An early divergence of KhoeSan ancestors from those of other modern humans is supported by an ABC-based analysis of autosomal resequencing data.

Sub-Saharan Africa has consistently been shown to be the most genetically diverse region in the world. Despite the fact that a substantial portion of this variation is partitioned between groups practicing a variety of subsistence strategies and speaking diverse languages, there is currently no consensus on the genetic relationships of sub-Saharan African populations. San (a subgroup of KhoeSan) and many Pygmy groups maintain hunter-gatherer lifestyles and cluster together in autosomal-based analysis, whereas non-Pygmy Niger-Kordofanian speakers (non-Pygmy NKs) predominantly practice agriculture and show substantial genetic homogeneity despite their wide geographic range throughout sub-Saharan Africa. However, KhoeSan, who speak a set of relatively unique click-based languages, have long been thought to be an early branch of anatomically modern humans based on phylogenetic analysis. To formally test models of divergence among the ancestors of modern African populations, we resequenced a sample of San, Eastern, and Western Pygmies and non-Pygmy NKs individuals at 40 nongenic (∼2 kb) regions and then analyzed these data within an Approximate Bayesian Computation (ABC) framework. We find substantial support for a model of an early divergence of KhoeSan ancestors from a proto-Pygmy-non-Pygmy NKs group ∼110 thousand years ago over a model incorporating a proto-KhoeSan-Pygmy hunter-gatherer divergence from the ancestors of non-Pygmy NKs. The results of our analyses are consistent with previously identified signals of a strong bottleneck in Mbuti Pygmies and a relatively recent expansion of non-Pygmy NKs. We also develop a number of methodologies that utilize "pseudo-observed" data sets to optimize our ABC-based inference. This approach is likely to prove to be an invaluable tool for demographic inference using genome-wide resequencing data.

Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.

ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.

Nonmedical costs associated with rotavirus disease requiring hospitalization.

BACKGROUND: As the most common cause of severe diarrhea among children, rotavirus has a significant economic impact. Previous studies focused on the direct medical costs of rotavirus infections; however, nonmedical costs account for the majority of the financial burden from this disease. Herein, we report the results from the largest prospective study in the United States determining the nonmedical costs of severe rotavirus infections. METHODS: Prospective, active, gastroenteritis case surveillance was conducted between November 1997 and December 1999 at 3 pediatric medical centers. Rotavirus infection was identified for 548 children admitted between 2 weeks and 5 years of age. Detailed information about nonmedical costs during the prehospitalization, hospitalization and posthospitalization periods was obtained through interviews. RESULTS: The average nonmedical cost per case of rotavirus disease was USD $448.77, including $359.04 for missed work, $56.66 for transportation, $11.90 for oral rehydration solutions, $9.59 for diapers, $6.83 for child care changes, $3.82 for special foods and $0.93 for formula changes. More than one-half of these expenses (53%) occurred outside the hospitalization period, and 80% of the cost was attributable to missed work. CONCLUSIONS: With an estimated 50,000 hospitalizations attributable to rotavirus each year in the United States, the nonmedical costs of severe rotavirus infections may exceed USD $22 million annually. Previous cost effectiveness analyses of rotavirus vaccines substantially underestimated this burden, suggesting that the nonmedical costs associated with mild to moderate rotavirus disease have been similarly underestimated. These findings are needed to assess accurately the cost effectiveness of future rotavirus immunization strategies.

Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia.

Although it is life saving, transfusion therapy has resulted in the majority of sickle cell anemia and thalassemia patients being at risk for hemosiderosis-induced organ damage. It is unknown whether the complications of iron overload are affected by the underlying disease. In order to address this problem, we compared the prevalence of organ dysfunction in both groups of patients receiving chronic transfusion therapy (beta thalassemia, N = 30; sickle cell anemia, N = 43). Both groups had similar quantitative liver iron. Thalassemia patients had greater cardiac disease (20% vs. 0%), growth failure (27% vs. 9%), and endocrine failure (37% vs. 0%). The strongest predictors of combined endocrine and cardiac disease in multivariate analysis were duration of chronic transfusion (P = 0.03) and diagnosis (P = 0.03). Quantitative liver iron concentration on a single liver biopsy was not predictive of cardiac or endocrine injury. Viral hepatitis is the strongest predictor of hepatocellular damage (P = 0.009), while the development of liver fibrosis is more closely related to liver iron concentration (P = 0.04). In conclusion, sickle cell anemia and thalassemia differ in the prevalence of organ injury. This difference is related to the duration of iron exposure and the specific hemoglobinopathy. A prospective study with a larger number of subjects is needed to confirm the relationships between specific diagnosis, liver iron concentration over time, and organ dysfunction.

Contrasting patterns of Y chromosome and mtDNA variation in Africa: evidence for sex-biased demographic processes.

To investigate associations between genetic, linguistic, and geographic variation in Africa, we type 50 Y chromosome SNPs in 1122 individuals from 40 populations representing African geographic and linguistic diversity. We compare these patterns of variation with those that emerge from a similar analysis of published mtDNA HVS1 sequences from 1918 individuals from 39 African populations. For the Y chromosome, Mantel tests reveal a strong partial correlation between genetic and linguistic distances (r=0.33, P=0.001) and no correlation between genetic and geographic distances (r=-0.08, P>0.10). In contrast, mtDNA variation is weakly correlated with both language (r=0.16, P=0.046) and geography (r=0.17, P=0.035). AMOVA indicates that the amount of paternal among-group variation is much higher when populations are grouped by linguistics (Phi(CT)=0.21) than by geography (Phi(CT)=0.06). Levels of maternal genetic among-group variation are low for both linguistics and geography (Phi(CT)=0.03 and 0.04, respectively). When Bantu speakers are removed from these analyses, the correlation with linguistic variation disappears for the Y chromosome and strengthens for mtDNA. These data suggest that patterns of differentiation and gene flow in Africa have differed for men and women in the recent evolutionary past. We infer that sex-biased rates of admixture and/or language borrowing between expanding Bantu farmers and local hunter-gatherers played an important role in influencing patterns of genetic variation during the spread of African agriculture in the last 4000 years.

Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression.

OBJECTIVE: When children acquire HIV infection from their mothers (with whom they share at least 50% of their HLA alleles), they acquire virus with a history of encounter with maternal HLA-mediated immune responses. We investigated whether maternal HLA selection pressures on the virus would adversely influence clinical outcomes of HIV-infected children. METHODS: We tested whether time to AIDS diagnosis or death, among a cohort of 59 HIV-infected children in New York City followed from birth for up to 12 years, was associated with maternally- or paternally-inherited child HLA class I alleles, and with HLA similarity between mother and child. RESULTS: HIV-infected children with an HLA allele usually associated with slow disease experienced a slower progression to AIDS or death only if the allele was paternally inherited. If the allele was present in the mother, no association was observed. Children who were homozygous or who shared both alleles with their mothers at more than one HLA class I locus were more likely to progress to AIDS or death than other children (relative hazard, 3.46; 95% confidence interval, 1.24-9.71). CONCLUSION: Genetic similarity between mother and child may compromise the child's capacity to control HIV replication when the virus is acquired from the mother. HLA-mediated selective pressures on the virus in a transmitting mother-infant pair may undermine future HLA-mediated viral control in the child.

Mycobacterium tuberculosis/HIV-1 coinfection and disease: role of human leukocyte antigen variation.

Genetic variation influences immune responses and may contribute to differential development of tuberculosis (TB), particularly in immunosuppressed individuals. To examine the risk of Mycobacterium tuberculosis infection progressing to disease in the context of M. tuberculosis/human immunodeficiency virus (HIV) type 1 coinfection, HIV-1 RNA load and human leukocyte antigen (HLA) genotypes were determined among subjects from Harare, Zimbabwe, an area where both TB and HIV-1 are endemic. Patients with TB were compared with control subjects, stratified by HIV-1 infection status and progression of TB disease. Alleles of class I HLA-A and -C were associated with risk of developing active TB, depending on HIV-1 status. Among HIV-positive subjects, HIV-1 load was independently associated with increased risk of developing pulmonary TB. HLA DRB1 homozygosity among HIV-positive subjects was associated with reduced risk of developing pulmonary TB but increased risk of rapid progression to pleural effusion TB. These observations suggest that HLA plays a role in risk of developing symptomatic TB at various stages of disease and that these effects are modified by HIV-1 coinfection.

Association of high HIV-1 RNA levels and homozygosity at HLA class II DRB1 in adults coinfected with Mycobacterium tuberculosis in Harare, Zimbabwe.

HIV-1 mRNA levels (virus load) were quantified for 191 pulmonary tuberculosis (TB) patients and 132 HIV-1 seropositive controls. Human leukocyte antigen (HLA) class I and II genes were typed for 188 patients and 121 HIV-1 seropositive controls. The mean log virus load was higher among cases than HIV-1 seropositive controls (p < 0.0001). Among the controls, mean log virus load was higher among males than females (p = 0.04). There was no association between virus load and homozygosity at HLA class I and II among the controls. In contrast, among the cases, HLA-DRB1 homozygosity was associated with high virus load (p = 0.008), conferring risk for rapid progression to AIDS, thus lending support to the heterozygote advantage hypothesis. The observed decreased virus load in HLA-DRB-1 heterozygotes may be due to a better control of M. tb. infection in the context of HIV-1 disease.

Distribution of chemokine receptor CCR2 and CCR5 genotypes and their relative contribution to human immunodeficiency virus type 1 (HIV-1) seroconversion, early HIV-1 RNA concentration in plasma, and later disease progression.

At the CC (beta) chemokine receptor 2 (CCR2) and CCR5 loci, combinations of common single-nucleotide polymorphisms (SNPs) and a 32-bp deletion (Delta32) form nine stable haplotypes (designated A through G*2). The distribution of these CCR2-CCR5 haplotypes was examined among 703 participants in the Multicenter AIDS Cohort Study (MACS), the District of Columbia Gay (DCG) Study, and the San Francisco Men's Health Study (SFMHS). Highly exposed and persistently seronegative (HEPS; n = 90) Caucasian men from MACS more frequently carried heterozygous G*2 (Delta32) genotypes (especially A/G*2) and less frequently carried the homozygous E/E genotype compared with 469 Caucasian seroconverters (SCs) from the same cohort (P = 0.004 to 0.042). Among 341 MACS Caucasian SCs with 6- to 12-month human immunodeficiency virus type 1 (HIV-1) seroconversion intervals and no potent antiretroviral therapy, mean plasma HIV-1 RNA level during the initial 42 months after seroconversion was higher in carriers of the E/E genotype and lower in those with the 64I-bearing haplotype F*2 or the Delta32-bearing haplotype G*2 (and especially genotypes A/G*2 and F*2/G*2). A multivariable model containing these CCR markers showed significant composite effects on HIV-1 RNA at each of four postconversion intervals (P = 0.0004 to 0.050). In other models using time to AIDS as the endpoint, the same markers showed more modest contributions (P = 0.08 to 0.24) to differential outcome during 11.5 years of follow-up. Broadly consistent findings in the larger MACS Caucasian SCs and the smaller groups of MACS African-American SCs and the DCG and SFMHS Caucasian SCs indicate that specific CCR2-CCR5 haplotypes or genotypes mediate initial acquisition of HIV-1 infection, early host-virus equilibration, and subsequent pathogenesis.