E. J. Van Rensburg

Strong association of de novo copy number mutations with sporadic schizophrenia

Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively ∼8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.

Hypochlorous acid potentiates hydrogen peroxide-mediated DNA-strand breaks in human mononuclear leucocytes.

In this study the formation of DNA single-strand breaks in MNL in close proximity to activated phagocytes, or in contact with added H2O2 and/or HOCl, were evaluated. Neutrophils activated by phorbol myristate acetate (PMA), induced DNA-strand breaks in neighboring lymphocytes which increased after 1-2 h incubation in a repair medium. These DNA-strand breaks could be prevented by the addition of catalase or substitution of the neutrophils with cells from a patient with chronic granulomatous disease. Inclusion of the myeloperoxidase (MPO) inhibitor, sodium azide (NaN3), to the system was associated with less damage after 1-2 h incubation and a faster repair rate. Exposure of MNL to added reagent H2O2 (12-100 microM) was also accompanied by DNA damage. Addition of reagent HOCl (3-25 microM) did not induce any DNA-strand breaks. However, when combined with H2O2 (12.5 microM), HOCl increased H2O2-mediated DNA damage and compromised the repair process. Interactions between the phagocyte-derived reactive oxidants H2O2 and HOCl are probably involved in the etiology of inflammation-related cancer.

Cancer prevalence in 129 breast-ovarian cancer families tested for BRCA1 and BRCA2 mutations

BACKGROUND Women who carry germline mutations in the breast-ovarian cancer susceptibility genes, BRCA1 and BRCA2, are at very high risk of developing breast and/or ovarian cancer. Both genes are tumour suppressor genes that protect all cells from deregulation, and there are reports of their involvement in other cancers that vary and seem to depend on the population investigated. It is therefore important to investigate the other associated cancers in different populations to assist with risk assessments. OBJECTIVES To assess the cancer risk profile in BRCA-mutation-positive and negative South African breast-ovarian cancer families, mainly of Caucasian origin. DESIGN Descriptive study in which the prevalence of all cancers in the pedigrees of BRCA1- and BRCA2-mutation-positive groups and a group of families without mutations in either gene were compared with the general population. RESULTS As expected, female breast and ovarian cancer was significantly increased in all three groups. Furthermore, male breast cancer was significantly elevated in the BRCA2-positive and BRCA-negative groups. Stomach cancer prevalence was significantly elevated in the BRCA2-positive families compared with the general population. CONCLUSIONS These results can be applied in estimation of cancer risks and may contribute to more comprehensive counselling of mutation-positive Caucasian breast and/or ovarian cancer families.

Nucleoid Sedimentation Analysis of DNA Superstructure, γ-Radiation-induced Damage and Repair in Human and Chacma Baboon (Papia Ursinus) Peripheral Lymphocytes

The use of the chacma baboon (Papio ursinus) in radiobiological investigations justifies special attention because it answers many of the criteria of parallelism to the human. The present study was undertaken to establish whether in vitro gamma-radiation effects in chacma baboon and human lymphocytes are comparable. The sensitive and rapid nucleoid sedimentation technique was employed to evaluate in vitro DNA superstructure, damage and repair in readily obtainable radiosensitive peripheral lymphocytes. Dose-response curves after 60Co gamma-irradiation were obtained, and by applying single-hit kinetics of the target theory, an estimation of molecular masses of the supercoiled domains was made. The baboon and human lymphocytes produced analogous results, while an ethidium bromide intercalation study also revealed a similarity in average DNA superhelical density. Lymphocyte DNA repair after 0.5-4.0 Gy gamma-irradiation and repair times from 0.5 to 5.0 h were evaluated. The repair data obtained from baboon and human cells after 2.0 Gy irradiation compared favourably in extent of DNA repair as well as the profiles of the kinetic curves. These findings indicate that the chacma baboon would be a useful and relevant model for further in vivo radiobiological studies on lymphocytes. The effects of sedimentation conditions and advantages of using vertical-tube rotors in the nucleoid sedimentation technique are also discussed.

Investigation by scintigraphic methods of neutrophil kinetics under normal and septic shock conditions in the experimental baboon model.

The purpose of this study was the correlation of neutrophil kinetics with the pathogenic course of septic shock in the baboon model. Radioactively labelled neutrophils were traced in vivo in normal baboons (n= 6) and inEscherichia coli-infected baboons, which were reinjected with labelled autologous neutrophils either 2 h after the onset of theE. coli infusion (procedure A) (n= 3) or simultaneously with the infusion (procedure B) (n=3). Cell isolation was done according to a method developed in this laboratory. The cells were labelled with tropolonate In 111. resuspended in 1–2 ml plasma and reinjected. One-minute images were taken every 5th min and then hourly for 4 h with a gamma camera and analysed with a data processor. Time-activity curves were obtained for neutrophil washout from the lungs and neutrophil accumulation in the liver and spleen. These curves were compared for normal baboons and for those treated according to procedures A and B. A significant retention of neutrophils in the lungs of baboons withE. coli-induced septic shock was noted as well as an abnormally slow rate of accumulation in the liver and spleen. It also seems that any lung injury which could be attributed to changes in neutrophil behaviour should be traced back to events during the early exposure of neutrophils to bacterial infection.