Bibliothek

Notizen: Summary Cultured fibroblasts from patients suffering from Duchenne's Muscular Dystrophy were examined by indirect immunofluorescent techniques using antibodies against actin, myosin, tubulin, and intermediate-sized filaments. The cells display normal patterns of microfilamentous bundles (stress fibres), microtubules, and intermediate-sized filaments suggesting a normal organization of these cytoskeletal structures.

Notizen: Summary Duchenne muscular dystrophy (DMD) is the most common sex linked lethal disease in man (one case in about 4000 male live births). The patients are wheelchair bound around the age of 8–10 years and usually die before the age of 20 years. The mutation rate, estimated by different methods and from different population studies, is in the order of 7×10-5, which is higher than for any other X-linked genetic disease. Moreover, unlike other X linked diseases such as hemophilia A or Lesh-Nyhan's disease, there seems to be no sex difference for the mutation rates in DMD. Several observations of DMD in girls bearing X-autosomal translocations and linkage studies on two X chromosomal DNA restriction fragment length polymorphisms indicate that the DMD locus is situated on the short arm of the X chromosome, between Xp11 and Xp22. It may be of considerable length, and perthaps consisting of actively coding and non-active intervening DNA sequences. Thus unequal crossing over during meiosis in females could theoretically account for a considerable proportion of new mutations. However, there is no structurally or functionally abnormal protein known that might represent the primary gene product, nor has any pathogenetic mechanism leading to the observed biochemical and histological alterations been elucidated. Among the numerous pathogenetic concepts the hypothesis of a structural or/and functional defect of the muscular plasma membrane is still the most attractive. It would explain both the excess of muscular constituents found in serum of patients and carriers, such as creatine kinase (CK), as well as the excessive calcium uptake by dystrophic muscle fibres, which, prior to necrosis, could lead to hypercontraction, rupture of myofilaments in adjacent sarcomeres and by excessive Ca uptake to mitochondrial damage causing crucial energy loss. The results of studies on structural and functional memthrane abnormalities in cells other than muscle tissue, e.g., erythrocytes, lymphocytes and cultured fibroblasts, indicate that the DMD mutation is probably demonstrable in these tissues. However, most of the findings are still difficult to reproduce or even controversial. DMD is an incurable disease; therefore most effort, in research as well as in practical medicine, is concentrated upon its prevention. Unfortunately the disease cannot yet be diagnosed prenatally. Potential DMD carriers among female relatives of the patients may be identified by pathological heterozygote tests, of which determination of serum CK activity is probably still the most reliable method, allowing the detection of about 70% of adult and probably up to 90% of carriers at school age. Because of the high mutation rate, assessment of individual heterozygote risks in female relatives of isolated DMD cases is of special importance. For the calculations a maximum of genealogical and phenotype information on unaffected male and on heterozygote tests in female relatives is needed to obtain credible risk figures. However, estimating a consultand's risk and passing on this information is only one aspect of genetic counselling in DMD. At least as important is information on the medical, psychological and social impacts of the disease (burden) and the possibility of maintaining a long-term contact between the couples at risk and the team involved in medical, genetic and social problems of the disease. Neonatal CK screening for DMD, although without any therapeutical consequence, could theoretically lead to the prevention of “secondary” cases, accounting for some 15% of all DMD patients born, but an almost equal prevention rate of such cases would be achieved if CK examinations were limited to all boys with delayed motor development during the first 2 years of life. Finally, it is believed that the two most important preventive problems in DMD, carrier detection and prenatal diagnosis, will ultimately be solved by means of the rapidly advancing DNA technology.

Notizen: Summary A syndrome due to 3:1 meiotic segregation of balanced 11/22 translocation is defined from nine personally observed patients and 22 cases from the literature with apparently the same aberration. Frequent findings include a characteristic face with deepset eyes, flat nose, prominent upper lip, receding mandible and preauricular pits or tags, male genital hypoplasia, anal atresia or other anomalies of the anus, cleft palate, and congenital heart defect. Less frequent are severe reduction of the auricles, an additional pair of ribs, and hypoplasia of the diaphragm. Perinatal mortality is high. Growth is usually and psychomotor development is invariably and severely delayed. Balanced 11/22 translocations are apparently disproportionally frequent; as the balanced rearrangement is not easy to detect, it is important to be aware of it at the family investigation of cases with extra chromosomes similar to a No.22 or 22q-.The unbalanced products are most probably trisomic for both a segment of 22 (22q-) and a distal segment of 11q; the exact determination of the breakpoints is not possible at present due to the similar banding characteristics of the two segments involved in the translocation.

Notizen: Summary Hairless mice were immunized with herpes simplex virus type 1 (HSV-1) envelope antigen (EAG), EAG in association with polyriboinosinic · polyribocytidylic acid-poly-L-lysine complexed with carboxymethylcellulose (PICLC), and inactivated purified HSV-1 (VAG). After 2 weeks the mice were challenged by a percutaneous HSV-1 infection in the orofacial (OF) or lumbosacral (LS) skin area. Following immunization a consistent cell-mediated immune response was observed in all immunized mice, although the humoral immune response was very low, or not detectable. After challenge, a marked secondary humoral and cell-mediated immune response developed in all immunized mice, and the animals were protected against the development of skin lesions and the fatal outcome of infection. However, the establishment of latent infections in the sensory ganglia was not prevented by the immunization procedure.

Notizen: Abstract The efficacy of a herpes simplex virus type 1 (HSV-1) envelope antigen (EAG) preparation against HSV infection was studied in T cell competent and T cell deficient mice. Immuno-competent mice were successfully protected against herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) infection when immunized 2 weeks prior to this infection with a heat-inactivated whole virus preparation or a HSV-1 envelope antigen (HSV-1 EAG) preparation. Since HSV-1 EAG was considerably less effective than the whole virus preparation, a polyriboinosinic-polyribocytidylic acid complex with poly-L-lysine and carboxymethylcellulose (PICLC) was used as adjuvant. Immunization with HSV-1 EAG plus PICLC resulted in a pronounced increase of this protection rate as compared with that obtained after immunization solely with HSV-1 EAG. PICLC alone, however, offered no protection when given 2 weeks before challenge. In T cell deficient nu/nu mice no protection was achieved with HSV-1 EAG while their T cell competent, heterozygous littermates were protected. From these results it may be concluded that T cell competence is a prerequisite for establishing a protective immunity against HSV infection after immunization with HSV-1 EAG.

Notizen: Abstract A new approach particularly appropriate in bioequivalence studies is outlined. Two formulations of a drug are considered as bioequivalent if the ratio θ=ΜN/Μs of the expected values of the formulation means lies between specified limits r1 and r2.We use the posterior probability P,which provides, in histogram form, interpretational flexibility in bioequivalence assessment.