A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.     

Two new beta3 integrin mutations in Indian patients with Glanzmann thrombasthenia: localization of mutations affecting cysteine residues in integrin beta3

New mutations in the beta3 integrin subunit have been identified in two unrelated Glanzmann thrombasthenia patients originating from India and Bangladesh. Both patients had histories of excessive bleeding and were found to have Glanzmann thrombasthenia based on absent ADP-induced platelet aggregation. Immunoblotting of platelet lysates of Patient 1 demonstrated reduced levels of alphaIIb and an unexpected high Mr beta3 band of approximately 260,000, with little or no normal-sized beta3. Upon reduction, a weak beta3 band of normal Mr was observed. Platelet lysates of Patient 2 demonstrated undetectable levels of beta3. Sequence analyses identified homozygous mutations in the beta3 genes of both patients. Patient 1 had a C506Y missense mutation resulting in the expression of an unpaired cysteine; we propose that the Mr approximately 260,000 band is a disulfide-bonded beta3 dimer. Patient 2 had an insertion mutation resulting in a frameshift and premature termination. Both mutations affect biogenesis of platelet alphaIIbbeta3 receptors.     

Mitochondrial disorders: a potentially under-recognized etiology of infantile spasms

Infantile spasms represent an age-dependent response of the immature brain to a wide variety of insults. An unselected group of children with infantile spasms were reviewed to determine etiology; a metabolic work-up was undertaken if the etiology was unclear from history and examination (cryptogenic). Of the 56 infants, 34 had a recognizable etiology (symptomatic), 1 had normal development (idiopathic), and 21 had cryptogenic infantile spasms. Among the latter, results of plasma lactate and pyruvate or urine organic acids were available in 17. In 2 infants (monozygotic twins), mitochondrial DNA testing revealed the relatively common A3243G mitochondrial mutation. In these twins and 11 of the remaining 15, body fluid metabolite testing suggested possible defective energy metabolism. Our twins and previous reports suggest that mitochondrial disorders should be considered in the differential diagnosis of infantile spasms. Among our cases remaining cryptogenic, signs of abnormal energy metabolism were prevalent, suggesting that metabolic derangements may be common causes or secondary consequences of infantile spasms.     

Status epilepticus and acute serial seizures in children

Status epilepticus is defined as a seizure that persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring epileptic condition of 30 minutes or longer. Status epilepticus is a life-threatening condition that often occurs in children. The degree of mortality and neurologic morbidity, as well as the risk for recurrence, is highly dependent on the etiology and duration of the seizures. Although much has been written about pediatric status epilepticus, many issues remain unresolved. A better understanding of the different types of seizures and their etiologies may help in the prevention and treatment of status epilepticus. The vast extent of status epilepticus in both children and adults mandates that new options for prevention and treatment be given a close scrutiny and high priority. This article will review the most current information on convulsive and nonconvulsive status epilepticus, including the potential for neurologic damage, changes in magnetic resonance imaging after status epilepticus, risk for recurrence, and current treatment options available for treating status epilepticus in children.     

Vigabatrin for infantile spasms

We reviewed 20 infants receiving vigabatrin for infantile spasms. Patients were not enrolled in a formal study. All families obtained the medication abroad. Age at initiation of vigabatrin ranged from 1 to 48 months; nine infants had received prior treatment with various antiepileptic medications. Patients were begun on the lowest practical dose of 125-250 mg/day, with gradual daily increments to a target of 100 mg/kg/day, but maintained at the lowest effective dosage. Video electroencephalogram was obtained to document resolution of spasms and hypsarrhythmia. Of 20 infants, 12 responded with cessation of spasms and resolution of hypsarrhythmia, at doses of 25-135 mg/kg/day (median = 58 mg/kg/day). Partial responses were observed in six patients, whereas two had no response at 111 and 125 mg/kg/day. Additional new seizure types developed in three infants after initial response to vigabatrin. Increasing the vigabatrin did not have any clinical benefit. Vigabatrin is an effective, well-tolerated treatment for infantile spasms. The response is dose-independent, suggesting that starting at a low dose and gradually increasing, rather than beginning with an arbitrary 100 mg/kg/day dose is advantageous.     

Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease

Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.     

Activation of histamine H2 receptors ameliorates experimental allergic encephalomyelitis

Experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis, is an autoimmune, demyelinating disease of the CNS. Pro-inflammatory cytokines (e.g. tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12) and reactive oxygen species are implicated in promoting EAE. Since histamine H(2) receptor activation suppresses production of O(2)*-, TNF-alpha, and IL-12 by inflammatory cells, we tested the hypothesis that dimaprit, an H(2) agonist, would reduce the clinical severity and pathology of EAE. Dimaprit treatment significantly reduced clinical signs compared to vehicle in both C57BL/6 and iNOS deficient EAE mice. Furthermore, dimaprit significantly reduced CNS staining for lectin-positive macrophages and decreased extravasated albumin staining, an indicator of blood-brain barrier leakage. These data provide a rationale for exploring H2 receptor activation for therapeutic value in multiple sclerosis.     

Reasons for poor understanding of when and how to access GP care for childhood asthma in Auckland,New Zealand

BACKGROUND: Attempts to explain why some patients lack the understanding needed to access GP care for childhood asthma are uncommon and have tended to be based on reported statistical associations. OBJECTIVES: The aims of this study were to describe and account for poor patient understanding of when and how to access GP care for childhood asthma in Auckland, New Zealand. METHODS: A general inductive approach was used to analyse 29 semi-structured, personal interviews, during March-May 2001, with Auckland key informants selected through maximum variation sampling. Informant checking and the literature supported the text analysis by two independent researchers. RESULTS: Key informants reported wide variations in the extent to which guardians and asthmatic children understand when and how to access GP services. Two sets of barriers to patient understanding were identified. The first limits the willingness of people to seek understanding and the second limits their ability to understand, even if they want to understand. CONCLUSIONS: Use of qualitative methodology was able to reveal barriers to patient understanding. Strategies operating at the GP and system levels were identified to help overcome these barriers.     

Elevated risk of high blood pressure: climate and the inverse housing law

BACKGROUND: In previous work the authors identified an 'inverse housing law' in Britain such that housing quality tends to be worse in areas of harsh climate than in areas where the climate is more benign. This study investigates whether an individual's risk of hypertension is associated with such a 'mismatch' between the quality of their housing and the climate to which they have been exposed. METHODS: Cross-sectional observational study based on Britain. Data came from the 5663 Health and Lifestyle Survey (HALS) participants for whom all relevant items were available. A two-stage study design was employed. First, the relationship between exposure to colder climate and housing quality was established. Second, the impact on risk of hypertension was determined for level of exposure to colder climate and housing quality. RESULTS: Analysis confirmed that amongst survey respondents, those with greater exposure to colder climate are more likely (1.32, 95% CI: 1.18-1.42) to live in poor quality housing than those with lower exposure to colder climate. This combination of higher exposure to colder climate plus residence in worse quality housing raises significantly the risk of diastolic hypertension (1.45, 95% CI: 1.18-1.77) and, more weakly, systolic hypertension (1.25, 95% CI: 1.01-1.53). CONCLUSIONS: There appears to be an 'inverse housing law' in Britain, whereby longer term residents of relatively cold areas are also more likely to live in worse quality housing and this combination of circumstances is associated with significantly higher risk of diastolic hypertension. The findings provide an example of how long term exposure to an adverse environment, which may stem from material disadvantage, can damage health.