Psychiatric disorders in the families of schizotypal subjects.

In a study of the families of 21 schizotypal patients, we found an increased morbidity risk for schizophrenia compared with that in the families of 21 nonschizotypal patients and 42 controls. The Axis I diagnoses did not influence the distribution of the morbidity risk in the families of the schizotypal patients. If the schizotypal subjects also had other personality disorders, the morbidity risk for schizophrenia among their relatives was lower, although not significantly.     

Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research. III. Development of a computerised clinical chart and its application to the comparison of different indices of disease activity. The European Consensus Study Group for Disease Activity in SLE.

In the first phase of this study, a data-base containing clinical and laboratory findings of 704 patients with systemic lupus erythematosus (SLE), originating from 29 centres and 14 countries, was used to assess the validity of 4 common indices of disease activity, SLAM, BILAG, SLEDAI and SIS. The physician's judgement of activity was assumed as the unique reference criterion (gold standard). Computer programmes were developed to calculate automatically the 4 activity indices; this computation appeared to correspond with manual computations in a sample of 60 appropriately selected cases. All 4 indices were closely correlated with each other (r in the range of 0.716 to 0.872), and with the physician's score (r in the range of 0.620 to 0.719). In the second phase of the study the activity index developed in part I (ECLAM) was prospectively validated, and its performance compared to that of the other scales, both as a single state index and as a transition index (i.e., its ability to assess disease activity at a single point in time and to detect variations in consecutive readings). A computer-assisted clinical chart was prepared for this purpose. This chart allowed us to calculate automatically all the indices. Two consecutive observation times (time 0, and time 1 three months later) were included in the study protocol. Data on 75 patients from 19 centres were collected, and each patient was observed twice. All the computed indices were closely correlated, both at time 0 (r ranging from 0.725 to 0.884), and at time 1 (r ranging from 0.607 to 0.833).(ABSTRACT TRUNCATED AT 250 WORDS)     

doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH)

Subcortical laminar heterotopia (SCLH), or 'double cortex', is a cortical dysgenesis disorder associated with a defect in neuronal migration. Clinical manifestations are epilepsy and mental retardation. This disorder, which mainly affects females, can be inherited in a single pedigree with lissencephaly, a more severe disease which affects the male individuals. This clinical entity has been described as X- SCLH/LIS syndrome. Recently we have demonstrated that the doublecortin gene, which is localized on the X chromosome, is implicated in this disorder. We have now performed a systematic mutation analysis of doublecortin in 11 unrelated females with SCLH (one familial and 10 sporadic cases) and have identified mutations in 10/11 cases. The sequence differences include nonsense, splice site and missense mutations and these were found throughout the gene. These results provide strong evidence that loss of function of doublecortin is the major cause of SCLH. The absence of phenotype-genotype correlations suggests that X-inactivation patterns of neuronal precursor cells are likely to contribute to the variable clinical severity of this disorder in females.      

Economy of locomotion in high-altitude Tibetan migrants exposed to normoxia

High-altitude Tibetans undergo a pattern of adaptations to chronic hypoxia characterized, among others, by a more efficient aerobic performance compared with acclimatized lowlanders. To test whether such changes may persist upon descent to moderate altitude, oxygen uptake of 17 male Tibetan natives lifelong residents at 3500–4500 m was assessed within 1 month upon migration to 1300 m. Exercise protocols were: 5 min treadmill walking at 6 km h⁻¹ on increasing inclines from +5 to +15% and 5 min running at 10 km h⁻¹ on a +5% grade. The data (mean ± s.e.m. ) were compared with those obtained on Nepali lowlanders. When walking on +10, +12.5 and +15% inclines, net     of Tibetans was 25.2 ± 0.7, 29.1 ± 1.1 and 31.3 ± 0.9 ml kg⁻¹ min⁻¹, respectively, i.e. 8, 10 and 13% less ( P < 0.05) than that of Nepali. At the end of the heaviest load, blood lactate concentration was lower in Tibetans than in Nepali (6.0 ± 0.9 versus 8.9 ± 0.6 m m ; P < 0.05) . During running,     of Tibetans was 35.1 ± 0.8 versus 39.3 ± 0.7 ml kg⁻¹ min⁻¹ (i.e. 11% less; P < 0.01). In conclusion, during submaximal walking and running at 1300 m, Tibetans are still characterized by lower aerobic energy expenditure than control subjects that is not accounted for by differences in mechanical power output and/or compensated for by anaerobic glycolysis. These findings indicate that chronic hypoxia induces metabolic adaptations whose underlying mechanisms still need to be elucidated, that persist for at least 1 month upon descent to moderate altitude.     

Incomplete rescue of cystic fibrosis transmembrane conductance regulator deficient mice by the human CFTR cDNA

We have used a mouse model to study the ability of human CFTR to correct the defect in mice deficient of the endogenous protein. In this model, expression of the endogenous Cftr gene was disrupted and replaced with a human CFTR cDNA by a gene targeted 'knock-in' event. Animals homozygous for the gene replacement failed to show neither improved intestinal pathology nor survival when compared to mice completely lacking CFTR. RNA analyses showed that the human CFTR sequence was transcribed from the targeted allele in the respiratory and intestinal epithelial cells. Furthermore, in vivo potential difference measurements showed that basal CFTR chloride channel activity was present in the apical membranes of both nasal and rectal epithelial cells in all homozygous knock-in animals examined. Ussing chamber studies showed, however, that the cAMP-mediated chloride channel function was impaired in the intestinal tract among the majority of homozygous knock-in animals. Hence, failure to correct the intestinal pathology associated with loss of endogenous CFTR was related to inefficient functional expression of the human protein in mice. These results emphasize the need to understand the tissue- specific expression and regulation of CFTR function when animal models are used in gene therapy studies.