Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity.

Angiogenesis is essential for normal mammalian development and is controlled by the local balance of pro- and antiangiogenic factors. Here we describe a novel mouse cDNA sequence encoding sFLT-1 that is a potent antagonist to vascular endothelial growth factor (VEGF) and show for the first time its in vivo production. In situ hybridization and Northern blot analysis with probes specific for sFLT-1 or FLT-1 showed that the relative abundance of their mRNAs changed markedly in spongiotrophoblast cells in the placenta as gestation progressed. On day 11 of pregnancy, sFLT-1 mRNA was undetectable but FLT-1 readily apparent, and by day 17 sFLT-1 mRNA was abundant but FLT-1 barely detectable. sFLT-1 was identified in conditioned medium of cultured placenta from day 17 pregnant mice and likely to be present in the circulation, as there is a substantial increase of VEGF-binding activity in the serum from day 13 of pregnancy, which coincides with the abundant sFLT-1 expression in placenta. Expression of sFLT-1 was also observed in adult lung, kidney, liver, and uterus. These data suggest a novel mechanism of regulation of angiogenesis by alternative splicing of FLT-1 pre-mRNA. Treatment of pregnant mice with exogenous VEGF from day 9 to 17 of pregnancy, which alters the ratio of VEGF to sFLT-1, resulted in an increase in the number of resorption sites and fibrin deposition in the placenta of ongoing pregnancies. These findings have important implications for understanding placental function and may be relevant in a range of disease states.

A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation.

Vascular endothelial growth factor (VEGF) is a potent secreted factor that promotes angiogenesis and maintains the integrity of the endothelium. Levels of VEGF are increased in many tumors and are elevated in women with pre-eclampsia, a serious disease of pregnancy. Here we show by in situ hybridization that the trophoblast contains the mRNA encoding a soluble version of the VEGF receptor known as Flt-1 (sFlt-1: initially described by Kendall and Thomas, PNAS 90:10705-10709). Binding assays and Western blotting of villus-conditioned media confirmed the production of sFlt-1. Serum from pregnant women was found to contain a VEGF-binding protein that was not present in serum from men or nonpregnant women. As determined by heparin affinity, column fractionation, and cross-linking, this protein was identical to sFlt-1. Taken together, these results show that the placenta secretes sFlt-1, which would be expected to be a VEGF antagonist. This is the first report of production of the sFlt-1 receptor in vivo, and it reveals a new mechanism for naturally regulating this potent angiogenic agent. The presence of such an antagonist suggests that regulation of VEGF action is essential to successful pregnancy. This has important implications for the activity of VEGF locally and systemically in other conditions.

Rapid cycling bipolar affective disorder and familial learning disability associated with temporal lobe (occipitotemporal gyrus) cortical dysplasia.

This case report describes a hitherto unreported association between temporal cortical dysplasia and rapid cycling bipolar affective disorder in a learning disabled young man with a family history of rapid cycling bipolar affective disorder in two dysmorphic and learning disabled maternal uncles, and probably learning disability in the mother and grandmother. An identical family with similar findings could not be located in the English literature.

Gender differences in the phenotypic expression of Alzheimer's disease in Down's syndrome (trisomy 21).

Twenty-eight individuals with typical Down's syndrome (DS) phenotype (17 males and 11 females; age range: 10-74 years) were investigated for gender differences in the phenotypic expression of Alzheimer-type pathology (ATP). Quantitative neuropathology was performed in the 4 neocortical lobes of the right hemisphere, by counting senile plaques (SP), and neurofibrillary tangles (NFT). ATP was present in 25 middle-aged (> 40 years) individuals (16 males and 9 females). Females had significantly higher (p = 0.03) mean neocortical NFT densities (36.6 per mm2; s.e.m. +/- 6.6) than males (17.9 per mm2; s.e.m. +/- 4.7). None of the females had NFT densities below 10 per mm2, compared with 6 males in whom NFT were either absent or seen in very low densities (< 4 per mm2). Assessment of SP densities in the same cortical regions showed non-significant differences in females (42.4 per mm2; s.e.m. +/- 5.1) compared with males (33.6 per mm2; s.e.m. +/- 2.1). There was clinical evidence of dementia in all the female (8/8) individuals who were prospectively assessed, compared with only 54% (7/13) of males. The male individuals without clinical dementia had absent or low neocortical NFT densities regardless of high SP densities. Female DS cases (mean age: 48.8 years; s.e.m. +/- 1.9) had an earlier onset of dementia than males (mean age: 53.6 years; s.e.m. +/- 1.3; p = 0.05). Female middle-aged DS individuals have an earlier onset, and a more severe form of AD which correlates with higher neocortical NFT rather than SP density.

Mental health services for people with mental retardation: a framework for the future.

The mental health needs of mentally retarded people cannot be met satisfactorily with generic mental health services. Specialized services are required. A number of different service models have evolved which require evaluation. They include subregional units, community-based services with a small admission facility, integrated services and specialist teams. Staff working in specialist mental health services must be appropriately trained.

The elderly mentally handicapped in hospital: a clinical study.

In a study of 99 long-stay hospital residents aged 65 years and over, two thirds were functioning in the moderately to mildly handicapped range, two thirds were under the age of 75 years and there was an overall female to male ratio of 2:1. As in the general population, mobility problems, a tendency to falls and fractures, cardiorespiratory disease, deteriorating eyesight, and hearing and urinary incontinence were commonly found; all increased in frequency with age. A fifth exhibited psychiatric disorder: the commonest conditions, as expected, were the psychoses and dementia. It is suggested that retirement provision for the elderly mentally handicapped should be made within the mental handicap services and that the small group with significant geriatric problems would be most appropriately cared for within the generic geriatric services. A plea is made for evaluative studies before large scale implementation of resettlement programmes for the elderly mentally handicapped in hospital.

Temperamental patterns in aggressive boys.

Four groups of aggressive body ( and one group of controls) were studied, on the basis of: clinical referrals to a hospital clinic; teacher reports of assaultive behaviour in school; teacher reports of severe aggressive behaviour in school; and peer reports of aggressive behaviour. Questionnaire techniques were used to study behaviour and temperament. The last three groups proved to have rather similar patterns of behaviour and temperament and, therefore, they have been combined to give rise to an 'any school criterion' group. We compared three main groups: (i) clinical referrals; (ii) 'any criterion' (school-identified); and (iii) controls. On behaviour, the clinical group had the most adverse scores, especially on antisocial behaviour. The school-identified group also had a higher score than the controls on this dimension, and differed in degree from the clinical referral group. On temperament, the clinical referral group had a significantly more adverse score on all dimensions than both the controls and the 'any criterion' group. The 'any criterion' group scores were intermediate between the other two sets of scores. The differences on temperament between the control and the 'any criterion' groups appeared to be one of degree but not of type. Moreover, no specific type of temperament was associated with the different kinds of aggression we have studied. Principal components analysis supports the notion of no qualitative temperamental differences between the 'any criterion' and the control groups.