DFNA54, a third locus for low-frequency hearing loss

Nonsyndromic hereditary hearing impairment (NSHHI) is a highly heterogeneous disorder with more than 90 loci mapped, of which nearly one-half of the responsible genes are identified. In dominant NSSHI hearing loss is typically biased towards the high frequencies while low-frequency hearing loss is unusual. Only two NSHHI loci, DFNA1 and DFNA6/14/38, are associated with predominantly low- frequency loss. We mapped the loci harboring the gene responsible for autosomal dominant low-frequency hearing loss in a multigenerational family. The pedigree of a Swiss family with low-frequency hearing loss was established. Using genomic DNA, DFNA1 and DFNA6/14/38 were excluded by linkage analysis or by direct sequencing of the responsible gene. Genome-wide linkage analysis was performed using commercially available microsatellite markers. Two-point linkage analysis demonstrated linkage to chromosome 5q31, the locus for DFNA15, with a lod score of 6.32 at recombination fraction =0 for marker D5S436. Critical recombinations were seen at markers D5S1972 and D5S410. Sequencing of the corresponding gene POU4F3 yielded no pathogenic mutation segregating with the affected members. In addition to Wolfram syndrome gene 1 (DFNA6/14/38) and diaphanous (DFNA1) there is evidence for a third gene involved in low-frequency hearing loss located at DFNA15. Because of the differences in auditory phenotype and the absence of pathogenic mutation in the coding region of POU4F3 it is likely that there is a second gene in 5q31, designated DFNA54, associated with NSHHI.     

Role of tumor necrosis factor in macrophage leishmanicidal activity in vitro and resistance to cutaneous leishmaniasis in vivo.

Recombinant human tumor necrosis factor (TNF) and purified murine TNF were both able to activate macrophages to destroy intracellular Leishmania major in vitro. In addition, parasitizing macrophages with L. major markedly increased the ability of the cells to produce TNF. Finally, when mice were vaccinated with an avirulent form of L. major, the animals produced large amounts of TNF but no gamma interferon in response to infection with virulent L. major. Treating these mice with a neutralizing anti-TNF antibody led to partial but not complete inhibition of the resistant state, which suggests that factors other than TNF and gamma interferon contribute to resistance to L. major.     

Long-term protective immune response elicited by vaccination with an expression genomic library of Toxoplasma gondii

Immunization of BALB/c mice with an expression genomic library of Toxoplasma gondii induces a Th1-type immune response, with recognition of several T. gondii proteins (21 to 117 kDa) and long-term protective immunity against a lethal challenge. These results support further investigations to achieve a multicomponent anti-T. gondii DNA vaccine.     

Self-perceptions of competence in children with ADHD and comparison children

The self-perceptions of children with attention-deficit/hyperactivity disorder (ADHD; n = 487) were compared with those of children in a local normative comparison group (n = 287), relative to teacher- and parent-rated perceptions of their competence. Children were participants in the ongoing follow-up portion of the Multimodal Treatment Study of Children with ADHD. Children with ADHD were much more likely than comparison children to overestimate their competence relative to adult report, regardless of who was used as the criterion rater (teacher, mother, or father). Examination by comorbidity subgroups revealed that children with ADHD inflated their self-perceptions the most in domains of greatest deficit. Gender effects also are reported.     

Consanguinity and congenital heart disease in Saudi Arabia

First-cousin marriage may be a significant risk factor for specific types of congenital heart disease in a consanguineous population. Inbreeding studies suggest an autosomal recessive component in the cause of some congenital heart defects. We studied a large sample of patients with structural congenital heart defects (CHD) identified through the Congenital Heart Disease Registry at King Faisal Specialist Hospital in Riyadh, Saudi Arabia. After exclusions of chromosome abnormalities and non-participation, data were collected on 891 consecutive patients who were registered between January and August, 1998. Data on first-cousin consanguinity and type of CHD diagnosis were collected. A z test of proportions was used to determine the association between consanguinity and subtypes of CHD. Data indicate that the proportion of first cousins in the CHD sample is higher than the proportion in the general population, supporting a hypothesis of autosomal recessive gene involvement in congenital heart disease. When subgroups of CHD were analyzed, first-cousin consanguinity was significantly associated with ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defect (AVSD), pulmonary stenosis (PS), and pulmonary atresia (PA). There was no relationship between consanguinity and tetralogy of Fallot (TOF), tricuspid atresia (TA), aortic stenosis (AS), co-arctation of the aorta (CoA), and patent ductus arteriosus (PDA). Thus, in a population with a high degree of inbreeding, consanguinity may exacerbate underlying genetic risk factors, particularly in the offspring of first cousins. There may be a recessive component in the causation of some cardiac defects. Copyright Wiley-Liss. Inc.     

Inhibition of ras by farnesylthiosalicylate significantly reduces the levels of autoantibodies in two animal models of the antiphospholipid syndrome

BACKGROUND: Stimulation and proliferation of lymphocytes require activation of Ras. S-farnesylthiosalicylic acid (FTS) is a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. Antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies detected in patients with antiphospholipid syndrome (APS), which is associated with thrombosis, pregnancy losses, and thrombocytopenia. OBJECTIVE: To examine the effect of FTS treatment on aPL levels in a genetic autoimmune model (the MRL/lpr mice) and in an induced model of APS. METHODS: Female Balb/C mice immunized once with beta2-glycoprotein I (beta2-GPI) in complete Freund's adjuvant (CFA) and female MRL/lpr mice were treated intraperitoneally with either FTS (5 mg/Kg/day) or saline 3-5 times a week. aPL and anti-beta2-GPI antibodies were measured by ELISA. RESULTS: FTS treatment 3 times a week resulted in significant decreases of aPL and anti-beta2-GPI antibodies in both animal models. In contrast, more frequent treatment (5 times a week) had no significant effect on autantibody levels in both animal models. We further compared 2 protocols in the induced APS model, one for alternate day treatment and the other for daily treatment on the first 3 days each week, and found a decrease in autoantibody levels only in the alternate day protocol. CONCLUSIONS: Inhibition of Ras activation by FTS is effective in decreasing autoantibody levels in models of APS. The differential modulation of immune function by alternate day compared to daily treatment may provide better understanding of the role of Ras activation in this system.     

