Response to therapy in carnitine/acylcarnitine translocase (CACT) deficiency due to a novel missense mutation

Deficiency of carnitine/acylcarnitine translocase (CACT) is an autosomal recessive disorder of the carnitine cycle resulting in the inability to transfer fatty acids across the inner mitochondrial membrane. Only a limited number of affected patients have been reported and the effect of therapy on this condition is still not well defined. Here, we report a new patient with this disorder and follow the response to therapy. Our patient was the product of a consanguineous marriage. He presented shortly after birth with cardiac myopathy and arrhythmia coupled with severe non-ketotic hypoglycemia. Initial metabolic studies indicated severe non-ketotic C6-C10 dicarboxylic aciduria, plasma carnitine deficiency, and a characteristic elevation of plasma C:16:0, C18:1, and C18:2 acylcarnitine species. Enzyme assay confirmed deficiency of CACT activity. Molecular studies indicated that this child was homozygous, and both parents heterozygous, for a single bp change converting glutamine 238 to arginine (Q238R). Therapy with a formula providing most of the fat via medium chain triglycerides (MCT) and carnitine supplementation reduced the concentration of long-chain acylcarnitines and reversed cardiac symptoms and the hypoglycemia. These results suggest that carnitine and MCT may be effective in treating this defect of long-chain fatty acid oxidation.     

High prevalence of autoimmune urticaria in children with chronic urticaria

BACKGROUND: The etiology of chronic urticaria (CU) in childhood often remains unrecognized. Recently, in adults it has been shown that approximately 40% of patients with CU have autoimmune urticaria (AU); however, no data are available in children. OBJECTIVE: To determine the prevalence and possible risk factors for AU in children with CU. METHODS: Ninety-three consecutive children (52 male; median age, 7.8 years) with CU were evaluated for AU by means of autologous serum skin test (ASST) in all and serum-induced basophil histamine release (HR-urticaria test) in 52. All other known causes of CU were excluded as appropriate. RESULTS: A cause for CU was identified in 44 children (47%), whereas 49 (53%) remained idiopathic. ASST and HR-urticaria test had positive results in 22 of 49 (45%) and in 16 of 31 (52%) children with idiopathic CU compared with 1 of 44 (2%) and 5 of 21 (24%) with CU of a known cause, respectively ( P <.00001; P=.09). Sensitivity, specificity, and positive and negative predictive values of the ASST for diagnosing AU are 78%, 85%, 74%, and 88%. The prevalence of AU in childhood is 31% (15/52; 95% CI, 24%-51%). None of the variables studied were predictive for development of AU. CONCLUSION: Our results demonstrate for the first time that children have the same ability as adults to produce functionally active autoantibodies directed against IgE or IgE receptor and that AU occurs in children in as many as 30% of cases. The addition of screening for AU dramatically decreases the rate of the idiopathic form from 52% to 20%.     

Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection

B cell repertoire in three biological compartments (liver, bone marrow and peripheral blood) of 30 unselected patients chronically infected with HCV has been characterized. Restriction of humoral immune response defined by enrichment of B cell clonal expansions occurred in the liver of 15 patients (50%), in the bone marrow and peripheral blood of 2 (6.7%) and 8 (26.7%) patients, respectively. An in situ hybridization technique was developed for the detection of dominant B cell clones in patients with monoclonal expansions. It was shown that morphologically distinct B cell expansion contributes to the formation of intraportal follicle-like structures. Sequence analyses of CDRH3 gene segments revealed a wide range of variations. Clones derived from the same founder were demonstrated simultaneously in the three compartments explored. The occurrence of B cell clonal expansions profoundly influenced the clinical expression of HCV infection, since it was associated with extrahepatic manifestations. In sharp contrast, no extrahepatic signs or disease occurred in patients without evidence of intrahepatic B cell clonalities. These findings emphasize the profound B cell function derangement in at least half of HCV-infected patients. Thus, the restriction of V gene usage has a direct impact on the clinical spectrum of HCV infection.     

