Genetics and epidemiology of gallbladder disease in New World native peoples.

Native peoples of the New World, including Amerindians and admixed Latin Americans such as Mexican-Americans, are highly susceptible to diseases of the gallbladder. These include cholesterol cholelithiasis (gallstones) and its complications, as well as cancer of the gallbladder. Although there is clearly some necessary dietary or other environmental risk factor involved, the pattern of disease prevalence is geographically associated with the distribution of genes of aboriginal Amerindian origin, and levels of risk generally correspond to the degree of Amerindian admixture. This pattern differs from that generally associated with Westernization, which suggests a gene-environment interaction, and that within an admixed population there is a subset whose risk is underestimated when admixture is ignored. The risk that an individual of a susceptible New World genotype will undergo a cholecystectomy by age 85 can approach 40% in Mexican-American females, and their risk of gallbladder cancer can reach several percent. These are heretofore unrecognized levels of risk, especially of the latter, because previous studies have not accounted for admixture or for the loss of at-risk individuals due to cholecystectomy. A genetic susceptibility may, thus, be as "carcinogenic" in New World peoples as any known major environmental exposure; yet, while the risk has a genetic basis, its expression as gallbladder cancer is so delayed as to lead only very rarely to multiply-affected families. Estimates in this paper are derived in part from two studies of Mexican-Americans in Starr County and Laredo, Texas.

Molecular and evolutionary genetics of the X -linked visual pigment genes in humans and New World monkeys

Normal humans have one red and at least one green visual pigment genes. These genes are tightly linked as tandem repeats on the X chromosome and each of them has six exons. There is only one X-linked visual pigment gene in New World monkeys (NWMs) but the locus has three polymorphic alleles encoding red, yellow and green visual pigments, respectively. The spectral properties of the squirrel monkey and the marmoset (both NWMs) have been studied and partial sequences of the three alleles are available. To study the evolutionary history of these X-linked opsin genes in humans and NWMs, coding and intron sequences of the three squirrel monkey alleles and the three marmoset alleles were amplified by PCR followed by subcloning and sequencing. Introns 2 and 4 of the human red and green pigment genes were also sequenced. The results obtained are as follows: (1) The sequences of introns 2 and 4 of the human red and green opsin genes are significantly more similar between the two genes than are coding sequences, contrary to the usual situation where coding regions are better conserved in evolution than are introns. The high similarities in the two introns are probably due to recent gene conversion events during evolution of the human lineage. (2) Phylogenetic analysis of both intron and exon sequences indicates that the phylogenetic tree of the available primate opsin genes is the same as the species tree. The two human genes were derived from a gene duplication event after the divergence of the human and NWM lineages. The three alleles in each of the two NWM species diverged after the split of the two NWMs but have persisted in the population for at least 5 million years. (3) Allelic gene conversion might have occurred between the three squirrel monkey alleles. (4) A model of additive effect of hydroxyl-bearing amino acids on spectral tuning is proposed by treating some unknown variables as groups. Under the assumption that some residues have no effect, it is found that at least five amino acid residues, at positions 178 (3 nm), 180 (5 nm), 230 ($-$4 nm), 277 (9 nm) and 285 (13 nm), have linear spectral tuning effects. (5) Adaptive evolution of the opsin genes to different spectral peaks was observed at four residues that are important for spectral tuning. ^

A prospective cohort study evaluating the state of medical readiness in the United States Air Force and risk factors to improve the medical readiness posture

A cohort of 418 United States Air Force (USAF) personnel from over 15 different bases deployed to Morocco in 1994. This was the first study of its kind and was designed with two primary goals: to determine if the USAF was medically prepared to deploy with its changing mission in the new world order, and to evaluate factors that might improve or degrade USAF medical readiness. The mean length of deployment was 21 days. The cohort was 95% male, 86% enlisted, 65% married, and 78% white.^ This study shows major deficiencies indicating the USAF medical readiness posture has not fully responded to meet its new mission requirements. Lack of required logistical items (e.g., mosquito nets, rainboots, DEET insecticide cream, etc.) revealed a low state of preparedness. The most notable deficiency was that 82.5% (95% CI = 78.4, 85.9) did not have permethrin pretreated mosquito nets and 81.0% (95% CI = 76.8, 84.6) lacked mosquito net poles. Additionally, 18% were deficient on vaccinations and 36% had not received a tuberculin skin test. Excluding injections, the overall compliance for preventive medicine requirements had a mean frequency of only 50.6% (95% CI = 45.36, 55.90).^ Several factors had a positive impact on compliance with logistical requirements. The most prominent was "receiving a medical intelligence briefing" from the USAF Public Health. After adjustment for mobility and age, individuals who underwent a briefing were 17.2 (95% CI = 4.37, 67.99) times more likely to have received an immunoglobulin shot and 4.2 (95% CI = 1.84, 9.45) times more likely to start their antimalarial prophylaxsis at the proper time. "Personnel on mobility" had the second strongest positive effect on medical readiness. When mobility and briefing were included in models, "personnel on mobility" were 2.6 (95% CI = 1.19, 5.53) times as likely to have DEET insecticide and 2.2 (95% CI = 1.16, 4.16) times as likely to have had a TB skin test.^ Five recommendations to improve the medical readiness of the USAF were outlined: upgrade base level logistical support, improve medical intelligence messages, include medical requirements on travel orders, place more personnel on mobility or only deploy personnel on mobility, and conduct research dedicated to capitalize on the powerful effect from predeployment briefings.^ Since this is the first study of its kind, more studies should be performed in different geographic theaters to assess medical readiness and establish acceptable compliance levels for the USAF. ^

Is paromomycin an effective and safe treatment against cutaneous leishmaniasis? A meta-analysis of 14 randomized controlled trials.

