Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin.

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

Induction of puberty in the hypogonadal girl--practices and attitudes of pediatric endocrinologists in Europe.

The management of children and adolescents with hypogonadism and in particular the induction of puberty in the hypogonadal girl is subject to controversy. Therefore, under the auspices and through organization of the Drugs and Therapeutics Committee of the European Society of Paediatric Endocrinology (ESPE), an interactive voting session and workshop was held at the 39th ESPE Annual Meeting in Brussels to discuss these topics. Common practice in Europe and attitudes of pediatric endocrinologists in Europe were questioned and recorded in the 1.5-hour program. We now report on some of the results of the questionnaires and discussions of that session to further the discussion on and knowledge of current concepts of induction of puberty in the hypogonadal girl in Europe. It became clear from the data accumulated here that the start of treatment, the aims of therapy and the modalities of how to treat the hypogonadal girl vary amongst pediatric endocrinologists in Europe. For example, a chronological age > or =11 years was considered appropriate for the start of estrogen therapy by 40.4% (out of 188 answers), while 47.8 and 7.5% felt that a chronological age > or =13 and > or =15 years respectively was appropriate. In respect to the form and route of estrogen administration, the audience was asked for their common estrogen replacement practice: 31.9% used oral 17beta-estradiol treatment, while 10% would prescribe 17beta-estradiol transdermal patches. Another 12.2% would recommend conjugated estrogens (e.g. Premarin) orally, 4.8% use oral estradiol valerate and 39.3% ethinylestradiol orally. Only 1.8% out of 229 physicians answering were undecided. In addition, counseling of patients and their families is quite variable and perceptions for example regarding potential pregnancies in affected women are also not uniform. In this report the authors do not want to provide their own personal views but rather reflect current practice in Europe. It is hoped that a more uniform picture will emerge once European and international guidelines on how to treat the girl with hypogonadism will be available and even more discussions amongst doctors from different countries have been led.

[Boy or girl? Molecular mechanisms in sex differentiation]. / Pojke eller flicka? Molekylära mekanismer vid könsdifferentiering.

A growing number of factors have been recognized as crucial in sexual development, and many clinical conditions have become understandable as mutations in relevant genes have been identified. In some cases this has led to the development of DNA diagnostics, which can be of some aid in the workup of this type of patient. So far it is mainly more serious disorders which have been elucidated, thanks to the identification of extensive mutations in the key genes for sexual development. Exactly to what extent less severe damage in these genes underlies more subtle disorders of sexual development, such as disturbances in pubertal development and diminished fertility, is with few exceptions unknown. We are still aware of only a fraction of the information hidden in our genetic heritage. Developments in this field are nonetheless rapid, and molecular analyses will probably become more and more part and parcel of the workup of patients with a wide variety of disturbances in sexual development.

[Evaluation of the new admission procedures for medical education at the Karolinska Institute: selection based on tests and interviews is best]. / Utvärdering av Karolinska institutets nya antagningsformer till läkarutbildningen: PIL-arna klarade sig bäst.

To develop an admission procedure permitting selection of highly motivated medical students with personality characteristics appropriate for a future as practising physicians, from 1992 and onwards the Karolinska Institute based admission on a written test and two interviews (PIL group, n = 135), on upper secondary school grade point average (on a 5-point scale; GPA group, n = 161), on Scholastic Aptitude Test results (SAT group, n = 80), or other criteria (mainly foreign grades), the groups being compared at evaluation of the procedures in 1996. The PIL group scored highest in all respects, including clinical suitability, motivation, relations with classmates, and realistic expectations as to their future work as physicians, and none of them left medical school. Academic results were similar in the GPA group, though the two groups differed in secondary school GPAs (PIL group 4.0, GPA group 4.8(5.0). The evaluation suggested that admission via written test and interviews is a good alternative to conventional admission based on GPA or SAT.

Effect of growth hormone (GH) during puberty in GH-deficient children: preliminary results from an ongoing randomized trial with different dose regimens.