Role of topoisomerase mutations and efflux in fluoroquinolone resistance of Bacteroides fragilis clinical isolates and laboratory mutants

Twelve laboratory mutants and 32 ciprofloxacin-resistant isolates of Bacteroides fragilis were examined for the mechanism(s) of fluoroquinolone resistance. Five mutants had mutations in gyrA. One mutant and two clinical isolates contained a mutation in gyrB. Eight mutants and five clinical isolates accumulated significantly less ciprofloxacin than did wild-type isolates; the mutants and clinical isolates were restored to wild-type characteristics when carbonyl cyanide m-chlorophenylhydrazone was used.     

Cloning and expression of two fragments of the S gene of canine coronavirus type I

Two fragments, S66 and S55, of the S glycoprotein of the newly identified canine coronavirus type I (CCoV type I), were expressed in a procariotic system. The purified recombinant proteins of 350 and 366 amino acids in length, respectively, were employed to develop an enzyme-linked immunosorbent assay (ELISA) for the detection of CCoV type I antibodies in dog sera. Four canine sera-positive for CCoV type II, four sera-positive for CCoV type I and 10 negative control sera were examined. Only the sera-positive for CCoV type I strongly reacted with both the proteins, whereas the sera-positive for CCoV type II showed low reactivity in the ELISA test. As CCoV type I seems to be not cultivable in cell cultures, the recombinant fragments of the S protein represent a unique method to study, preliminarily, the immunological and the pathogenetic characteristics of this new virus.     

The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies

The IL-12Rbeta2 gene is expressed in human mature B cell subsets but not in transformed B cell lines. Silencing of this gene may be advantageous to neoplastic B cells. Our objective was to investigate the mechanism(s) and the functional consequence(s) of IL-12Rbeta2 gene silencing in primary B cell tumors and transformed B cell lines. Purified tumor cells from 41 patients with different chronic B cell lymphoproliferative disorders, representing the counterparts of the major mature human B cell subsets, tested negative for IL-12Rbeta2 gene expression. Hypermethylation of a CpG island in the noncoding exon 1 was associated with silencing of this gene in malignant B cells. Treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine restored IL-12Rbeta2 mRNA expression in primary neoplastic B cells that underwent apoptosis following exposure to human recombinant IL-12 (hrIL-12). hrIL-12 inhibited proliferation and increased the apoptotic rate of IL-12Rbeta2-transfected B cell lines in vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12Rbeta2-transfected Burkitt lymphoma RAJI cells in SCID-NOD mice through antiproliferative and proapoptotic effects, coupled with neoangiogenesis inhibition related to human IFN-gamma-independent induction of hMig/CXCL9. The IL-12Rbeta2 gene acts as tumor suppressor in chronic B cell malignancies, and IL-12 exerts direct antitumor effects on IL-12Rbeta2-expressing neoplastic B cells.     

Modified Bondy radical mastoidectomy: long-term personal experience

The 'Bondy operation', or modified Bondy radical mastoidectomy, consists of a modification of the radical procedure by which the mastoid and epitympanum are exteriorized with preservation of the pars tensa and ossicular chain. In the 10-year period from 1986 to 1996, 53 patients of the ENT Department of the University of Pisa underwent a modified Bondy radical mastoidectomy, performed with a personalized procedure; 45 of them had a follow up of at least five years. After the surgical operation, the ears were free of complications in 38 cases (84.5 per cent), while in the other seven cases residual cholesteatoma (one case), tympanic retraction (four cases) or recurrent otorrhoea and phlogosis (two cases) were observed. The post-operative hearing level was unchanged or improved in 41 patients (91 per cent) (33 subjects had an unchanged gap and eight an improved gap), and only in the remaining four cases was the gap made worse. Based on our experience, the modified Bondy radical mastoidectomy is an extremely effective operation with a clear place in modern ENT surgery. When performed on carefully selected patients, it has been proven to offer good functional and anatomical results.