CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens.

Congenital bilateral aplasia of the vas deferens (CBAVD) was suggested to be a mild form of cystic fibrosis (CF). Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in males with CBAVD revealed that in some males CBAVD is caused by two defective CFTR alleles. The genetic basis of CBAVD in the other males and its association with CF remained unclear. We undertook this study to test the hypothesis of commonality of CBAVD and CF by haplotype analysis, in the CFTR locus, of males suffering from CBAVD and of their families. According to the hypothesis of commonality of CBAVD and CF, two brothers with CBAVD are expected to carry the same two CFTR alleles, while their fertile brothers are expected to carry at least one different allele. Eleven families were studied, of which two families, with unidentified CFTR mutations, did not support this hypothesis. In these families two brothers with CBAVD inherited different CFTR alleles. Their fertile brothers inherited the same CFTR alleles as their brothers with CBAVD. These results provide evidence for genetic heterogeneity in CBAVD. Though in some families CBAVD is associated with two CFTR mutations, we suggest that in others it is caused by other mechanisms, such as mutations at other loci or homozygosity or heterozygosity for partially penetrant CFTR mutations.

Prognostic evaluation of cutaneous malignant melanoma based on the pTNM classification.

The prognoses of 100 consecutive melanoma patients were analyzed on the basis of Breslow's thickness and Clark's levels as well as according to stage employing the 1987 UICC pTNM classification. Among patients with lesions < or = 1.50 mm thick, the 10-year survival rate was 100% for both pT1 (n = 13) and pT2 (n = 6) disease, 73.4% for pT3a disease (n = 26), 62.2% for pT3b disease (n = 15), 69.3% for pT3 (n = 41) disease, and 38.7% for pT4 disease (n = 38). Significant differences in survival were found between the pT4 group and the pT1/pT3a or pT3 groups. The 10-year survival rate was 100% for level II (n = 13) and level III (n = 13) disease, 58.3% for level IV (n = 46) disease, and 34.5% for level V (n = 26) disease. Significant differences were found between level V and other levels. The survival rate at 10 years was 100% for stage I (n = 18), 63.3% for stage II (n = 24), and 52.5% for stage III (n = 55). In stage IV (n = 3), there was only one patient who survived for 42 months. There were significant differences in survival among all stages except I and II. The 10-year survival rate in 3 subgroups of stage III was 58.9% for pT4pN0M0 patients (n = 14), 63.2% for pT,pN1M0 patients (n = 31), and 20% for pT,pN2M0 patients (n = 10). Significant differences were found between the pT,pN1M0 and pT,pN2M0 subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

G-protein mediating the slow depolarization induced by FMRFamide in the ganglion cells of Aplysia.

Application of FMRFamide (Phe-Met-Arg-Phe-NH2) induced a slow depolarization in neurons of the Aplysia abdominal ganglion. In voltage-clamped cells, FMRFamide induced a slow inward current that increased when the membrane was depolarized beyond -85 mV, showing a negative slope conductance. However, this inward current never reversed to outward current when hyperpolarized beyond the equilibrium potential for K+. The FMRFamide-induced response was markedly augmented in Ca(2+)-free media, but depressed in Na(+)-free media. It was unaffected by a change in external potassium. Intracellular injection of guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) significantly depressed the FMRFamide response in a dose-dependent way. Injection of cholera toxin (CTX) which did not cause any current response, selectively and irreversibly blocked the FMRFamide response. Neither 3'-deoxyadenosine, an inhibitor of adenylate cyclase, nor H-8, an inhibitor of cyclic adenosine 3',5'-monophosphate (cyclic AMP)-dependent kinase, depressed the FMRFamide response. 3-Isobutyl-1-methylxanthine (IBMX) did not augment the FMRFamide response appreciably. The FMRFamide response was not occluded at all by a relatively large injection of 8-bromo-cyclic AMP. It was concluded that the FMRFamide response is produced by the opening of the voltage-dependent Na(+)-channels via activation of a certain CTX-sensitive G-protein which is different from conventional "Gs" that activates adenylate cyclase.