This paper reports results from an ongoing, randomized, multicentre national trial. The aim is to elucidate whether a dose of growth hormone (GH) of 0.2 IU/kg (0.07 mg/kg), given either as once-daily or twice-daily injections during puberty, is more effective than a once-daily dose of 0.1 IU/kg/day (0.03 mg/kg/day) in improving final height in children with GH deficiency (GHD). The twice-daily regimen comes closer to the spontaneous GH secretion pattern in puberty. Ninety-two children with GHD who had been receiving GH therapy for at least 1 year, and with spontaneous puberty or who were prepubertal and due to be started on replacement therapy to induce puberty, were randomly assigned to receive GH as follows: group A, 0.1 IU/kg/day (0.03 mg/kg/day), administered once daily; group B, 0.2 IU/kg/day (0.07 mg/kg/day), administered once daily; and group C, 0.2 IU/kg/day (0.07 mg/kg/day), divided into two equal injections given at 12-hour intervals. Pubertal height gain was 0.7, 0.7 and 1.3 SDS for groups A, B and C, respectively. The gain in height during puberty was thus most marked in group C. Mean final height, when corrected for parental height, was between 0 and 1 SDS in all treatment groups. All but seven children reached a final height within +/- 2 SD of the general population. There was a wide range of final heights in all three treatment groups. This variation in response suggests the need to individualize treatment in order to achieve an appropriate final height for most individuals.

Androgens and fetal growth.

Boys are heavier than girls at term birth. Children with a 46,XY karyotype and androgen insensitivity syndrome (clinically complete form and/or proven mutations in the androgen receptor gene) were found to have a birth weight comparable to that of girls. These findings support the hypothesis that the difference in birth weight between boys and girls is generated by androgen action.

Chlorinated contaminants, growth and thyroid function in schoolchildren from the Aral Sea region in Kazakhstan.

It has been shown by others that offspring of mothers who had been exposed to dioxins and polychlorinated biphenyls (PCBs) during pregnancy have elevated plasma levels of thyroid-stimulating hormone (TSH) for at least 3 months after birth and reduced plasma levels of free and total thyroxine during the second week after birth. As elevated levels of dioxins and PCB s can thus alter thyroid hormone status, the relation between the levels of some polychlorinated organic compounds in the blood lipids and growth and thyroid hormone status was studied in 12 hospitalized schoolchildren from the Aral Sea region known to have high exposure to such compounds. Their level of PCBs was two to four times higher than in healthy Stockholm children. Their height was found to be lower than in healthy Swedish children of the same age mean (SDS -0.52) and the body mass index (BMI) was inversely correlated to the total concentrations of PCBs and dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorophenyldichloroethylene (DDE) in the blood lipids. As the levels of insulin-like growth factor- were reduced to the same extent as the BMI it seems likely that PCBs and DDT cause malnutrition as a result of malabsorption. None of the children had any impairment of thyroid function, as revealed by the plasma levels of TSH and thyroxine. Although the concentrations of beta-hexachlorocyclohexane (beta-HCH) and DDE were extremely high in some of the children there was no relation between thyroid hormone status and the blood lipid levels of PCBs, hexachlorocyclohexane and DDT. However, the concentration of dioxins was not analysed.

Total body bone mineral measurements in children with Prader-Willi syndrome: the influence of the skull's bone mineral content per area (BMA) and of height.

Background. The aim of this study was to investigate the influence of body height and growth on total body measurements with dual energy X-ray absorptiometry (DEXA) in children. Material and methods. Seventeen children with Prader-Willi syndrome were studied as part of a clinical investigation of the effect of growth hormone (Genotropin) treatment. Bone mineral areal mass (BMA), in g/cm2, was studied with DEXA at 0, 12, 24 and 30 months after the start of the study. The effect of increased bone volume on BMA was studied by making a rough estimate of bone width, which was correlated with BMA. Results. There was a weak correlation between total body BMA and body height (r = 0.58), which increased after exclusion of the head (r = 0.84). The BMA of the head was more than twice as high as that of the rest of the body. In the shortest children more than 50 % of the total bone mineral was contained in the skull, which decreased with height to below 20 % in the tallest children. The correlation between the so-called bone width and BMA (total body, head excluded) was 0.97. Conclusion. The results indicate that (a) the bone mineral content (BMC) of the head and (b) the bone volume and body height have a major influence on BMA measurements with DEXA in children. A theoretical method for evaluating the relative bone density (g/cm3) has also been described.

[Prenatal diagnosis and treatment of adrenogenital syndrome. Prevent virilization of female fetuses]. / Fostermedicin. Prenatal diagnostik och behandling av adrenogenitalt syndrom. Förhindra virilisering av flickfoster.

Congenital adrenal hyperplasia (CAH) is the common name of a constellation of diseases that impair cortisol synthesis in the adrenal cortex. As defects in each of three steroidogenic enzymes, 21-hydroxylase, 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase, promote overproduction of adrenal androgens, affected female fetuses may be virilised. The major cause of CAH is 21-hydroxylase deficiency, the incidence of which is 1:10,000 live births in the Swedish population. Of the 10-15 children born in Sweden each year with 21-hydroxylase deficiency, 3-5 will be virilised girls who must undergo traumatic surgery of the external genitalia. This can be prevented by administration of dexamethasone to the gravida during pregnancy. Prenatal treatment was introduced in Sweden in 1985, prenatal diagnosis being based in most cases on direct mutational analysis using allele-specific PCR on DNA from chorionic villus samples. In our experience, genotype corresponds well to phenotype, and we recommend that all children with 21-hydroxylase deficiency be genotyped in order to prepare the family for rapid and reliable prenatal diagnosis and possible treatment when the next child is awaited. Since 1985, 35 women have received prenatal treatment in Sweden, six of the 35 fetuses being found to be affected females and treated until term. As compared with their older sisters, all of these six girls were characterised by no signs, or only minor signs, of virilisation, and only one required surgery because of labial fusion and recurrent urinary tract infections. As a group, the 35 infants were characterised by normal birth weight and length, and normal growth during the first year of life. Passage of developmental milestones was normal though several adverse events, both in treated mothers and infants, have been reported. Approximately one fourth of the women treated throughout pregnancy reported some side-effect (e.g., excessive weight gain, severe cutaneous striae, mood fluctuations and irritability, acne and hirsutism, or oedema). One unaffected boy, treated for seven weeks, was born with severe hydrocephalus and agenesis of the corpus callosum; two affected sisters and one unaffected girl were characterised by failure to thrive during the first year of life, but later recovered (one of the affected sisters was later diagnosed as suffering from mitochondrial disease). Although in our experience prenatal treatment with dexamethasone is effective in preventing virilisation of girls with 21-hydroxylase deficiency, some adverse events have been noted in treated infants. As it remains unknown whether these events were attributable to the treatment, it must still be regarded as experimental, and its use should be centralised and meticulously monitored until more experience has been gained.

Genetic homogeneity of autoimmune polyglandular disease type I.

Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21.

Improved final height in girls with Turner's syndrome treated with growth hormone and oxandrolone.

The spontaneous growth process in Turner's syndrome is characterized by a progressive decline in height velocity during childhood and no pubertal growth spurt. Therefore, therapy aimed at improving height during childhood as well as increasing final height is desirable for most girls with Turner's syndrome. Forty-five girls with Turner's syndrome, 9-16 yr of age (mean age, 12.2 yr), were allocated to three study groups. Group 1 (n = 13) was initially treated with oxandrolone alone; after 1 yr of treatment, GH without (group 1a; n = 6) or with (group 1b; n = 7) ethinyl estradiol was added. Group 2 (n = 17) was treated with GH plus oxandrolone. Group 3 (n = 15) was treated with GH, oxandrolone, and ethinyl estradiol. The dosage were: GH, 0.1 IU/kg.day; oxandrolone, 0.05 mg/kg.day; and ethinyl estradiol, 100 ng/kg.day. A height of 150 cm or more was achieved in 61%, 75%, and 60% of the girls in groups 1, 2, and 3, respectively. The most impressive increase in height was seen in group 2. In this group the mean final height was 154.2 cm (SD = 6.6), which is equivalent to a mean net gain of 8.5 cm (SD = 4.6) over the projected final height. In group 3, in which ethinyl estradiol was included from the start of therapy, the initially good height velocity decelerated after 1-2 yr of treatment. Their mean final height was 151.1 (SD = 4.6) cm, equivalent to a mean net gain of 3.0 cm (SD = 3.8). A similar growth-decelerating effect of ethinyl estradiol was seen in group 1b. We conclude that in girls with Turner's syndrome who are older than 9 yr of age, treatment with GH in combination with oxandrolone results in significant growth acceleration, imitating that in normal puberty, leading to a more favorable height during childhood. This mode of treatment also results in a significantly increased final height, permitting a great number of the girls to attain a final height of more than 150 cm. However, early addition of estrogen decelerates the height velocity and reduces the gain in height.

