A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia,skin disorder,and woolly hair

OBJECTIVES: The goal of this study was to analyze the genetic disorder of a family with cardiomyopathy, skin disorder, and woolly hair. BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder causing arrhythmia and sudden cardiac death. We report a patient with familial autosomal recessive ARVD, woolly hair, and a pemphigous-like skin disorder with a new mutation in the desmoplakin gene. METHODS: Genomic deoxyribonucleic acid was extracted from the patient's blood and 12 first- and second-degree family members, and was amplified by polymerase chain reaction. Linkage analysis with polymorphic microsatellites was performed for 11 genes that code for structural desmosomal proteins. The genetic locus of the disease in this family was mapped to the chromosomal region 6p24 that contains the desmoplakin gene. Exons of the desmoplakin gene were analyzed by single-strand conformational polymorphism and direct sequencing. Confirmation of the mutation was carried out by restriction enzyme analysis. RESULTS: We identified in the patient a homozygous missense mutation in exon 24 of the desmoplakin gene, leading to a Gly2375Arg substitution in the C-terminal of the protein where the binding site to intermediate filaments is located. Eight of 12 family members without hair or skin abnormalities were heterozygous for this mutation. The remaining 4, as well as 90 unrelated healthy control individuals of the same ethnic origin, were homozygous for the normal allele. CONCLUSIONS: We have described a new mutation in the desmoplakin gene that causes familial ARVD. These findings suggest that desmosomal proteins play an important role in the integrity and function of the myocardium. Dysfunction of these proteins can lead to the development of cardiomyopathies and arrhythmias.     

The emergence and treatment of anorexia and bulimia nervosa. A comprehensive and practical model

The objective was to propose and describe a new bio-psycho-social model of emergence and maintenance of anorexia nervosa and bulimia nervosa, and demonstrate its application to treatment. An original model, based on literature review and our own clinical experience, was created. Therapeutic guidelines were derived from the theoretical model and applied in the treatment of 97 anorexia and bulimia nervosa patients presented at the eating disorders unit at Kaplan Hospital in Israel over 18 months. A team comprising a pediatrician, a child psychiatrist, a dietician, and trained nurses collaborated in a comprehensive systemic therapeutic approach involving parents, schools, and community agents. RESULTS: Ninety-one girls and six boys were treated in the eating disorder unit (55 had AN, 29 had BN and 13 had EDNOS). Thirty-seven patients were hospitalized and sixty were treated in the outpatient clinic. Mean hospitalization time of the first five patients was 108 days. Mean hospitalization time of the remaining 32 patients was reduced to 32 days. The mean number of outpatient clinic interventions was 12. At the one-year follow up, 74 patients were doing well in all respects. Fourteen patients still needed a lot of supervision in eating. Five are still hospitalized and four were lost to follow up. CONCLUSIONS: The proposed model proves to be more than just another theory in that it is successfully applied in treatment. Short systemic therapy is very effective. The longer the delay in drastic, aggressive treatment, the worse the prognosis. Extended hospitalization periods worsen the prognosis. Weakness of the parental unit is a strong indication for inpatient care. The longer the experience in treating eating disorders, the shorter the hospitalization and number of interventions.     

The haematopoietic specific signal transducer Vav1 is expressed in a subset of human neuroblastomas

Vav1 is a signal transducer protein expressed exclusively in the haematopoietic system, where it plays a pivotal role in growth factor-induced differentiation and proliferation. Vav1 couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, leading to cell differentiation and/or proliferation. Vav1 was originally detected as an oncogene, but its involvement in human malignancies has not been reported thus far. We report here that Vav1 is expressed in a neuroblastoma cell line, SK-N-MC. Molecular analysis indicated that there are no gross rearrangements or mutations in the Vav1 gene in SK-N-MC cells. Vav1 protein from SK-N-MC cells was similar to wild-type Vav1 in apparent molecular weight, phosphorylation state, and ability to associate with active EGFR. We also analysed the expression of Vav1 in 42 specimens of human neuroblastoma. Vav1 was expressed in the majority of these tumours. Our results suggest that Vav1 may play a role in the neoplastic process in a subset of neuroblastomas.     

Effect of repeated orthodontic treatment on the dental and periodontal tissues of the rat incisor

This study evaluated the response of treated teeth to renewed orthodontic force. Thirty female rats (201 +/- 2.7 g) were divided into groups A and B. Linguointrusive loads (20.58 +/- 1.88 g) generated by springs were applied to the lower left incisor for 2 weeks and then removed to allow recovery during 27 weeks (group A). Identical loading was then repeated in group A and applied as primary treatment in group B. Five animals from each group were killed with the springs in situ (A-1 and B-1), while the remaining 20 animals were killed after a 3-month recovery (A-2, B-2). The decalcified incisors were cross-sectioned serially (2 microm), and the distance of each section from the apex was computed. Dental and periodontal injuries were evaluated by light microscopy and plotted according to their location on the tooth axis. The intrusion of the teeth in group A-1 was significantly greater, whereas recovery of the normal eruption rate in group A-2 was significantly slower compared with groups B-1 and B-2. The histopathologic lesions in groups A-1 and B-1 did not differ. However, group A-2 showed a higher frequency of injured enamel organ, tissue infiltration by inflammatory cells, necrotic areas, and dentin resorption than group B-2. Initial orthodontic loading had a detrimental effect on the ability of the periodontal and dental tissues to cope with, and to recover from, repeated stress, probably because of a decrease in the number of periodontal fibroblasts and damage to the dentin-protecting cementoblastic layer.     

NMR studies of recombinant active site peptides of the nicotinic acetylcholine receptor.

Interactions of ligands with recombinant cholinergic binding sites have been monitored by NMR. Monitoring the selective T1 relaxation of the protons of acetylcholine, nicotine, d-tubocurarine, and gallamine reveals specific binding to peptide constructs containing the alpha 183-204 or shorter sequences of the nicotinic acetylcholine receptor of Torpedo, Human, Chicken, Xenopus, Mouse, Calf, and Drosophila. The trend of the KD values of the different ligands shows that the binding of the low molecular weight agonists and antagonists is very weak to the Drosophila sequence which is different from the vertebrate sequences in the N and C terminals. Within the vertebrates, the antagonists d-tubocurarine and gallamine display a KD trend different from that of acetylcholine and alpha-bungarotoxin. Specificity of binding is proven by the fact that atropine, a muscarinic inhibitor, binds non-specifically. Temperature dependence indicates a fast exchange limit (T1 bound greater than tau bound) for gallamine bound to the Torpedo alpha 184-200 sequence. This limit should apply also for the other ligands which have weaker binding constants.