Mutations affecting pigmentation in man: I. Neuroectodermal melanolysosomal disease.

We describe a syndrome identified in three consanguineous families who had two and probably four common ancestors five generations ago. The syndrome is characterized by profound dysfunction of the central nervous system, silver-leaden colored hair, abnormal melanosomes and melanocytes, and abnormal inclusion bodies in fibroblasts, bone marrow histiocytes and lymphocytes which appear to represent abnormal lysosomal bodies. Because of the biochemical relationships between melanin-melanosomes and neuromelanin, we think that all the manifestations of the condition are related to and represent pleiotropic effects of a newly identified gene in man in its homozygous state. Biochemical reactions of the cells of these patients indicate presence of tyrosinase in the melanosomes.and show that the substance accumulated in cultured fibroblasts and in the bone marrow histiocytes is a PAS and Oil-red-O positive material but is Oil-red-O negative after extraction; it has the typical reactions of melanin withe the Masson and Fontana stain, but cannot be considered typical melanin, since without stain it is colorless. The ultrastructural studies showed round granules with variable matrix, similar in fibroblast and bone marrow, and with variable intensity of reaction to osmium. This mutation principally affects the neuroectoderm, but also the mesoderm.     

Expression of CD4 on peripheral blood granulocytes. a novel finding in a case of myelodysplastic syndrome in association with t(5;12)

Myelodysplastic syndromes (MDS) are associated with cell maturation defects that can manifest as abnormal surface antigen expression. We describe a patient with refractory anemia with excess blasts, who presented with infection and extensive dysplastic features in peripheral blood granulocytes. The granulocytes expressed CD11b, CD13, CD15, CD33, and CD43. The granulocytes also expressed CD4 antigen. Cytogenetic analysis showed a clonal t(5;12)(q33;p13). The patient improved on antibiotics with partial improvement in the dysplastic features. However, shortly after, the patient experienced paravertebral extramedullary blast transformation followed by a leukemia phase of acute monoblastic leukemia. The patient died a few days later. This is the first report describing anomalous expression of CD4 on granulocytes in MDS. Since the breakpoint on chromosome 12 is near the CD4 gene, which is mapped to 12p12, we hypothesize that dysregulation of the CD4 gene may have occurred resulting in its persistent expression on mature and maturing granulocytes.     

An in vivo role for Trypanosoma cruzi calreticulin in antiangiogenesis

Angiogenesis leads to neovascularization from existing blood vessels. It is associated with tumor growth and metastasis and is regulated by pro- and antiangiogenic molecules, some of them currently under clinical trials for cancer treatment. During the last few years we have cloned, sequenced and expressed a Trypanosoma cruzi calreticulin gene (TcCRT). Its product, TcCRT, a 45 kDa protein, is more than 50% identical to human CRT (HuCRT). TcCRT, present on the surface of trypomastigotes, binds both C1q and mannan binding lectin and inhibits the classical activation pathway of human complement. Since TcCRT is highly homologous to a functional antiangiogenic fragment from HuCRT (aa 120–180), recombinant (r) and native (n) TcCRT were tested in their antiangiogenic effects, in the chick embryonic chorioallantoid membrane (CAM) assay. Both proteins mediated highly significant antiangiogenic effects in the in vivo CAM assay. This effect was further substantiated in experiments showing that the plasmid construct pSecTag/TcCRT also displayed significant antiangiogenic properties, as compared to the empty vector. Most likely, the fact that antiangiogenic substances act preferentially on growing neoplasic tissues, but not on already established tumors, is due to their effects on emerging blood vessels. The results shown here indicate that TcCRT, like its human counterpart, has antiangiogenic properties. These properties may explain, at least partly, the reported antineoplasic effect of experimental T. cruzi infection.     

Mantle cell lymphoma, in leukaemic phase with prominent splenomegaly. A report of eight cases with similar clinical presentation and aggressive outcome

Mantle cell lymphoma (MCL) is a well-defined peripheral B-cell lymphoma usually diagnosed upon peripheral lymph node biopsy. We report eight cases of peripheral B-cell leukaemia that demonstrate presumptive evidence of mantle cell characteristics. The patients had a median age of 68.5 years, and five were male. All presented with an enlarged spleen without any peripheral lymphadenopathies, and they were leukaemic at presentation (median lymphocytosis, 38x10(9)/l). Morphological diagnosis of MCL was very difficult in five cases but easier in three because we were able to analyse either pre- or post-mortem lymph nodes and spleen. The immunophenotype of blood lymphocytosis using flow cytometry, the presence of a t(11;14)(q13;q32) and a cyclin D1 expression by leukaemic cells all fit with the diagnosis of MCL. All patients progressed and died with a median overall survival of 8 months. Multifocal areas of transformation in blastoid or large cell variants were observed in the three autopsied patients. In summary, one should consider the diagnosis of MCL at presentation in leukaemic phase even in the absence of peripheral adenopathies.