Meta-analysis of randomised trials comparing a penicillin or cephalosporin with a macrolide or lincosamide in the treatment of cellulitis or erysipelas.

PURPOSE: Beta-lactam antibiotics, such as penicillin, flucloxacillin or cephalexin, are widely considered first-line treatment for cellulitis and erysipelas, while macrolides and lincosamides, such as erythromycin, azithromycin or clindamycin, are widely considered second-line agents. We attempted to determine whether outcomes differed between patients treated either with a beta-lactam or with a macrolide or lincosamide. METHODS: We conducted a meta-analysis of published trials in which patients with cellulitis or erysipelas were randomised to treatment either with a beta-lactam or with a macrolide or lincosamide. We searched PUBMED, EMBASE, MEDLINE and SCOPUS (up to March 2014) using the terms: cellulitis/erysipelas, penicillin/beta-lactam, macrolide/lincosamide, random*/controlled*/trial* as keywords. We included randomised trials that compared monotherapy with a beta-lactam with monotherapy with a macrolide or lincosamide for cellulitis or erysipelas. RESULTS: We identified 15 studies, 9 in patients with cellulitis or erysipelas and 6 in patients with various skin and soft tissue infections including cellulitis and erysipelas. The efficacy of treatment of cellulitis or erysipelas was similar with a beta-lactam [27/221 (12 %) not cured] and a macrolide or lincosamide [21/241 (9 %) not cured, RR 1.24, 95 % CI 0.72-2.41, p = 0.44]. Treatment efficacy was also similar for skin or soft tissue infections including cellulitis and erysipelas (RR 1.28, 95 % CI 0.96-1.69, p = 0.09). Risk of adverse effects was similar for beta-lactams [148/1295 (11 %) not cured] and macrolides or lincosamides [228/1737 (13 %) not cured, RR 0.86, 95 % CI 0.64-1.16, p = 0.31]. CONCLUSION: Treatment with a macrolide or lincosamide for cellulitis or erysipelas has a similar efficacy and incidence of adverse effects as treatment with a beta-lactam.

Spontaneous diabetes in hemizygous human amylin transgenic mice that developed neither islet amyloid nor peripheral insulin resistance.

OBJECTIVES: We sought to 1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes. RESEARCH DESIGN AND METHODS: We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [(25,28,29)Pro]human amylin, in an FVB/n background. RESULTS: Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive beta-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals. [(25,28,29)Pro]human amylin transgenic mice developed neither beta-cell degeneration nor glucose intolerance. CONCLUSIONS: Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused beta-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with beta-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

Microsatellite association mapping of a primary osteoarthritis susceptibility locus on chromosome 6p12.3-q13.

OBJECTIVE: To test a high density of microsatellite markers from within a primary osteoarthritis (OA) locus on chromosome 6 for association with OA as a means of narrowing and focusing our search for the susceptibility gene. METHODS: One hundred forty-six families, each with 2 or more women concordant for primary OA (ascertained by total hip replacement), were genotyped for 36 microsatellite markers from within a narrow interval at 6p12.3-q13 which we had previously shown to be linked to OA. Each marker was tested for linkage and for association, the latter by means of the transmission disequilibrium test and by a case-control analysis. RESULTS: The highest 2-point logarithm of odds (LOD) score was 4.8, with 11 markers having LOD scores > or =2.0. Several markers demonstrated evidence of association, in particular, a cluster of markers positioned within or near the functional candidate gene BMP5. CONCLUSION: Our linkage data reinforce the evidence of a major susceptibility locus on chromosome 6. We had previously failed to detect an association with BMP5 using gene-based single-nucleotide polymorphisms. The association data reported here prompt us to speculate that the chromosome 6 susceptibility may be coded for by cis-acting polymorphism in the regulatory elements of this gene, rather than by variation in its protein coding sequence.

Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.

Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder. A previous genome scan mapped a primary hip OA susceptibility locus to chromosome 2q with a maximum multipoint logarithm of odds score of 1.6 in 378 affected sibling pair families. Here, microsatellite targeting of eight candidate genes in this region from 2q23-2q32 demonstrated significant associations with the tumor necrosis factor alpha-induced protein 6 gene in all probands and the integrin alpha 6 and frizzled motif associated with bone development (FRZB) genes in female probands. However, genotyping showed lack of association for a nonsynonymous single-nucleotide polymorphism in tumor necrosis factor alpha-induced protein 6, whereas a single-nucleotide polymorphism in FRZB resulting in an Arg324Gly substitution at the carboxyl terminus was associated with hip OA in the female probands (P = 0.04). This association was confirmed in an independent cohort of female hip cases (n = 338; P = 0.04). In addition, a haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (P = 0.004). FRZB encodes secreted frizzled-related protein 3, which is a soluble antagonist of wingless (wnt) signaling. Variant secreted frizzled-related protein 3 with the Arg324Gly substitution had diminished ability to antagonize wnt signaling in vitro. Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease.