Publications

Human mast cell tryptases vary strikingly in secretion, catalytic competence, and inheritance. To explore the basis of variation, we compared genes from a range of primates, including humans, great apes (chimpanzee, gorilla, orangutan), Old- and New-World monkeys (macaque and marmoset), and a prosimian (galago), tracking key changes. Our analysis reveals that extant soluble tryptase-like proteins, including alpha- and beta-like tryptases, mastins, and implantation serine proteases, likely evolved from membrane-anchored ancestors because their more deeply rooted relatives (gamma tryptases, pancreasins, prostasins) are type I transmembrane peptidases. Function-altering mutations appeared at widely separated times during primate speciation, with tryptases evolving by duplication, gene conversion, and point mutation. The alpha-tryptase Gly(216)Asp catalytic domain mutation, which diminishes activity, is present in macaque tryptases, and thus arose before great apes and Old World monkeys shared an ancestor, and before the alphabeta split. However, the Arg(-3)Gln processing mutation appeared recently, affecting only human alpha. By comparison, the transmembrane gamma-tryptase gene, which anchors the telomeric end of the multigene tryptase locus, changed little during primate evolution. Related transmembrane peptidase genes were found in reptiles, amphibians, and fish. We identified soluble tryptase-like genes in the full spectrum of mammals, including marsupial (opossum) and monotreme (platypus), but not in nonmammalian vertebrates. Overall, our analysis suggests that soluble tryptases evolved rapidly from membrane-anchored, two-chain peptidases in ancestral vertebrates into soluble, single-chain, self-compartmentalizing, inhibitor-resistant oligomers expressed primarily by mast cells, and that much of present numerical, behavioral, and genetic diversity of alpha- and beta-like tryptases was acquired during primate evolution.

Asthma is a significant health problem among Latinos, the largest minority population in the US. Asthma prevalence, morbidity and mortality are highest in Puerto Ricans, intermediate in Dominicans and Cubans, and lowest in Mexicans and Central Americans. From a cultural and social perspective, Latinos represent a wide variety of national origins and ethnic and cultural groups, with a full spectrum of social class. From a genetic perspective, Latinos have descended from Native American, European and African populations. Here, we review results from recent genetic and clinical studies to illustrate the unique opportunity Latino groups offer for studying the interaction between racial, genetic and environmental contributions to asthma and drug responsiveness.

Among the idiopathic interstitial pneumonias, the two entities-idiopathic pulmonary fibrosis (IPF) characterised by the presence of the usual interstitial pneumonia pattern of histopathology (IPF/UIP) and non-specific interstitial pneumonia (NSIP; same nomenclature for the histopathological pattern and idiopathic disease) - have provoked considerable debate. IPF/UIP and NSIP closely mimic each other clinically but NSIP has a far better outcome. However, it remains unclear if NSIP is a truly separate and distinct entity. The histopathological pattern of NSIP can be found in a wide variety of clinical and radiological contexts. This review addresses these and other uncertainties regarding NSIP and UIP.

BACKGROUND

Malaria and HIV are common causes of mortality in sub-Saharan Africa. The effect of HIV infection on morbidity and mortality in children with severe malarial anaemia was assessed.

METHODS

Children <5 years old were followed as part of a prospective cohort study to assess the transfusion-associated transmission of blood-borne pathogens at Mulago Hospital, Kampala, Uganda. All children were hospitalized with a diagnosis of severe malarial anaemia requiring blood transfusion. Survival to different time points post-transfusion was compared between HIV-infected and uninfected children. Generalized estimating equations were used to analyse repeated measurement outcomes of morbidity, adjusting for confounders.

FINDINGS

Of 847 children, 78 (9.2%) were HIV-infected. Median follow-up time was 162 days (inter-quartile range: 111, 169). HIV-infected children were more likely to die within 7 days (Hazard ratio [HR] = 2.86, 95% Confidence interval [CI] 1.30-6.29, P = 0.009) and within 28 days (HR = 3.70, 95% CI 1.91-7.17, P < 0.001) of an episode of severe malarial anaemia, and were more likely to die in the 6 months post-transfusion (HR = 5.70, 95% CI 3.54-9.16, P < 0.001) compared to HIV-uninfected children. HIV-infected children had more frequent re-admissions due to malaria within 28 days (Incidence rate ratio (IRR) = 3.74, 95% CI 1.41-9.90, P = 0.008) and within 6 months (IRR = 2.66, 95% CI 1.17 - 6.07, P = 0.02) post-transfusion than HIV-uninfected children.

CONCLUSION

HIV-infected children with severe malarial anaemia suffered higher all-cause mortality and malaria-related mortality than HIV-uninfected children. Children with HIV and malaria should receive aggressive treatment and further evaluation of their HIV disease, particularly with regard to cotrimoxazole prophylaxis and antiretroviral therapy.

OBJECTIVES

We compared use of preventive care among veterans receiving care through the Veterans Health Administration (VHA), Medicare fee-for-service (FFS) plans, and Medicare health maintenance organizations (HMOs).

METHODS

Using both the Costs and Use, and Access to Care files of the Medicare Current Beneficiary Survey (2000-2003), we performed a cross-sectional analysis examining self-reported use of influenza vaccination, pneumococcal vaccination, serum cholesterol screening, and serum prostate-specific antigen measurement among male veterans 65 years or older. Veterans' care was categorized as received through VHA, Medicare FFS, Medicare HMOs, VHA and Medicare FFS, or VHA and Medicare HMOs.

RESULTS

Veterans receiving care through VHA reported 10% greater use of influenza vaccination (P<.05), 14% greater use of pneumococcal vaccination (P<.01), a nonsignificant 6% greater use of serum cholesterol screening (P=.1), and 15% greater use of prostate cancer screening (P<.01) than did veterans receiving care through Medicare HMOs. Veterans receiving care through Medicare FFS reported less use of all 4 preventive measures (P<.01) than did veterans receiving care through Medicare HMOs.

CONCLUSIONS

Receiving care through VHA was associated with greater use of preventive care.