Molecular assessment of drug resistance in Plasmodium falciparum from Bahr El Gazal province, Sudan

AIMS: To assess resistance to chloroquine (CQ) and sulphadoxine/pyrimethamine (SP) in a Sudanese parasite population. METHODS: Recurrent security problems in Akuem, Sudan, prevented us from conducting a classical in vivo treatment efficacy study. Instead we genotyped key mutations in the chloroquine resistance transporter (pfcrt), the multidrug resistance gene (pfmdr1), dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). We genotyped the K76T mutation in pfcrt and the N86Y mutation in (pfmdr) by restriction digestion of fluorescent end-labelled polymerase chain reaction (PCR) products, while we genotyped codons 16, 51, 59, 108 and 164 in dhfr and codons 436, 437, 540, 581 and 613 in dhps by primer extension in 100 blood samples. RESULTS: Sixty-three percent of parasites carried the 76T mutation at pfcrt critical for CQ resistance, while 31% carried the 86Y mutation at pfmdr that is associated with, although not essential, for CQ resistance. We found five dhfr alleles: 60% of infections contained wild-type dhfr alleles, 3% had one mutation, 34% had two mutations, while 3% had three mutations. We found three dhps alleles: 47% were wild type, 44% had one mutation, while 9% had two mutations. CONCLUSIONS: We expect high levels of treatment failure (RI-RIII) with CQ (20-40%) and predict efficient treatment with SP. However, dhfr alleles with three mutations (51I, 59R, 108N) are present as are dhps alleles with two mutations (437G, 540E). Successful treatment with SP is therefore likely to be short-lived.     

Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder

OBJECTIVE: The relationships of age at onset and childhood psychopathology to 2-year clinical and functional outcomes in first-admission patients with bipolar I disorder were examined. METHOD: Patients with bipolar I disorder (N=123) presenting with psychotic symptoms were followed over a 2-year period. Age at onset was stratified into <19 and >or=19 years. Childhood psychopathology was categorized as behavior problems, other psychopathology, and none. Functional and clinical outcomes were rated with standard measures. RESULTS: Childhood psychopathology and age at onset were independently related to poorer functional and clinical outcome. In the multivariate models that included psychopathology, age at onset, sex, and education, early age at onset was related to incomplete remission, and childhood psychopathology was related to functional outcome. CONCLUSIONS: Childhood psychopathology and age at onset contribute independently to outcomes of bipolar disorder. Childhood psychopathology is a much stronger predictor of functioning than age at onset.     

Use of the Research Diagnostic Criteria for Temporomandibular Disorders for multinational research: translation efforts and reliability assessments in The Netherlands

AIMS: To outline the steps taken to conduct and to culturally adapt Dutch translations of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) history questionnaire, clinical examination form, and verbal instructions to the patients, and to assess the reliability of the clinical examination. METHODS: For the linguistic translation from English into Dutch, the forward and back-translation approach was followed. For cultural adaptation, an expert panel reviewed the translation, and a pretest was performed on a small clinical sample. Examiner training and calibration were carried out, and the clinical reliability of a "gold standard examiner" and 3 clinicians was assessed on 18 symptomatic TMD patients and 6 asymptomatic controls. The order of the examinations was based on a quasi-random Latin square design. Intraclass correlation coefficients (ICCs) were calculated to assess the overall interexaminer reliability of the clinical examination. RESULTS: A linguistically valid and culturally equivalent translation of the RDC/TMD into Dutch resulted from the above-outlined procedure. As for the clinical reliability, the ICC values obtained could mostly be considered "excellent" or, less frequently, as "fair to good." Poor reliability was found only for some of the palpation tests. For uncommon diagnoses (disc displacement without reduction and without limited mouth opening; osteoarthritis), no reliable ICC value could be calculated. CONCLUSION: The mode described by the authors for preparing clinical sites for RDC/TMD-based research is a feasible one.     

Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy

In this study, we characterized five Ullrich scleroatonic muscular dystrophy patients (two Italians, one Belgian, and two Turks) with a clinical phenotype showing different degrees of severity, all carrying mutations localized in COL6A1. We sequenced the three entire COL6 complementary DNA. Three of five patients have recessive mutations: two patients (P1and P3) have homozygous single-nucleotide deletions, one in exon 9 and one in exon 22; one patient (P2) has a homozygous single-nucleotide substitution leading to a premature termination codon in exon 31. The nonsense mutation of P2 also causes a partial skipping of exon 31 with the formation of a premature termination codon in exon 32 in 15% of the total COL6A1 messenger RNA. The remaining two patients carry a heterozygous glycine substitution in exons 9 and 10 inside the triple-helix region; both are dominant mutations because the missense mutations are absent in the DNA of their respective parents. As for the three homozygous recessive mutations, the apparently healthy consanguineous parents all carry a heterozygous mutated allele. Here, for the first time, we report a genotype-phenotype correlation demonstrating that heterozygous glycine substitutions in the triple-helix domain of COL6A1 are dominant and responsible for a milder Ullrich scleroatonic muscular dystrophy phenotype, and that recessive mutations in COL6A1 correlate with more severe clinical and biochemical Ullrich scleroatonic muscular dystrophy phenotypes.     

Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction

Context  The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear. Objective  To determine whether the ESR1 haplotype created by the c.454-397T>C (PvuII) and c.454-351A>G (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk. Design, Setting, and Participants  In 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989-1993 and follow-up to January 2000), a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397T>C and c.454-351A>G haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed. Main Outcome Measure  The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality. Results  Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (–397 T and –351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD. Conclusions  In this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.      

The relationship between self-reported emotional health, demographics, and perceived satisfaction with prenatal care

Aims to describe pregnant women with poor emotional health and the relationship between self-reported emotional health and prenatal care satisfaction. To this end, 1,265 women who delivered a live-born singleton infant were interviewed and information abstracted from prenatal records. Concludes that patient assessment of satisfaction with prenatal care may be related to both self-reported emotional health and delivery of medical care. Identifying and addressing emotional health of prenatal patients may improve compliance with medical recommendations, ultimately improving health outcomes.     

IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells

Estrogen-receptor (ER) status is an important parameter in breast cancer management as ER-positive breast cancers have a better prognosis than ER-negative tumors. This difference comes essentially from the lower aggressiveness and invasiveness of ER-positive tumors. Here, we demonstrate, that interleukin-8 (IL-8) was clearly overexpressed in most ER-negative breast, ovary cell lines and breast tumor samples tested, whereas no significant IL-8 level could be detected in ER-positive breast or ovarian cell lines. We have also cloned human IL-8 from ER-negative MDA-MB-231 cells, and we show that IL-8 produced by breast cancer cells is identical to monocyte-derived IL-8. Interestingly, the invasion potential of ER-negative breast cancer cells is associated at least in part with expression of IL-8, but not with IL-8 receptor levels. Moreover, IL-8 increases the invasiveness of ER-positive breast cancer cells by two fold, thus confirming the invasion-promoting role of IL-8. On the other hand, exogenous expression of estrogen receptors in ER-negative cells led to a decrease of IL-8 levels. In summary, our data show that IL-8 expression is negatively linked to ER status of breast and ovarian cancer cells. We also support the idea that IL-8 expression is associated with a higher invasiveness potential of cancer cells in vitro, which suggests that IL-8 could be a novel marker of tumor aggressiveness.     

Risk-adjusted outcome analysis of endovascular abdominal aortic aneurysm repair in a large population: how do stent-grafts compare?

PURPOSE: To compare differences in the applicability and incidence of postoperative adverse events among stent-grafts used for repair of infrarenal aortic aneurysms. METHODS: An analysis of 6787 patients from the EUROSTAR Registry database was conducted to compare aneurysm morphological features, patient characteristics, and postoperative events for the AneuRx, EVT/Ancure, Excluder, Stentor, Talent, and Zenith devices versus the Vanguard device (control) and each other. Annual incidence rates of complications were determined, and risks were compared using the Cox proportional hazards analysis. RESULTS: The annual incidence rates were: device-related endoleak (types I and III) 6% (range 4%-10%), type II endoleak 5% (range 0.3%-11%), migration 3% (range 0.5%-5%), kinking 2% (range 1%-5%), occlusion 3% (range 1%-5%), rupture 0.5% (range 0%-1%), and all-cause mortality 7% (range 5%-8%). After adjustment for factors influencing outcome, AneuRx, Excluder, Talent, and Zenith devices were associated with a lower risk of migration, kinking, occlusion, and secondary intervention compared to the Vanguard device. Significant increased risk for conversion (EVT/Ancure) and reduced risk of aneurysm rupture (AneuRx and Zenith) and all-cause mortality (Excluder) were found compared to the Vanguard device. CONCLUSIONS: Significant differences exist between stent-grafts of different labels in terms of applicability and complications during intermediate to long-term follow-up. Since each stent-graft has its drawbacks, no single label can be identified as the best. It is reassuring that developments in stent-grafts indeed result in better performance than the early stent-grafts. However, a single device incorporating all the perceived improvements should still be pursued.