Smoking and occupational allergy in workers in a platinum refinery.

OBJECTIVE--To test the hypothesis that smoking increases the risk of sensitisation by occupational allergens. DESIGN--Historical prospective cohort study. SETTING--Platinum refinery. SUBJECTS--91 Workers (86 men) who started work between 1 January 1973 and 31 December 1974 and whose smoking habit and atopic state (on skin prick testing with common allergens) had been noted at joining. MAIN OUTCOME MEASURES--Results of skin prick tests with platinum salts carried out routinely every three to six months and records of any respiratory symptoms noted by the refinery''s occupational health service. Follow up was until 1980 or until leaving refinery work, whichever was earlier. RESULTS--57 Workers smoked and 29 were atopic; 22 developed a positive result on skin testing with platinum salts and 49 developed symptoms, including all 22 whose skin test result was positive. Smoking was the only significant predictor of a positive result on skin testing with platinum salts and its effect was greater than that of atopy; the estimated relative risks (95% confidence interval) when both were included in the regression model were: smokers versus non-smokers 5.05 (1.68 to 15.2) and atopic versus non-atopic 2.29 (0.88 to 5.99). Number of cigarettes smoked per day was the only significant predictor of respiratory symptoms. CONCLUSION--Smokers are at increased risk of sensitisation by platinum salts.     

Quantitative and phenotypic analysis of bone marrow-derived cells in the intact and inflamed central nervous system

Bone marrow has been proposed as a possible source of cells capable of replacing injured neural cells in diseases such as Multiple Sclerosis (MS). Previous studies have reported conflicting results regarding the transformation of bone marrow cells into neural cells in vivo. This study is a detailed analysis of the fate of bone marrow derived cells (BMDC) in the CNS of C57Bl/6 mice with and without experimental autoimmune encephalomyelitis using flow cytometry to identify GFP-labeled BMDC that lacked the pan-hematopoietic marker CD45 and co-expressed neural markers polysialic acid-neural cell adhesion molecule or A2B5. A small number of BMDC displaying neural markers and lacking CD45 expression was identified within both the non-inflamed and inflamed CNS. However, the majority of BMDC exhibited a hematopoietic phenotype.Key words: bone marrow, transplantation, transdifferentiation, central nervous system, green fluorescence protein, experimental autoimmune encephalomyelitis, multiple sclerosis     

Waardenberg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: First report of the WS consortium

Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal portion of chromosome 2q, near the ALPP locus. We pooled linkage data obtained from 41 WS type I and 3 WS type II families which were typed for six polymorphic loci on chromosome 2q in order to refine the location of the WS locus (WS1) and evaluate the extent of genetic heterogeneity. In the course of this work, we developed diagnostic criteria for genetic and phenotypic studies. Our findings, based on two-locus and multilocus analysis using a linkage map established from reference pedigrees, suggest that there are two or more mutations causing WS, one of which (i.e., WS1) is located on chromosome 2q, between the ALPP and FN1 loci, at distances of 7.8 cM and 11.2 cM for each marker, respectively. The results also indicate that WS1 is responsible for the illness in approximately 45% of all families in this sample. However, the odds favoring this position over a location between ALPP and SAG are only 2:1 when alternate assumptions about the proportion of linked families are considered. We conclude that a more saturated map of this region of chromosome 2q, including highly polymorphic markers, will be needed to accurately distinguish linked families and, ultimately, isolate the mutant gene.     

Genetic elements associated with antimicrobial resistance in enteropathogenic <Emphasis Type="Italic">Escherichia coli</Emphasis> (EPEC) from Brazil

Background  

We recently observed an association of resistance with a certain enteropathogenic Escherichia coli (EPEC) serotypes and identified a conjugative plasmid, similar to plasmid pED208, that was conserved among archival O111:H2/NM and O119:H2 strains of diverse geographical origin. In this study, we sought to determine the prevalence and distribution of this plasmid among a collection of EPEC isolates from Brazil, as well as to study the susceptibilities of these isolates to antimicrobial agents.     

Expression of Sulfated Gangliosides in the Central Nervous System

Abstract: Several sulfated lipids were detected in the ganglioside fraction isolated from a cell line of oligodendrocyte progenitors that had been metabolically labeled with [³⁵S]sulfate. Separation of the ganglioside fraction by two-dimensional TLC showed that, except for galactosylceramide-sulfate, none of the sulfate-labeled lipids comigrated with those glycosphingolipids visualized by orcinol staining, indicating that these sulfolipids were quantitatively minor components. At least eight sulfate-labeled lipid bands were susceptible to desialylation by Arthrobacter ureafaciens neuraminidase, which resulted in the formation of three new bands that retained the labeled sulfate. Six of the sulfate-labeled lipid bands containing sialic acid were also susceptible to Vibrio cholerae neuraminidase, which generated two labeled bands that appeared identical to the two major products formed after treatment with A. ureafaciens neuraminidase. In vivo labeling of lipids from 14-day-old rat brain with [³⁵S]sulfate demonstrated that the synthesis of sulfated lipids containing sialic acid also occurred in intact brain tissue. These results show that sulfated gangliosides are synthesized in the CNS and that oligodendrocytes are one cell type that contributes to this synthesis.     

CpG‐related SNPs in the MS4A region have a dose‐dependent effect on risk of late–onset Alzheimer disease

CpG‐related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome‐wide association study using a sliding‐window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome‐wide significant (p < 5 × 10^?8) associations were identified with 171 1.0 kb‐length windows spanning 932 kb in the APOE region (top p < 2.2 × 10^?308), five windows at BIN1 (top p = 1.3 × 10^?13), two windows at MS4A6A (top p = 2.7 × 10^?10), two windows near MS4A4A (top p = 6.4 × 10^?10), and one window at PICALM (p = 6.3 × 10^‐9). The total number of CGS‐derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10^?10), brain DNA methylation (p = 2.15 × 10^?10), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10^?4). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage‐derived genetic score to predict AD risk.     

Acylation of exogenous glycosylsphingosines by intact neuroblastoma (NCB-20) cells

Acylation of exogenously added galactosylsphingosine was demonstrated in intact NCB-20 neuroblastoma cells, a cell line that normally does not synthesize galactosylceramide. Labeling of cells with [3H]palmitic acid for 6 h in the presence of 100 microM exogenous galactosylsphingosine (GalSph) resulted in a more than 3-fold increase in the incorporation of label into the ceramide monohexoside fraction relative to controls. This increase, which was almost entirely due to the incorporation of labeled nonhydroxy fatty acid into galactosylceramide, was linear over a concentration range of 1-100 microM galactosylsphingosine and for the first 5 h after the addition of galactosylsphingosine. Similarly, the addition of 100 microM glucosylsphingosine resulted in a 3-fold increase of label incorporated into glucosylceramide. Incubation of cells with 100 microM GalSph and labeled fatty acids of various chain lengths revealed that the acylation of GalSph was specific for medium chain (C16-C18) nonhydroxy fatty acids, suggesting that this was an enzyme-mediated reaction. The enzymatic nature of GalSph acylation was further demonstrated when cells were incubated for 72 h with 15 microM [3H]galactosylsphingosine labeled in the galactose moiety. [3H]Galactosylceramide containing only medium chain non-hydroxy fatty acids accumulated linearly with time reaching a maximum at 48 h and was observed to be further metabolized to ceramide dihexoside. This acylation reaction may be potentially important for the removal of glycosylsphingosines in the cell.