Maternal recall bias, obstetric history and schizophrenia.

BACKGROUND: This study sought to clarify the role of obstetric complications (OCs) and maternal recall bias for patients with first episodes of schizophrenia and those at increased risk of the disorder. METHOD: Subjects at high risk of schizophrenia were compared with people with first-episode schizophrenia and with healthy volunteers. Consenting mothers of subjects were interviewed using a standardised questionnaire for the recall of OCs, and OCs were also measured from records collected at the time of pregnancy and delivery. RESULTS: High-risk subjects and first-episode patients had higher rates of OCs recalled by their mother than controls, but hospital records showed no differences in OCs between groups. The number of OCs recalled by mothers of the high-risk group was not related to whether the mother had schizophrenia or not, but was related to the maternally rated abnormal childhood behaviour as measured by the Child Behaviour Checklist. CONCLUSIONS: These results suggest that studies that rely on maternal recall alone are susceptible to bias. The excess of OCs recalled by the mother could be related to abnormal behaviour in their child rather than maternal illness, family history or psychotic symptoms.

Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin.

Critical functions of hamartin and tuberin, encoded by the TSC1 and TSC2 genes, are likely to be closely linked. The proteins interact directly with one another and mutations affecting either gene result in the tuberous sclerosis phenotype. However, the regions of hamartin and tuberin that interact have not been well defined, and the relationship between their interaction and the pathogenesis of tuberous sclerosis has not been explored. To address these issues a series of hamartin and tuberin constructs were used to assay for interaction in the yeast two-hybrid system. Hamartin (amino acids 302-430) and tuberin (amino acids 1-418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346-371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719-998) predicted to encode coiled-coils was capable of oligermerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin (N198_F199delinsI;593-595delACT) or tuberin (G294E and I365del), abolished or dramatically reduced interaction of the proteins as assessed by yeast two-hybrid assays and by co-immunoprecipitation of the full-length proteins from Cos7 cells. In contrast, three non-pathogenic missense polymorphisms of tuberin (R261W, M286V, R367Q) in the same region as the disease-causing TSC2 mutations did not. These results indicate a requirement for interaction in critical growth suppressing functions of hamartin and tuberin.

Molecular analysis of the TSC1 and TSC2 tumour suppressor genes in sporadic glial and glioneuronal tumours.

Reduced expression of the TSC2 tumour suppressor gene product, tuberin, has been reported in sporadic astrocytomas, suggesting that the TSC genes may play a role in formation of sporadic glial or glioneuronal tumours. We studied paired constitutional and tumour DNA samples from 100 patients with sporadic glial and glioneuronal tumours for loss of heterozygosity (LOH) at the TSC1 and TSC2 loci using a combination of seven previously reported and seven novel polymorphic markers. LOH was seen in 1/16 astrocytomas, 3/15 ependymomas, 5/16 gangliogliomas, 2/14 glioblastoma multiforme, 0/7 oligodendrogliomas, 0/7 tumours of mixed oligodendrocytic/astrocytic histology, 2/11 pilocytic astrocytomas and 0/1 subependymal giant cell astrocytomas informative at both loci. However, SSCP screening of all coding exons of the TSC1 or TSC2 genes in the tumours displaying LOH, and of both genes in 21 gangliogliomas, revealed no intragenic mutations. The lack of demonstrable inactivation of both alleles of either TSC gene in any of the tumours investigated suggests that they do not play a frequent role in the aetiology of sporadic glial or glioneuronal tumours.

Nutritional dependence of insulin-like growth factor (IGF) receptors in skeletal muscle: measurement by light microscopic autoradiography.

To determine the cellular location, capacity, and nutritional sensitivity of insulin-like growth factor (IGF) receptors, we measured the in vitro binding of [125I]-IGFs to skeletal muscle using light microscopic autoradiography. Muscle was collected from 8-month lambs that had received high or low nutrition diets (3% and 1.25% of body weight/day in pellets, respectively). Half of each group had also received growth hormone (0.25 mg/kg/day). Cryosections were incubated with [125I]-IGF alone or with unlabeled IGF-1, IGF-2, or insulin to characterize binding sites as probable Type 1 IGF, Type 2 IGF, or insulin receptors. [125I]-IGF-1 was found to bind to blood vessels and Type 1 receptors in connective tissue (p < or = 0.001), but not to muscle fiber or nerves. In muscle from 6-month lambs that were fed or fasted, [125I]-IGF-1 bound to Type 1 receptors in connective tissue (p < or = 0.01 fed; p < or = 0.05 fasted) and muscle fiber (p < or = 0.05). The binding to connective tissue was also greater in fasted than in fed animals (p < or = 0.05). Binding of [125I]-IGF-2 to the Type 2 receptor was located in blood vessels and connective tissue (p < or = 0.01) and did not alter with fasting. Therefore, these experiments have demonstrated that Type 1 and Type 2 receptors vary in their distribution and nutritional sensitivity in skeletal muscle.