Evaluating genetic susceptibility to Staphylococcus aureus bacteremia in African Americans using admixture mapping.

The incidence of Staphylococcus aureus bacteremia (SAB) is significantly higher in African American (AA) than in European-descended populations. We used admixture mapping (AM) to test the hypothesis that genomic variations with different frequencies in European and African ancestral genomes influence susceptibility to SAB in AAs. A total of 565 adult AAs (390 cases with SAB; 175 age-matched controls) were genotyped for AM analysis. A case-only admixture score and a mixed χ2(1df) score (MIX) to jointly evaluate both single-nucleotide polymorphism (SNP) and admixture association (P<5.00e-08) were computed using MIXSCORE. In addition, a permutation scheme was implemented to derive multiplicity adjusted P-values (genome-wide 0.05 significance threshold: P<9.46e-05). After empirical multiplicity adjustment, one region on chromosome 6 (52 SNPs, P=4.56e-05) in the HLA class II region was found to exhibit a genome-wide statistically significant increase in European ancestry. This region encodes genes involved in HLA-mediated immune response and these results provide additional evidence for genetic variation influencing HLA-mediated immunity, modulating susceptibility to SAB.

Clinical and dermoscopic features of 88 scalp naevi in 39 children.

BACKGROUND: Paediatric scalp naevi may represent a source of anxiety for practitioners and parents, as the clinical and dermoscopic features of typical naevi have yet to be defined. Prompted by concern about the large size, irregular borders and colour variation of scalp naevi, clinicians and parents may request unnecessary excision of these naevi. OBJECTIVES: To establish the typical clinical and dermoscopic patterns of scalp naevi in children younger than 18 years old to help optimize clinical care and management. METHODS: Scalp naevi were imaged with a camera (Canon Rebel, XSi; Canon, Tokyo, Japan) and dermoscopic attachment (Dermlite Foto, 30 mm lens; 3Gen, San Juan Capistrano, CA, U.S.A.) to the camera. The clinical and dermoscopic images were reviewed and analysed. Both acquired and congenital scalp naevi were included but were not further differentiated from each other. RESULTS: We obtained clinical and dermoscopic images of 88 scalp naevi in 39 white children. Two subjects had received chronic immunosuppressive medication. Nineteen children had a family history of melanoma. Boys (18/39 subjects, 46%) possessed 68% (60 naevi) of scalp naevi imaged. Younger (< 10 years old) subjects (24/39 subjects, 62%) possessed 42% (37 naevi) of scalp naevi. The main clinical patterns included eclipse (n=18), cockade (n = 3), solid brown (n=42) and solid pink (n=25) naevi. Solid-coloured naevi showed the following dermoscopic patterns: globular (57%), complex (reticular-globular) (27%), reticular (9%), homogeneous (6%) and fibrillar (1%). The majority of naevi had a unifying feature - perifollicular hypopigmentation, which caused the appearance of scalloped, irregular borders if occurring on the periphery, or variegation in pigmentation, if occurring within the naevi. CONCLUSIONS: Older subjects and boys tend to harbour a larger proportion of scalp naevi. The main clinical patterns include solid-coloured and eclipse naevi. The most common dermoscopic pattern of scalp naevi is the globular pattern. Perifollicular hypopigmentation is a hallmark feature of signature scalp naevi. Dermoscopy is a noninvasive tool in the evaluation of cutaneous melanocytic lesions in children and may decrease the number of unnecessary excisions.

The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90.

BACKGROUND: Epothilones are produced by the myxobacterium Sorangium cellulosum So ce90, and, like paclitaxel (Taxol((R))), they inhibit microtubule depolymerisation and arrest the cell cycle at the G2-M phase. They are effective against P-glycoprotein-expressing multiple-drug-resistant tumor cell lines and are more water soluble than paclitaxel. The total synthesis of epothilones has been achieved, but has not provided an economically viable alternative to fermentation. We set out to clone, sequence and analyze the gene cluster responsible for the biosynthesis of the epothilones in S. cellulosum So ce90. RESULTS: A cluster of 22 open reading frames spanning 68,750 base pairs of the S. cellulosum So ce90 genome has been sequenced and found to encode nine modules of a polyketide synthase (PKS), one module of a nonribosomal peptide synthetase (NRPS), a cytochrome P450, and two putative antibiotic transport proteins. Disruptions in the genes encoding the PKS abolished epothilone production. The first PKS module and the NRPS module are proposed to co-operate in forming the thiazole heterocycle of epothilone from an acetate and a cysteine by condensation, cyclodehydration and subsequent dehydrogenation. The remaining eight PKS modules are responsible for the elaboration of the rest of the epothilone carbon skeleton. CONCLUSIONS: The overall architecture of the gene cluster responsible for epothilone biosynthesis has been determined. The availability of the cluster should facilitate the generation of designer epothilones by combinatorial biosynthesis approaches, and the heterologous expression of epothilones in surrogate microbial hosts.