BACKGROUND: High cost, poor compliance, and systemic toxicity have limited the use of pentavalent antimony compounds (SbV), the treatment of choice for cutaneous leishmaniasis (CL). Paromomycin (PR) has been developed as an alternative to SbV, but existing data are conflicting. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, without language restriction, through August 2007, to identify randomized controlled trials that compared the efficacy or safety between PR and placebo or SbV. Primary outcome was clinical cure, defined as complete healing, disappearance, or reepithelialization of all lesions. Data were extracted independently by two investigators, and pooled using a random-effects model. Fourteen trials including 1,221 patients were included. In placebo-controlled trials, topical PR appeared to have therapeutic activity against the old world and new world CL, with increased local reactions, when used with methylbenzethonium chloride (MBCL) compared to when used alone (risk ratio [RR] for clinical cure, 2.58 versus 1.01: RR for local reactions, 1.60 versus 1.07). In SbV-controlled trials, the efficacy of topical PR was not significantly different from that of intralesional SbV in the old world CL (RR, 0.70; 95% confidence interval, 0.26-1.89), whereas topical PR was inferior to parenteral SbV in treating the new world CL (0.67; 0.54-0.82). No significant difference in efficacy was found between parenteral PR and parenteral SbV in the new world CL (0.88; 0.56-1.38). Systemic side effects were fewer with topical or parenteral PR than parenteral SbV. CONCLUSIONS/SIGNIFICANCE: Topical PR with MBCL could be a therapeutic alternative to SbV in selected cases of the old world CL. Development of new formulations with better efficacy and tolerability remains to be an area of future research.

Origins and evolution of VNTR loci: The apolipoprotein B 3$\sp\prime$ VNTR

I studied the apolipoprotein (apo) B 3$\sp\prime$ variable number tandem repeat (VNTR) and did computer simulations of the stepwise mutation model to address four questions: (1) How did the apo B VNTR originate? (2) What is the mutational mechanism of repeat number change at the apo B VNTR? (3) To what extent are population and molecular level events responsible for the determination of the contemporary apo B allele frequency distribution? (4) Can VNTR allele frequency distributions be explained by a simple and conservative mutation-drift model? I used three general approaches to address these questions: (1) I characterized the apo B VNTR region in non-human primate species; (2) I constructed haplotypes of polymorphic markers flanking the apo B VNTR in a sample of individuals from Lorrain, France and studied the associations between the flanking-marker haplotypes and apo B VNTR size; (3) I did computer simulations of the one-step stepwise mutation model and compared the results to real data in terms of four allele frequency distribution characteristics.^ The results of this work have allowed me to conclude that the apo B VNTR originated after an initial duplication of a sequence which is still present as a single copy sequence in New World monkey species. I conclude that this locus did not originate by the transposition of an array of repeats from somewhere else in the genome. It is unlikely that recombination is the primary mutational mechanism. Furthermore, the clustered nature of these associations implicates a stepwise mutational mechanism. From the high frequencies of certain haplotype-allele size combinations, it is evident that population level events have also been important in the determination of the apo B VNTR allele frequency distribution. Results from computer simulations of the one-step stepwise mutation model have allowed me to conclude that bimodal and multimodal allele frequency distributions are not unexpected at loci evolving via stepwise mutation mechanisms. Short tandem repeat loci fit the stepwise mutation model best, followed by microsatellite loci. I therefore conclude that there are differences in the mutational mechanisms of VNTR loci as classed by repeat unit size. (Abstract shortened by UMI.) ^

TRANSOVARIAL TRANSMISSION OF YELLOW FEVER VIRUS BY A SYLVATIC VECTOR, HAEMAGOGUS EQUINUS (THEOBALD)

The potential of a sylvatic vector to act as reservoir of yellow fever virus was assessed in Haemagogus equinus (Theobald). Mosquitoes from the Maje'75 laboratory colony and a Panamanian human isolated strain of yellow fever virus were used. Female mosquitoes infected with yellow fever virus had a minimum transovarial transmission rate of 1:5745. This is the first time transovarial transmission of yellow fever virus has been demonstrated in a New World sylvatic vector. Transovarial transmission of yellow fever virus in this sylvatic mosquito species may be an alternative mechanism for biological survival of the virus during adverse periods or in the absence of susceptible vertebrate hosts. ^