Human mtDNA shows striking regional variation, traditionally attributed to genetic drift. However, it is not easy to account for the fact that only two mtDNA lineages (M and N) left Africa to colonize Eurasia and that lineages A, C, D, and G show a 5-fold enrichment from central Asia to Siberia. As an alternative to drift, natural selection might have enriched for certain mtDNA lineages as people migrated north into colder climates. To test this hypothesis we analyzed 104 complete mtDNA sequences from all global regions and lineages. African mtDNA variation did not significantly deviate from the standard neutral model, but European, Asian, and Siberian plus Native American variations did. Analysis of amino acid substitution mutations (nonsynonymous, Ka) versus neutral mutations (synonymous, Ks) (k a /k s ) for all 13 mtDNA protein-coding genes revealed that the ATP6 gene had the highest amino acid sequence variation of any human mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins. Comparison of the k a /k s ratios for each mtDNA gene from the tropical, temperate, and arctic zones revealed that ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b was particularly variable in the temperate zone, and cytochrome oxidase I was notably more variable in the tropics. Moreover, multiple amino acid changes found in ATP6, cytochrome b , and cytochrome oxidase I appeared to be functionally significant. From these analyses we conclude that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate.

We report a retrospective study of 253 patients with vertebral osteomyelitis (VO) who had long-term follow-up. Eleven percent of the patients died, r

Objective: To evaluate treatment with methotrexate (MTX) in patients with newly diagnosed giant cell arteritis (GCA) to determine if MTX reduces GCA relapses and cumulative corticosteroid (CS) requirements and diminishes disease‐ and treatment‐related morbidity.Methods: This was a multicenter, randomized, double‐blind study. Over 4 years, 16 centers from the International Network for the Study of Systemic Vasculitides enrolled patients with unequivocal GCA. The initial treatment was 1 mg/kg/day (≤60 mg every day) prednisone, plus either 0.15 mg/kg/week MTX (increased to 0.25 mg/kg/week, for a maximum weekly dosage of 15 mg) or placebo. Two physicians, both blinded to treatment allocation, evaluated each patient at every trial visit. One physician was responsible for providing global medical care. The other assessed GCA status according to a standard protocol. Treatment failure was defined as 2 distinct relapses or persistence of disease activity after the first relapse, in spite of increased CS therapy.Results: Ninety‐eight patients were enrolled. No significant differences between treatment groups were noted with regard to age, frequency of positive findings on temporal artery biopsy (placebo 87%, MTX 79%), or comorbidities at the time of enrollment. The median dosage of MTX was 15 mg/week. The incidence of treatment failure was comparable between groups after 12 months: 57.5% in the MTX group failed treatment (95% confidence interval [95% CI] 41.6–73.4%) compared with 77.3% in the placebo group (95% CI 61.9–92.8%) (P = 0.26). In a Cox regression analysis, MTX was not associated with a reduced risk of treatment failure (relative risk 0.72; 95% CI 0.41–1.28). There were no significant differences between groups with regard to abnormal elevations of the erythrocyte sedimentation rate following initial remissions, serious morbidity due to GCA, cumulative CS dose, or treatment toxicity. In the MTX group, there were fewer cases of GCA relapse heralded by symptoms of isolated polymyalgia rheumatica (1 case versus 5 in the placebo group; P = 0.05).Conclusion: The results of this randomized, multicenter trial do not support the adjunctive use of MTX to control disease activity or to decrease the cumulative dose and toxicity of CS in patients with GCA.

Continuous venovenous hemofiltration (CVVH) is used for renal replacement and fluid management in critically ill children. A previous small study suggested that survival was associated with less percent fluid overload (%FO) in the intensive care unit (ICU) before hemofiltration. We reviewed our experience with a large series of pediatric CVVH patients to evaluate factors associated with outcome. Retrospective chart review. Tertiary children’s hospital. CVVH pediatric ICU patients from November 1997 to January 2003. None. %FO was defined as total fluid input minus output (up to 7 days before CVVH for both hospital stay and ICU stay) divided by body weight. One hundred thirteen patients received CVVH; 69 survived (61%). Multiple organ dysfunction syndrome (MODS) was present in 103 patients; 59 survived (57%). Median patient age was 9.6 yrs (25th, 75th percentile: 2.5, 14.3). Median %FO was significantly lower in survivors vs. nonsurvivors for all patients (7.8% [2.0, 16.7] vs. 15.1% [4.9, 25.9]; p = .02] and in patients with ≥3-organ MODS (9.2% [5.1,16.7] vs. 15.5% [8.3, 28.6]; p = .01). The Pediatric Risk of Mortality Score III at CVVH initiation also was associated with survival in these groups, but by multivariate analysis, %FO was independently associated with survival in patients with ≥3-organ MODS (p = .01). Survival in critically ill children receiving CVVH in this large series was higher than in previous reports. CVVH survival may be associated with less %FO in patients with ≥3-organ MODS. Prospective studies are necessary to determine whether earlier use of CVVH to control fluid overload in critically ill children can improve survival.