Nephrogenic diabetes insipidus: an X chromosome-linked dominant inheritance pattern with a vasopressin type 2 receptor gene that is structurally normal.

Nephrogenic diabetes insipidus is a rare hereditary disorder, most commonly transmitted in an X chromosome-linked recessive manner and characterized by the lack of renal response to the action of antidiuretic hormone [Arg8]vasopressin. The vasopressin type 2 receptor (V2R) has been suggested to be the gene that causes the disease, and its role in disease pathogenesis is supported by mutations within this gene in affected individuals. Using the PCR, denaturing gradient gel electrophoresis, and direct DNA sequencing, we examined the V2R gene in four unrelated kindreds. In addition, linkage analysis with chromosome Xq28 markers was done in one large Brazilian kindred with an apparent unusual X chromosome-linked dominant inheritance pattern. In one family, a mutation in codon 280, causing a Tyr-->Cys substitution in the sixth transmembrane domain of the receptor, was found. In the other three additional families with nephrogenic diabetes insipidus, the V2R-coding region was normal in sequence. In one large Brazilian kindred displaying an unusual X chromosome-linked dominant mode of inheritance, the disease-related gene was localized to the same region of the X chromosome as the V2R, but no mutations were found, thus raising the possibility that this disease is caused by a gene other than V2R.

Expression of beta-nerve growth factor receptor mRNA in Sertoli cells downregulated by testosterone.

Nerve growth factor (NGF) is synthesized in male germ cells. The NGF receptor (NGFR) mRNA was found in the Sertoli cells of rat testis. Hypophysectomy increased both NGFR mRNA in testis and the number of NGFR hybridizing cells in seminiferous tubules. This was suppressed by treatment with chorionic gonadotropin or testosterone, but not with follicle-stimulating hormone. The NGFR mRNA also increased after destruction of Leydig cells or blocking of the androgen receptor. This suggests that NGF produced by male germ cells regulates testicular function in an androgen-modulated fashion by mediating an interaction germ and Sertoli cells.

Genotropin 16 IU KabiVial is more convenient than conventional administration systems for children on growth hormone therapy.

The use of a new device for reconstitution and storage of growth hormone (GH), Genotropin KabiVial, was studied in 20 children, aged 9-17 years, who had been receiving GH therapy using conventional administration systems. After 2 weeks of treatment, the convenience of the device and the patients' tolerance of it were assessed by the patients/families through a questionnaire. They were asked to compare the new device with the conventional method (standard vials and syringes). Most of the patients found the new device superior to the conventional method; they found that it was easier to reconstitute the GH and considered the multi-dose system and the smaller injection volume to be advantageous. Ninety per cent of the patients (p less than 0.001) expressed a preference for Genotropin 16 IU KabiVial for their future therapy.

Administration of growth hormone by disposable preloaded syringes.

The convenience of Genotropin KabiQuick, a novel single-use disposable injection system for growth hormone (GH) administration, was studied in 20 GH-treated children aged 8-16 years. The convenience of the device and tolerance to it were assessed by means of a questionnaire, which was completed by the patients and their families after a treatment period of 2 weeks. The families were asked to compare the new device with the conventional system of GH administration, involving the use of standard ampoules and ordinary syringes. The majority of patients considered the new device superior to the conventional system; 85% of patients found reconstitution easier and 70% found dosing easier. Sixty-five per cent of patients expressed a preference for using Genotropin KabiQuick for future therapy. It is concluded that Genotropin KabiQuick is well tolerated and that the majority of patients prefer it to conventional injection systems for GH administration.

Molecular Xp deletion in a male: suggestion of a locus for hypogonadotropic hypogonadism distal to the glycerol kinase and adrenal hypoplasia loci.

We have analyzed one patient with a syndrome of glycerol kinase deficiency (GKD), adrenal hypoplasia (AH), mental retardation (MR) and hypogonadotropic hypogonadism (HH). Although a cytogenetic analysis of the patient failed to reveal any detectable chromosomal abnormality, Southern blot analysis, using DNA probes from the Xp21-Xp22 region, revealed a molecular deletion localized between the DXS41 and the DXS268 loci. Our results together with those of others (van Ommen et al. 1986, 1987, Francke et al. 1987, Yates et al. 1987, Chelly et al. 1988) suggest that the GK gene is located between the DXS68 and DXS268 loci. In addition, we propose a locus for HH in Xp, distal to the genes for GK and AH.