Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B.

Niemann-Pick disease (NPD) types A and B are autosomal, recessively inherited, lysosomal storage disorders caused by deficient activity of acid sphingomyelinase (E.C. 3.1.4.12) because of mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Here, we present the molecular analysis and clinical characteristics of 15 NPD type A and B patients. Sequencing the SMDP1 gene revealed eight previously described mutations and seven novel mutations including four missense [c.682T>C (p.Cys228Arg), c.1159T>C (p.Cys387Arg), c.1474G>A (p.Gly492Ser), and c.1795C>T (p.Leu599Phe)], one frameshift [c.169delG (p.Ala57Leufs*20)] and two splicing (c.316+1G>T and c.1341delG). The most frequent mutations were p.Arg610del (21%) and p.Gly247Ser (12%). Two patients homozygous for p.Arg610del and initially classified as phenotype B showed different clinical manifestations. Patients homozygous for p.Leu599Phe had phenotype B, and those homozygous for c.1341delG or c.316+1G>T presented phenotype A. The present results provide new insight into genotype/phenotype correlations in NPD and emphasize the difficulty of classifying patients into types A and B, supporting the idea of a continuum between these two classic phenotypes.

Cleavage of poly(A) tails on the 3'-end of RNA by ribonuclease E of Escherichia coli.

RNase E initiates the decay of Escherichia coli RNAs by cutting them internally near their 5'-end and is a component of the RNA degradosome complex, which also contains the 3'-exonuclease PNPASE: Recently, RNase E has been shown to be able to remove poly(A) tails by what has been described as an exonucleolytic process that can be blocked by the presence of a phosphate group on the 3'-end of the RNA. We show here, however, that poly(A) tail removal by RNase E is in fact an endonucleolytic process that is regulated by the phosphorylation status at the 5'- but not the 3'-end of RNA. The rate of poly(A) tail removal by RNase E was found to be 30-fold greater when the 5'-terminus of RNA substrates was converted from a triphosphate to monophosphate group. This finding prompted us to re-analyse the contributions of the ribonucleolytic activities within the degradosome to 3' attack since previous studies had only used substrates that had a triphosphate group on their 5'-end. Our results indicate that RNase E associated with the degradosome may contribute to the removal of poly(A) tails from 5'-monophosphorylated RNAs, but this is only likely to be significant should their attack by PNPase be blocked.

Chemokine/CD4 receptor density ratios correlate with HIV replication in lymph node and peripheral blood of HIV-infected individuals.

OBJECTIVES: Lymphoid tissue is a major reservoir for virus replication in HIV-infected subjects. The relationship of CCR5 and CXCR4 coreceptor density and HIV replication in peripheral blood mononuclear cells (PBMC) and lymph node (LN) mononuclear cells (LNMC) of HIV-infected subjects was examined. METHODS: PBMC and cervical LNMC from 12 HIV-infected patients were examined for virological and immunological parameters including chemokine receptor density, HIV plasma and cellular viral load, coreceptor usage and CD38/HLA-DR expression. RESULTS: The number of CCR5 and CXCR4 molecules on CD4 lymphocytes in the LN were significantly higher than in PBMC. In contrast the number of CD4 molecules/CD4 T cell was higher in PBMC than in LNMC. The CXCR4/CD4 and CCR5/CD4 ratios in the LN were significantly higher than in the PBMC. This was associated with a cellular viral load in the LN that was approximately 110-fold higher than in PBMC. The absolute number of coreceptor molecules per cell did not correlate with the viral load. However, the CCR5/CD4 and CXCR4/CD4 ratios in the LN positively correlated with HIV cellular and plasma RNA. Characterization of the viral isolates suggested an association between clinical isolates using a distinct coreceptor and the upregulation of the corresponding chemokine receptor. CONCLUSIONS: The ratios of chemokine receptors to CD4 molecules in CD4 T cells from LN is higher than in PBMC and may account for the relative difference in cellular viral load in these compartments. Additionally, the coreceptor/CD4 ratios, particularly in the lymphoid tissue, were highly related to HIV replication.

Chromosome one polymorphism in a girl with the Chediak-Higashi syndrome.

In a girl with the Chediak-Higashi syndrome, a remarkable polymorphism of chromosome number one was identified by G and C banding. The association of the polymorphisms of constitutive heterochromatin with abnormal phenotypes is discussed. It is suggested that further cytogenetic studies might be performed in humans and animals with this rare autosomal recessive disorder in order to confirm the present findings.

[Safety of meningococcal A and C vaccine. Data from the Spanish drug surveillance system. Meningococcal Vaccine Research Group of the Spanish System of Drug Surveillance]. / Seguridad de la vacuna antimeningocócica A+C. Datos recogidos por el Sistema Español de Farmacovigilancia. Grupo de Investigación sobre la vacuna antimeningocócica del Sistema Español de Farmacogigilancia.

OBJECTIVE: Data on meningococcal vaccines safety are scanty. In 1997 several vaccination campaign took place in Spain. Thus, this situation was used to improve our knowledge about the safety profile of this vaccine. METHODS: An inquiry was carried out to the Regional Centers of the Spanish Pharmacovigilance System to know the number of vaccinated people and the type and number of suspected cases of adverse reactions. RESULTS: There were 133 identified cases of suspected adverse reactions associated with meningococcal A and C vaccine until June 1st, 1998. Most of them affected the skin (25,3%) or nervous system (similar proportion). Those of allergic reactions accounted for 35,2%. Two cases were considered as severe, although they were resolved without secuelae. CONCLUSIONS: Serious risks were not detected. The Spanish Pharmacosurveillance System as an epidemiological surveillance resource has been useful to know the safety problems associated with antimeningococcal vaccine in the community.

