W. Distler

OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling

A major cause of the cerebral cortex expansion that occurred during evolution is the increase in subventricular zone (SVZ) progenitors. We found that progenitors in the outer SVZ (OSVZ) of developing human neocortex retain features of radial glia, in contrast to rodent SVZ progenitors, which have limited proliferation potential. Although delaminating from apical adherens junctions, OSVZ progenitors maintained a basal process contacting the basal lamina, a canonical epithelial property. OSVZ progenitor divisions resulted in asymmetric inheritance of their basal process. Notably, OSVZ progenitors are also found in the ferret, a gyrencephalic nonprimate. Functional disruption of integrins, expressed on the basal process of ferret OSVZ progenitors, markedly decreased the OSVZ progenitor population size, but not that of other, process-lacking SVZ progenitors, in slice cultures of ferret neocortex. Our findings suggest that maintenance of this epithelial property allows integrin-mediated, repeated asymmetric divisions of OSVZ progenitors, providing a basis for neocortical expansion.

Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal

The expansion of the neocortex during mammalian brain evolution results primarily from an increase in neural progenitor cell divisions in its two principal germinal zones during development, the ventricular zone (VZ) and the subventricular zone (SVZ). Using mRNA sequencing, we analyzed the transcriptomes of fetal human and embryonic mouse VZ, SVZ, and cortical plate. In mouse, the transcriptome of the SVZ was more similar to that of the cortical plate than that of the VZ, whereas in human the opposite was the case, with the inner and outer SVZ being highly related to each other despite their cytoarchitectonic differences. We describe sets of genes that are up- or down-regulated in each germinal zone. These data suggest that cell adhesion and cell–extracellular matrix interactions promote the proliferation and self-renewal of neural progenitors in the developing human neocortex. Notably, relevant extracellular matrix-associated genes include distinct sets of collagens, laminins, proteoglycans, and integrins, along with specific sets of growth factors and morphogens. Our data establish a basis for identifying novel cell-type markers and open up avenues to unravel the molecular basis of neocortex expansion during evolution.

Impact of antenatal synthetic glucocorticoid exposure on endocrine stress reactivity in term-born children.

CONTEXT Antenatal glucocorticoid (GC) exposure has been discussed as a potent programming factor of hypothalamus-pituitary-adrenal (HPA) axis activity, producing sustained alterations in cortisol secretion throughout life. So far, the assessment of HPA-axis activity in offspring of mothers treated with synthetic GC has been limited to a time period shortly after birth, with prematurity being an important confound in most prior studies. OBJECTIVE The present study aimed to investigate HPA-axis reactivity of term-born children with antenatal GC exposure in a larger sample, allowing us to further address sex- and drug-specific effects. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study comprised of 209 term-born children between 6 and 11 yr of age. Cortisol secretion patterns in response to a standardized laboratory stressor (Trier Social Stress Test for Children) were assessed in children with antenatal GC exposure (a single course of either dexamethasone or betamethasone) and compared to different control groups. RESULTS We observed significantly increased cortisol reactivity to acute psychosocial stress in 6- to 11-yr-old, term-born children exposed to antenatal synthetic GC treatment compared to controls (F(3.4,345.9)=5.8; P<0.001). This finding appeared to be independent of the specific synthetic GC used and was found to be more pronounced in females. CONCLUSIONS The present study provides the first evidence for long-lasting effects of antenatal synthetic GC exposure on HPA-axis reactivity in term-born children. These findings may bear important implications regarding the vulnerability for stress-related physical and psychiatric disorders, for which dysregulation of the HPA-axis has been discussed as a potential causal factor.

Retransplantation of Cryopreserved Ovarian Tissue: the First Live Birth in Germany

BACKGROUND Cryopreserved ovarian tissue can be retransplanted to restore fertility after radiation or chemotherapy. To date, 15 live births after retransplantation have been reported worldwide. We report the first pregnancy and the first live birth after retransplantation in Germany. CASE REPORT A 25-year-old female patient received initial chemotherapy and radiation of the mediastinum for Hodgkins lymphoma in 2003 and suffered a relapse two years later. Ovarian tissue was laparoscopically removed and cryopreserved, and she was then treated with high-dose chemotherapy and stem cell transplantation. She remained in remission for 5 years and she could not conceive during this time. The cryopreserved ovarian tissue was thawed and laparoscopically retransplanted into a peritoneal pouch in the ovarian fossa of the right pelvic wall. Three months later, her menopausal symptoms resolved, and she had her first spontaneous menstruation. Six months after retransplantation, after two normal menstrual cycles, low-dose follicle stimulating hormone (FSH) treatment induced the appearance of a dominant follicle in the tissue graft. Ovulation was then induced with human chorionic gonadotropin (HCG), whereupon the patient conceived naturally. After an uncomplicated pregnancy, she bore a healthy child by Caesarean section on 10 October 2011. Histological examination of biopsy specimens revealed that the ovarian tissue of the graft contained follicles in various stages of development, while the original ovaries contained only structures without any reproductive potential. CONCLUSION This was the first live birth after retransplantation of cryopreserved ovarian tissue in Germany and also the first case with histological confirmation that the oocyte from which the patient conceived could only have come from the retransplanted tissue. In general, young women who will be undergoing chemotherapy and/or radiotherapy for cancer must be informed and counseled about the available options for fertility preservation.

Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other malignancies: case report and review of the literature

BackgroundLi-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited tumour predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. Patients with LFS are at a high risk to develop early-onset breast cancer and multiple malignancies, among which sarcomas are the most common. A high incidence of childhood tumours and close to 100% penetrance has been described. Knowledge of the genetic status of the TP53 gene in these patients is critical not only due to the increased risk of malignancies, but also because of the therapeutic implications, since a higher rate of radiation-induced secondary tumours in these patients has been observed.Case reportWe report a patient with LFS harbouring heterozygous, pathogenic TP53 germline mutation, who was affected by four synchronous malignancies at the age of 40: a myxofibrosarcoma of the right upper arm, bilateral breast cancer and a periadrenal liposarcoma. Radiological treatments and a surveillance program were adjusted according to recommendations for LFS patients.ConclusionManagement of tumour treatment of patients with LFS is different to the general population because of their risk for secondary cancers in the radiation field. Screening procedures should take a possibly elevated risk for radiation induced cancer into account.

Chemiluminometric determination of tissue polypeptide antigen (TPA), cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA) in comparison with vascular endothelial growth factor (VEGF) in follow-up of breast cancer.

Vascular endothelial growth factor (VEGF), tissue polypeptide antigen (TPA), cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) were measured in 314 sera of breast cancer patients and in 58 sera of women without breast cancer. VEGF was determined using a sandwich enzyme immunoassay technique (ELISA) and the tumour markers TPA, CA 15-3 and CEA with an immunoluminometric assay (ILMA). The breast cancer patients were staged according to the TNM classification stages 0-IV (by UICC) in patient groups with a compatible prognosis. Median and range of each stage were investigated. The cut-off values (95th and 97.5th percentile of control group) of VEGF, TPA, CA15-3 and CEA were determined; sensitivities for each parameter and for all combinations of two parameters were investigated for these cut-offs and the receiver operating characteristic (ROC) curves were calculated. The differences between the control group and stages 0-3 were shown to be non-significant for CA 15-3 and CEA but significant for VEGF and TPA. Significant differences were found in stage 4 for VEGF and all three markers. The increase in sensitivity of VEGF from stage 0 to stage 3 and the decrease from stage 3 to stage 4 can be interpreted based on the role of VEGF in the angiogenesis. The quantification of VEGF could give additional information for selecting patients for systemic adjuvant therapy.

Impact of Antenatal Glucocorticoid Therapy and Risk of Preterm Delivery on Intelligence in Term-Born Children

CONTEXT Women at risk of preterm delivery are routinely treated with synthetic glucocorticoids (sGCs). Although this therapy substantially reduces neonatal morbidity, concerns remain whether sGC excess may disrupt neurodevelopmental trajectories underlying cognitive functioning. OBJECTIVE The present study is the first to disentangle direct effects of antenatal sGC treatment on possible long-term cognitive disadvantages from those of pregnancy complications and prematurity. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included a mixed-sex cohort of 222 term-born children (aged 6-11 years) consisting of three groups: children of mothers admitted to hospital for threatening preterm delivery who had been treated (n = 97) or untreated (n = 36) with sGCs, and controls without pregnancy complications (n = 89). INTERVENTION Antenatal sGC treatment consisted of single courses with dexamethasone or betamethasone. MAIN OUTCOME MEASURE Psychometric intelligence was assessed using a German adaption of Cattells Culture Fair Test. RESULTS Children born to mothers at risk for preterm delivery scored, on average, 6-7 IQ points below children of mothers without pregnancy complications, irrespective of antenatal sGC treatment. Compared to females, boys were found to be more susceptible to cognitive disadvantages associated with maternal risk for preterm delivery. CONCLUSIONS Our data indicate that conditions related to a threatening preterm delivery rather than antenatal sGC treatment per se are associated with long-term decreases in the childs intelligence. Although these findings imply that a single course of sGC therapy does not aggravate long-term cognitive deficits, they highlight the need for interventions to reduce the detrimental consequences of distress induced by a threatening preterm delivery.

Comparison of tissue polypeptide antigen (TPA) with cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) in follow-up of breast cancer.

Abstract Cancer antigen 15–3 (CA 15–3), carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) were measured in 679 sera of breast cancer patients and in 94 sera of women without breast cancer. The tumour markers were determined using immunoluminometric assays (ILMA). The assays are characterised by an inter-assay-imprecision and intra-assay-imprecision <4 %. The breast cancer patients were staged according to the TNM classification stage 0–IV (by UICC) in patient groups with a compatible prognosis. Median and range of each stage were investigated. The cut-off values (95th and 97.5th percentile of control group) of CA 15–3, CEA and TPA were determined; specificity, sensitivity, positive and negative predictive value (PV) and efficiency were investigated for these cut-offs and the receiver operating characteristic (ROC) curves were calculated. The differences between control group and stage 0–3 were shown as non-significant for CA 15–3 and CEA but significant for TPA. Significant differences were found in stage 4 for all three tumour markers. The three tumour markers did not have differences in specificity, positive and negative PV and efficiency. TPA and CA 15–3 demonstrated comparable results in sensitivity and ROC curve analyses. These results were better than those from CEA.

Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer

BackgroundHereditary Breast and Ovarian Cancer Syndrome (HBOCS) and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome) are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 are very rare.Case presentationWe identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years.ConclusionsAlthough carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes.

Die B-Lynch-Naht

ZusammenfassungDie B-Lynch-Technik ist eine etablierte, risikoarme Methode, um uteruserhaltend eine postpartale Hämorrhagie (PPH) zu beherrschen. Eine weniger invasive Alternative ist die bimanuelle Kompression der Gebärmutter. Beide Methoden stellen valide Optionen dar, um möglichst konservativ vorzugehen und letztendlich die Fertilität zu erhalten. AbstractThe B-Lynch suture technique is an established low-risk method for managing postpartum uterine haemorrhaging while conserving the uterus. A less invasive alternative is bimanual compression of the uterus. Both methods represent valid options for conservative procedures in order to maintain fertility.