Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Aims To measure the interdose milk to plasma ratio (M/P) of R-and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (>40 mg daily), and to assess likely infant exposure. Methods Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of i40 mg day . Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0±4, 4±8, 8±12, 12±16, 16±20, and 20±24 h after dose. R-and S-methadone were quanti®ed by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/P AUC was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg x1 . Results For immature milk (n=8) the M/P AUC for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n=2) the M/P AUCs for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R-and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R-plus S-methadone together was 2.8% (1.7, 3.9%). Conclusions Breastfeeding during medium to high dose methadone appears to be`safe' according to conventional criteria because the dosage is <10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the riskbene®t ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be suf®cient to prevent the neonatal abstinence syndrome.
At Makthlawaiya, in the Paraguayan Chaco, the prevalence of Trypanosoma (Schizotrypanum) cruzi infection among both domestic Triatoma infestans and domestic dogs was 38%, and IgG anti-T. cruzi antibody was detected by the quantitative enzyme-linked immunosorbent assay (ELISA) in 80% (105/133) of human sera. Ninety percent (25/28) of T. cruzi strains isolated from both T. infestans and dogs showed heterozygous isoenzyme profiles for glucose phosphate isomerase, phosphoglucomutase and 6-phosphogluconate dehydrogenase. These strains appeared to be closely related to Bolivian zymodeme 2. Three Paraguayan T. cruzi strains showed homozygous isoenzyme profiles, similar to those of major Brazilian zymodemes. It was concluded that T. cruzi strains with heterozygous isoenzyme profiles predominate in domestic transmission cycles in this highly endemic area of the Paraguayan Chaco.
The aim of this study was to assess the influence of maternal methadone dosage on the severity of neonatal withdrawal. The charts of 67 drug-abusing mothers and their 70 infants were examined to determine documented patterns of drug usage and the severity of neonatal withdrawal. Of these, 40 women were on a methadone programme. There was a strong relationship between maternal methadone dose at delivery and severity of neonatal withdrawal as assessed by the Neonatal Abstinence Score, length of stay and duration of treatment. Children whose mothers received methadone had mean peak symptom scores greater than 10 whereas the group receiving no methadone had mean scores of less than 4 (p < 0.001). These effects tended to increase with increasing doses of methadone. Length of stay and duration of neonatal treatment showed highly statistically significant increases (p < 0.001) with increasing methadone dose. Maternal methadone dose appears to be strongly related to the severity of neonatal withdrawal.
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