Models of <i>KPTN</i>-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.</p

A within-patient comparison between superovulation with intra-uterine artificial insemination using husband's washed spermatozoa and gamete intrafallopian transfer in unexplained infertility

The purpose of this study was to evaluate the success of gamete intrafallopian transfer (GIFT) and superovulation with intra-uterine artificial insemination (S-IUI) in couples with long-term unexplained infertility. Thirty-nine couples were offered three attempts at each treatment. Sixty-three IUI cycles were completed with a pregnancy rate of 1.5% per cycle. Forty-nine GIFT procedures were carried out with a pregnancy rate of 26.5% per cycle. The cumulative conception rate after three cycles of GIFT was 0.56. GIFT appears to offer a far greater chance of pregnancy than S-IUI in unexplained infertility

Frequency of child maltreatment in a representative sample of the German population

Iffland B, Brähler E, Neuner F, Häuser W, Glaesmer H. Frequency of child maltreatment in a representative sample of the German population. BMC Public Health. 2013;13(1): 980.Background Representative data about the frequency of child maltreatment is needed in order to estimate the extent of the problem in the wider population as well as to provide the basis for interpretation of frequency rates in clinical samples. However, previous representative studies on the frequency of child maltreatment in Germany and other countries were limited as they focused on the assessment of physical and sexual abuse whilst emotional forms of maltreatment were ignored. In addition, previous studies applied scales that had not been validated against external criteria. Methods In a cross-sectional study, standardized questionnaires were administered to a representative sample of the German population. Maltreatment in childhood and adolescence was assessed using the German version of the Childhood Trauma Questionnaire. Empirically derived threshold values for the five different types of child maltreatment including emotional maltreatment were applied to determine presence of abuse and neglect. Results Complete data was available from N = 2,500 subjects. Prevalence rates were 13.9% for emotional neglect, 10.2% for emotional abuse, 12.0% for physical abuse, 48.4% for physical neglect, and 6.2% for sexual abuse. Differences between sexes were found for the frequency of sexual abuse. Conclusions Although our analysis has found lower rates of child maltreatment than previous reports that used less well validated criteria, the results of this study confirm that child abuse, with its many different facets, is a significant problem in Germany