[Insomnia and somnolence in epilepsy]. / Insomnio y somnolencia en epilepsia.

INTRODUCTION AND METHODS: Based on the well-known association between sleep disorders and epilepsy which share common functional elements, we investigated the existence of sleep disorders in general as seen in a series of patients who attended the electrophysiology clinic, using a simple questionnaire method dealing with sleep disorders and somnolence. RESULTS: It was seen that there was a markedly greater prevalence of sleep disorders in epileptics as compared with non-epileptic controls. It was also observed that in partial crises these disorders are more important, mainly because of the global sleep deficit and increased nocturnal waking. Control of the crises was also important since patients with long periods free of critical episodes had fewer disorders than those with poor control. CONCLUSIONS: The discrepancy between clinical critical control and sleep anomalies may be explained by the subclinical effect (which is usually underestimated) of inter-ictal discharges.

[Treatment of drug resistant scabies]. / Tratamineto del enfermo escabiósico resistente a los medicamentos

Thirty patients suffering from scabies who had previonsly received other kinds of treatment were administered "Metrifonate" at daily doses of 10 mg./kg. b.w. during two consecutive days repeated every week and associated with atropine sulfate. The number of weeks lapse until the treatment finished was as follows. (see article.) Four patients developed intolerance, but it was transitory (nausea and vomiting). Cures (skin lesions and prutitus) were obtaind in 29 our of 30 cases.

Manejo de las complicaciones vasculares gestacionales y trombosis en la mujer / Management of gestational vascular complications and thrombosis in women

Objetivo: conocer la prevalencia de trombofilia en trombosis gestacional y complicaciones vasulares gestacionales en nuestro entorno y el manejo de las mismas. Material y métodos: estudio prospectivo y observacional en el que se incluyeron cuatro cohortes: trombosis, profilaxis de trombosis, complicaciones vasulares gestacionales, profilaxis de complicaciones vasulares gestacionales. Se registraron 1.032 episodios, de los cuales se incluyeron 994 en el análisis final. Resultados: la distribución de episodios fue: 5,5% trombosis, 30,2% profilaxis de trombosis, 35,7% complicaciones vasulares gestacionales y 24,9% profilaxis de complicaciones vasulares gestacionales. Las pérdidas gestacionales fueron la complicación más frecuente. Se realizó estudio de trombofilia en 82,6% de complicaciones vasulares gestacionales y 70,2% de trombosis. Los resultados fueron positivos en el 47% de trombosis y en 21% de complicaciones vasulares gestacionales. Los defectos más comunes en complicaciones vasulares gestacionales fueron la elevación del factor VIII, la presencia de anticuerpos antifosfolípidos y la mutación F12C46T en homocigosis. Se empleó tratamiento antitrombótico en el 85% de profilaxis de trombosis y en el 77% de profilaxis de complicaciones vasulares gestacionales. La tromboprofilaxis de complicaciones vasulares gestacionales no se relacionó con una mejora en el resultado de la gestación. Conclusiones: se realizaron estudios de trombofilia a la mayoría de las pacientes, con resultados diferentes en trombosis y complicaciones vasulares gestacionales. Se empleó tromboprofilaxis en más del 70% de las pacientes. La profilaxis farmacológica de complicaciones vasulares gestacionales no aportó beneficio significativo. Serían necesarios estudios futuros para confirmar nuestros resultados (AU)

Objective: The main objectives were to establish the prevalence of thrombophilia in pregnancy-related thrombosis and vascular placental complications and to evaluate the clinical management of these complications. Materials and methods: Multicenter, prospective and observational study. We analysed 4 patient cohorts: thrombosis, thrombosis prophylaxis, vascular placental complications, vascular placental complications prophylaxis. A total of 1032 episodes were registeredand 994 were included in the final analysis. Results: The distribution of the episodes was: 5.5% thrombosis, 30.2% thrombosis prophylaxis, 35.7% vascular placental complications and 24.9% vascular placental complications prophylaxis. Pregnancy loss was the most frequent complication registered. Thrombophilia studies were made in 82.6% patients in vascular placental complications cohort and in 70.2% of thrombosis patients. Positive results were obtained in 47% of patients in thrombosis group and in 21% of patients with vascular placental complications. In this group the most common defects found were high levels of FVIII, positive antiphospholipid antibodies and homocigosity for F12C46T polymorphism. Antithrombotic treatment was used in 85% of thrombosis prophylaxis episodes and in 77% of vascular placental complications prophylaxis episodes. Pharmacologic prophylaxis was not related with a better pregnancy outcome in vascular placental complications prophylaxis group. Conclusions: Thrombophilia studies were made to most patients in this registry. Results were different in patients with thrombosis and vascular placental complications. Most patients in vascular placental complications prophylaxis group with or without thrombophilia recieved LMWH +/- aspirin, but we did not find a benefit of these treatments. Further studies with more patients will be needed to confirm our findings (AU)