACH-SAND) and unidirectionally associated word pairs that have no association from the target response back to the stimulus cue (e.g., BONE-DOG). In the study phase, target words (e.g., SAND, DOG) were presented in an incidental learning task. In the test phase, participants generated an associate to the stimulus cues (e.g., BEACH, BONE). In both experiments, priming was obtained for targets (e.g., SAND) that had an association back to the cue, but not for targets (e.g., DOG) for which such a backward association was absent. These results are problematic for theoretical accounts that attribute priming in free association to the strengthening of target responses. It is argued that priming in free association depends on the strengthening of cue-target associations.

Adult↗
PubMed2005

Associating unseen events: semantically mediated formation of episodic associations.

In prior work, we developed a computational model of how episodic associations between words are formed. Simulating associative learning, the model indicated that strongly associated semantically unrelated words facilitate the episodic association of other exemplars included in their semantic neighborhoods. This prediction was supported empirically by the present study. First, the incidental formation of strong associations between unrelated words, such as dog and table, improved cued recall of weak associations formed incidentally between semantic neighbors, like cat and chair. Second, deciding that two words were semantically unrelated was facilitated by forming strong associations between other words in their respective semantic neighborhoods, even if the tested pair was not presented at study. Together with the computational model, the present results demonstrate that forming episodic associations between words can implicitly mediate the association of other exemplars from the same semantic categories and reveal a mechanism by which the semantic system contributes to the formation of new episodic associations.

Adolescent↗
PubMed2006

Spondylarthritis-associated and non-spondylarthritis-associated B27 subtypes differ in their dependence upon tapasin for surface expression and their incorporation into the peptide loading complex.

OBJECTIVE: B27 subtypes associated with susceptibility to ankylosing spondylitis (AS), and those reported not to be associated with AS, are found to differ in the amino acids that are known in other HLA class I molecules to alter the requirements for tapasin and incorporation into the peptide loading complex. The purpose of this study was to examine the behavior of B*2704 and B*2705 in comparison with B*2706 and B*2709 during early events in HLA class I antigen expression, and determine if their behavior correlates with disease association. METHODS: Cell lines with nonfunctional tapasin were transiently transfected with different B27 subtypes and their site-directed mutants, and surface expression analyzed by flow cytometry. The association with the peptide loading complex was determined by immunoprecipitation of heterodimeric transporter-associated peptide and analysis of coprecipitated B27. RESULTS: Amino acids at positions 114, 116, and 152 in the different B27 subtypes were shown to perform key roles in defining a requirement for interaction with tapasin. Not all disease-associated alleles were expressed optimally in the absence of tapasin; furthermore, dependence on tapasin for cell surface expression did not correlate with disease association. Although B*2706, which is not associated with disease, exhibited a number of properties different from those of the disease-associated subtypes, these properties were not displayed by the non-disease-associated allele B*2709. CONCLUSION: These results indicate that the ability to exhibit optimal cell surface expression in the absence of tapasin is not a prerequisite for susceptibility to AS.

Antiporters↗
PubMed1978

Patterns of association in the human metaphase complement: ring analysis and estimation of associativity of specific chromosome regions.

The pattern of metaphase chromosome association in the human complement was studied by two methods of statistical analysis of interchromosomal distances. Those methods included ring analysis in which a characteristic position of the centromere of each chromosome relative to the center of a two dimensional representation of a metaphase complement was defined, and estimation of the capacity for associativity of each of three regions of each chromosome: the centromere (c) and the ends of each arm (p, q). The following information was obtained: 1. In general, the distance from the center is directly related to chromosome size. 2. The most notable deviation from that size-related progression is displayed by the X chromosomes. The markedly peripheral position of the X is characteristic of both X's of the female and the single X of the male. 3. The relative associativity of each chromosome of the complement is, in general, inversely related to size with an additional preferential capacity of associativity displayed by the acrocentric chromosomes. Analyses of the different inter-regional classes established that the supplementary associativity factor of the acrocentric chromosomes was inherent in their pericentromeric and p-arm regions and excluded the ends of the q arms from participation in that factor. 4. Those analyses demonstrated that the specific morphology or 'geometry' of the acrocentric chromosomes contributes little to their high relative associativity. In addition to the tendency for the c/p regions of the acrocentric chromosomes to associate with each other, presumably because of their common function in nucleolar organization, those regions also displayed a propensity to associate with the distal regions of the arms of other chromosomes. A molecular basis for that propensity other than that of ribosomal DNA is postulated to be that of other fractions of highly reiterated DNA sequences. 5. Analysis of the relative associativities of each of the three regions of the Y chromosome revealed that the Yq displays a much stronger capacity to associate with the c's of other chromosomes than does the Yc or Yp.

