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J Med Genet 2004;41:25-30 Rett syndrome (RTT; MIM No 312750) is a neurodevelopmental disorder mainly affecting girls, with an incidence of 1:10 000 female births. (1) The clinical features of [...]

Rett syndrome (RTT) is caused by mutations in the transcriptional repressor methyl CpG-binding protein 2 (MECP2). Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis, and plasticity, and it has been shown that BDNF expression is regulated by MeCP2 through a complex interaction. A common polymorphism of BDNF(Val66Met p.V66M) has been found to correlate with severity and course of several neuropsychiatric disorders.

Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype–phenotype relationships and compares these with previous findings in a population-based cohort.

Background Increasing evidence suggests that patterns of T-cell immunity to inhalant allergens in genetically diverse human populations are more heterogeneous than previously assumed, and that covert differences in expression patterns might underlie variations in airway disease phenotypes. We tested this proposition in a community sample of childrenMethods We analysed data from 172 individuals who had been recruited antenatally to a longitudinal birth cohort study. Of the 194 birth cohort participants, data from the 147 probands (age range 8·6–13·5 years) who consented to blood collection were included along with data from 25 consenting siblings (mean age 11 years [range 7·4–17·4]). We ascertained clinical phenotypes related to asthma and allergy. We measured T-cell responses to allergens and mitogens, together with blood eosinophils and IgE/IgG antibodies, and assessed associations between these indices and clinical phenotypes.Findings Atopy was associated with allergen-specific T-helper (Th)2 responses dominated by interleukin 4, interleukin 5, interleukin 9, interleukin 13, whereas interleukin 10, tumour necrosis factor α, and interferon γ responses were common to both atopics and non-atopics. The wheal size from skin prick with allergen was positively associated with in-vitro interleukin 5 and interferon γ responses, and negatively associated with interleukin 10. Asthma, especially in atopics, was strongly associated with eosinophilia/interleukin 5, and bronchial hyper-responsiveness (BHR) was associated with eosinophilia plus polyclonal interferon γ production. BHR in non-atopics was associated with elevated allergen-specific and polyclonal interleukin 10 production.Interpretation Parallel immunological and clinical profiling of children identified distinctive immune response patterns related to asthma and wheeze compared with BHR, in atopics non-atopics. Immunological hyper-responsiveness, including within the Th1 cytokine compartment, is identified as a hallmark of BHR.Relevance to practice These findings highlight the heterogeneity of immune response patterns in asthmatic children, including those with seemingly homogeneous Th2-driven atopic asthma. Further elucidation of the covert relationships between wheezing phenotypes and underlying immunophenotypes in this age group will potentially lead to more effective treatments for what is an unexpectedly heterogeneous collection of disease subtypes.

Respiratory Morbidity and Exposure to Bauxite, Alumina and Caustic Mist in Alumina Refineries: Lin Fritschi, et al.Department of Epidemiology and Preventive Medicine, Monash University—A cross-sectional survey of 2404 employees in three alumina refineries was performed in 1996. The aims of this study were to investigate associations between respiratory symptoms and lung function and cumulative quantitative workplace exposure to alumina and bauxite dust, as well as recent workplace exposure to caustic mist. All participants answered questions about respiratory symptoms and the relationship of those symptoms to work, as well as having spirometry and providing a complete job history. The job histories were combined with a task exposure matrix for bauxite and alumina dust. The current job was also assigned a semi quantitative exposure to caustic mist. Prevalence ratios (PR) and 95% confidence intervals (Cl) for symptoms were calculated for each exposure. Subjects in the highest group of current caustic exposure reported increased prevalence of work related wheeze (PR=1.8 95% Cl 1.0-3.1) and rhinitis (PR=1.6 95% Cl 1.1-2.4) but did not have measurable changes in lung function. Alumina exposure was associated with minor increases in reporting of work related wheeze and rhinitis but no changes in lung function. Bauxite exposure at the levels experienced in these alumina refineries was not associated with either symptoms or lung function changes.