Adult↗
PubMed2005

Effects of blockade of glutamate NMDA receptors or of NO synthase on the development or the expression of associative or non-associative sensitization to locomotor activation by morphine.

The sensitization to the pharmacological actions of morphine is probably a critical factor in the addictive properties of this drug. A discrimination between associative and non-associative type of sensitization might be relevant for possible differences in drug effects on sensitization phenomena. Furthermore, blockade of NMDA receptors might lead to an inhibition of NO-synthesis, and, accordingly, both of these effects might influence sensitization phenomena in a similar way. Male Wistar rats were sensitized to morphine by administrations of 3 mg/kg of morphine i.p. on day 1, 3, 5, and 7 and saline on days 2, 4, and 6. In part of the animals, the administration of morphine was performed in association with conditional stimuli, CS (test cage plus an auditory and an olfactory stimulus), in the other part not (pseudoconditioned, PCS). On day 17, the sensitization was more pronounced in the CS than the PCS group. The effects of dizocilpine (MK-801; 0.1 mg/kg i.p.), a blocker of NMDA glutamate receptors, or of L-NAME (N(G)-nitro-L-arginine methylester; 10 mg/kg i.p.), a non-specific inhibitor of NO synthase and the effect of N(omega)-propyl-L-arginine (20 mg/kg i.p.), a specific inhibitor of neuronal NO synthase, on expression or development of sensitization to morphine was studied. Neither MK-801 nor L-NAME influenced the development of associative and non-associative behavioural sensitization to morphine. The expression of sensitization to morphine was not influenced by MK-801. L-NAME inhibited the expression of associative, but not of non-associative sensitization. Surprisingly, inhibition of neuronal NO synthase, did not influence the expression of associative sensitization. We suggest that NMDA receptors were not involved in development or expression of both types of sensitization. Furthermore, the manifestation of the associative, but not the non-associative sensitization to morphine appeared to be dependent on a type of NO synthase, which is not the neuronal NO synthase, but probably the inducible NOS.

Animals↗
PubMed2006

The effect of assortative mating upon genetic association studies: spurious associations and population substructure in the absence of admixture.

Spurious associations due to confounding factors are an often cited and intensely debated concern for genetic association studies. Great attention has been focused upon the specific threat of confounding due to population stratification. This emphasis has spurred the development of many statistical genetic methods to detect and correct for the potentially confounding effects of admixture. Unfortunately, this emphasis on admixture has led some authors to suggest that if ethnically homogenous populations are used, spurious associations are unlikely to occur. We show that under small and realistic degrees of assortative mating over time, spurious associations arise even in ethnically homogeneous populations. We demonstrate that structured association and genomic control tests can, under certain conditions, correct for these spurious associations. We conclude that investigators should not assume spurious associations will not occur in association studies using ethnically homogenous populations and recommend the use of genomic control methods and/or family-based association tests within genetic association studies.

Chromosome Mapping↗
PubMed2026

Differential impacts of exon 1-associated and exon 11-associated variants of the rat mu opioid receptor gene, Oprm1, on buprenorphine- and morphine-induced analgesia and respiratory depression in male rats.

Buprenorphine has long been recognized as a mu opioid agonist with a distinctive and intricate pharmacological profile. It is a partial agonist at the mu opioid receptor, an antagonist at the kappa and delta opioid receptors, and an agonist at the nociception opioid receptor. Similar to other mu agonists such as morphine and fentanyl, buprenorphine can produce side effects, including tolerance, physical dependence, respiratory depression, and addiction. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, generating an array of splice variants or isoforms, which are conserved from rodents to humans. These splice variants can be categorized into 2 main types, exon 1 (E1)-associated variants and exon 11 (E11)-associated variants. E1-associated variants primarily consist of full-length, 7-transmembrane C-terminal variants, whereas E11-associated variants are typically truncated 6-transmembrane variants. Previous studies established that buprenorphine analgesia in mice is dependent on both E1- and E11-associated variants. However, the role of these variants in buprenorphine analgesia and respiratory depression in rats remains unclear. In this study, we used CRISPR/Cas9 technology to develop 2 rat Oprm1 gene-targeting models in which E1- and E11-associated variants were selectively disrupted, aiming to investigate their roles in buprenorphine and morphine's actions. The results showed that both E1- and E11-associated variants are essential for buprenorphine's analgesic and respiratory depressional effects in rats, whereas morphine's effects are solely attributed to the E1-associated variants. These findings provide new and important insights into the distinct contributions of the E1- and E11-associated variants to the pharmacological actions of buprenorphine and morphine. SIGNIFICANCE STATEMENT: Differential dependences of buprenorphine and morphine analgesia and respiratory depression on Oprm1 exon 1- and exon 11-associated variants revealed in rat gene-targeting models provide new and important insights into unique contributions of these variants to buprenorphine and morphine actions.

Animals↗
PubMed2005

Possible association of the human KCNE1 (minK) gene and QT interval in healthy subjects: evidence from association and linkage analyses in Israeli families.

QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h(2)= 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.

Adult↗
PubMed2000

Risk factors for hyperplasia-associated versus atrophy-associated endometrial carcinoma.

OBJECTIVE: Endometrial cancer can be divided into atrophy-associated and hyperplasia-associated subtypes. It has been suggested that these subtypes have different pathologic features and prognoses. This preliminary study explores whether these subtypes are associated with different risk factors. STUDY DESIGN: Hysterectomies performed in cases of endometrial carcinoma with evaluable benign endometrium on routine processing were reviewed, and clinical data were abstracted from medical records. Forty-eight subjects with atrophy-associated and 28 subjects with hyperplasia-associated cancers were studied. RESULTS: We found younger age, higher weight, absence of cigarette smoking, and earlier menarche in subjects with hyperplasia-related cancers. CONCLUSIONS: Our findings support the idea that hyperplasia-associated endometrial cancer is estrogen-related but also suggest that atrophy-associated cases may result from a different causal pathway. Epidemiologic studies may yield more precise and accurate measures of association if atrophy-associated and hyperplasia-associated endometrial cancers are considered separately.

Adenocarcinoma↗
PubMed2006

Community-associated strains of methicillin-resistant Staphylococccus aureus as the cause of healthcare-associated infection.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with community-associated infection have been described as strains genetically distinct from the strains isolated from patients with healthcare-associated infection. This study examines the hypothesis that community-associated MRSA (CA-MRSA) strains now cause serious infections in hospitalized patients. METHODS: Thirty-seven clinical MRSA isolates were randomly selected from blood isolates obtained from July 2003 through June 2004. Strains were tested for staphylococcal chromosomal cassette mec (SCCmec) type, pulsed-field gel electrophoresis (PFGE) type, and presence of Panton-Valentine leukocidin (PVL) genes. Medical records review and epidemiologic classification was performed by an investigator blinded to the results of the bacterial strain analysis. Episodes of bloodstream infection were independently classified as either community-associated or healthcare-associated infections, and bacterial isolates were independently classified as either CA-MRSA strains or healthcare-associated MRSA (HA-MRSA) strains, according to established definitions. SETTING: A tertiary care Veterans Affairs Medical Center. RESULTS: Twenty-four (65%) of 37 MRSA isolates were SCCmec type IV, a genetic type characteristic of CA-MRSA strains; 22 of these 24 isolates belonged to the CA-MRSA clone USA300 and carried PVL genes. Thirteen (35%) of the 37 strains were SCCmec type II, of which 12 were USA100-ST5 and 12 lacked PVL genes. Thirty patients (81%) had healthcare-associated infections; 18 (60%) of these 30 were infected with isolates carrying markers of CA-MRSA strains. Of 7 patients with CA-MRSA infections, 6 were infected with isolates belonging to the USA300 clone. Patients with healthcare-associated bloodstream infections were as likely to be infected with a CA-MRSA strain as patients with a community-associated infection (P = .38). CONCLUSIONS: MRSA strains with molecular characteristics of CA-MRSA strains have emerged as an important cause of serious healthcare-associated infection in our hospital.

Adult↗
PubMed1999

Association of a tetraspanin CD9 with CD5 on the T cell surface: role of particular transmembrane domains in the association.

CD9 is a member of the tetraspanin superfamily which is characterized by four transmembrane (TM) domains and associates with other surface molecules. This tetraspanin was recently found to be expressed on mature T cells. Here, we investigated which molecules associate with CD9 on T cells and which CD9 domains are required for the association. Immunoprecipitation of T cell lysates with anti-CD9 mAb followed by immunoblotting with mAb against various T cell molecules showed the association of CD9 with CD3, CD4, CD5, CD2, CD29 and CD44. Because association with CD5 was most prominent, we determined the role of CD9 TM or extracellular (EC) domains in the association with CD5. CD9 mutant genes lacking each domain were constructed and introduced into EL4 thymoma cells deficient in CD9 but expressing CD5. Among various types of stable EL4 transfectants, EL4 transfected with the mutant gene lacking TM domains (TM2/TM3) between two EC domains expressed a small amount of the relevant protein without showing association with CD5. CD9(-)CD5(-) monkey COS-7 cells transfected with this mutant gene and the CD5 gene expressed both transfected gene products, but the association of these was not detected. EL4 cells transfected with a CD9/CD81 chimera gene (the CD9 gene containing TM2/TM3 of CD81) expressed the chimeric protein on the cell surface and showed association with CD5. These results suggest an essential role of particular CD9 TM domains in the surface expression of the CD9 molecule as well as the association with CD5.

Animals↗