A total of 8623 patients admitted to hospital in Western Australia with a diagnosis of diabetes mellitus during 1971-9 were linked with hospital admissions for road trauma during the same period, and their admission rates compared with the whole population. Although there was no overall difference, there was a significant excess of admissions in diabetic men aged under 55, the excess being produced by those in control of a vehicle and pedestrians. There were smaller excesses in the same female age group and a corresponding deficit in older diabetics. The results are limited through being based on routinely collected data on hospital admissions both for diabetics and victims of road crashes but indicate that there is a real problem of road accidents among diabetics that should be more fully investigated with a population based study that would collect important additional information unavailable in this study.

Trends in prevalence of cytological evidence of cervical intraepithelial neoplasia (CIN) and cervical infection with human papilloma virus (HPV), as indicated by HPV infection and dyskeratosis, were studied in 2,992 new attenders at a sexually transmitted diseases (STD) clinic between 1978 and 1982. Crude prevalence of CIN increased from 1.3% to 4.3% (P less than 0.001) and crude prevalence of HPV infection increased from 2.8% to 9.3% (P less than 0.001). Age adjustment had little effect on these trends. Review, in 1984-85, of samples of smears taken in 1978 and 1982 showed that recognition of koilocytosis by the laboratory had increased substantially over time while a tendency had developed to downgrade nuclear changes in the presence of koilocytosis. Correction of the 1978 and 1982 smear results to the 1984-85 classifications suggested that prevalence of koilocytosis had increased little (from 13.4% to 16.1%, P = 0.20) while there had been a substantial real increase in CIN (0.8% to 2.4%, P less than 0.001). To try to explain the trend in CIN, other characteristics of a sample of attenders at the STD clinic were studied. There were no appreciable trends in prevalence of past STD, number of sexual partners in the last 3 months, method of contraception, genital warts and culture of N. gonorrhoea, T. vaginalis, C. albicans and Chlamydia sp. from the vagina. There was an increase in the proportions in socioeconomic group I, as classified by postcode of residence (17.0% to 26.9%, P = 0.04), referred as contacts rather than with symptoms (24.0% to 41.6%, P less than 0.001), with a clinical diagnosis of genital herpes (5.0% to 8.6%, P = 0.08) and with herpes virus cultured from the cervix (2.1% to 6.3%, P = 0.03). The trend in prevalence of herpes virus infection was not explained by the other trends. It may explain the trend in prevalence of CIN.

Trends in the incidence of and mortality from myocardial infarction in Perth, Western Australia, were studied for the period 1971 to 1982. The estimated age-adjusted incidence rate of myocardial infarction fell by 24% in males and 37% in females over this period. The rate fell in each of six age-sex groups, but the proportional decrease in those aged less than 45 years was nearly double that in those aged 45 years and over, as it was in females compared with males and in fatal cases compared with nonfatal cases. Over 80% of the decline in mortality was in deaths outside hospital. This and seven other comparable studies all showed a net decrease in the estimated incidence of myocardial infarction in both sexes, with median annual decreases of 2% in males and 3% in females. It is concluded that the decline in the incidence of myocardial infarction contributed substantially to the observed decrease in ischemic heart disease mortality, and that the most plausible explanation for the decline in incidence is a reduction in the prevalence of risk factors for myocardial infarction.

Acquired resistance to standard chemotherapy for tuberculosis (TB) is an increasing problem worldwide. Vietnam has one of the highest incidences of TB and also has a large population of potential migrants to other countries. Since 1979 the International Organisation for Migration (IOM) has been running a supervised programme of TB treatment for intending migrants from Vietnam where few facilities for bacteriological culture and sensitivity testing exist. This study aimed to assess the most important factors for predicting non-response to first-line treatment as treatment starts and whether any further indicators occur during the course of treatment which may enable more accurate prediction of non-response.

The detrimental effects of fetal exposure to extreme levels of alcohol during pregnancy, such as the subsequent occurrence of childhood physical, cognitive, and behavioral deficits, are well known. Some investigators have suggested that there is a dose-response effect, with light drinking during pregnancy primarily affecting behavioral and adaptive functions and heavy drinking causing more serious developmental defects and problems. Accordingly, mild to moderate social drinking during pregnancy could be associated with long-term infant morbidity. The relatively few studies examining the long-term risk of fetal exposure to light–moderate levels of alcohol have failed to reach consensus, possibly due to deficiencies in study design.