Heterozygosity for CCR5-Delta32 but not CCR2b-64I protects against certain intracellular pathogens

Objective

To determine the association between CCR5 and CCR2b genotype and the clinical manifestation of first and subsequent AIDS‐defining illnesses (ADIs).

Methods

The distribution of ADIs was examined by CCR5 and CCR2b genotype in a subset of homosexual men enrolled in the Sydney AIDS Prospective Study. The expected number of ADIs was calculated from rates observed in the same tertiary hospital over the same period.

Results

Information on initial ADI was collected for 117 homosexual men diagnosed with AIDS before January 1998. Of these individuals, 17 were heterozygous for the CCR5‐DΔ32 mutation and 11 were heterozygous for CCR2b‐64I. The number of observed cases of Pneumocystis carinii pneumonia (PCP), toxoplasmosis, Mycobacterium avium complex (MAC) and cryptosporidiosis reported as a first ADI was substantially fewer in people heterozygous for the CCR5‐DΔ32 mutation than for those without the mutation, despite similar age, CD4 T‐cell count at AIDS diagnosis, year of AIDS diagnosis and receipt of antiretroviral treatment. In addition, among individuals heterozygous for CCR5‐DΔ32 there were fewer cases of PCP, toxoplasmosis, MAC, and cryptosporidiosis observed as subsequent ADIs compared to the number expected, based on rates measured in the same hospital during the same period (seven observed vs. 24 expected, RR = 0.3, 95% CI = 0.01–0.6). The distribution of first and subsequent ADIs did not differ from the number expected in individuals heterozygous for the CCR2b‐64I mutation.

Conclusion

Results from this study show that heterozygosity for CCR5‐DΔ32 but not CCR2b‐64I appears to protect against opportunistic infections.

     

Regulatory aspects of noninvasive glucose measurements

The Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Act (the Act) established three regulatory classes for medical devices. Section 513 of the Act specifies three classes based upon the degree of control and Food and Drug Administration (FDA) oversight that is necessary to assure that the various types of devices are safe and effective. High-risk devices are placed into the most regulated device class, Class III. Under Section 515 of the Act, all devices placed in Class III are subject to premarket approval (PMA) requirements. PMA by FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices. Advisory panel review is required of virtually all original submissions. Manufacturing facilities of devices requiring PMA approval are also subject to preapproval inspection to assure data integrity and compliance with good manufacturing practices. An approved PMA is granted for marketing a particular medical device for a particular intended use. FDA considers noninvasive and minimally invasive glucose devices that are intended to measure, monitor, or predict blood glucose levels in diabetics to be high-risk medical devices. These devices will have a significant potential impact on the medical care of people with diabetes. The technology offers potential improvements in the quality of life, enhanced blood glucose control through increased frequency of testing, or access to testing, in a broader range of patients. However, the technology is not yet well understood, and the information obtained from these devices is often different from the information that has been the traditional base for the management of diabetes. As a result, FDA requires both analytical and clinical studies to support the intended claims for these new devices.     

Update on didanosine

Didanosine (ddl) has been a cornerstone of HIV management since it was made available in October 1991. Didanosine was originally introduced as an alternative to zidovudine (ZDV) for patients who were intolerant of ZDV or experienced disease progression during ZDV monotherapy. Didanosine is now used extensively as an integral component of multidrug combination regimens in both adults and children with HIV infection, and is now available for once-daily administration in the United States, Canada, and Europe. The recently approved Videx EC is an enteric-coated didanosine capsule dosed as one capsule, once daily. This paper provides an update of recently published studies on the use of ddl in combination anti-HIV therapy. In particular, these studies examine the rationale for the use of ddl as first-line anti-HIV therapy, and describe newer findings concerning its long-term efficacy, side effects, compliance, resistance, and once-daily use. The increased survival of HIV-infected patients is largely attributed to the introduction of the triple combination drug therapy but is probably also due to the long-term clinical efficacy of ddl.     

Atopic dermatitis: review of immunopathogenesis and advances in immunosuppressive therapy

This paper reviews the theories of the pathogenesis of atopic dermatitis (AD), with a particular emphasis on its immunopathogenesis. The contribution of predisposing factors, immunopathogenic factors and provoking factors in the pathogenesis of AD are considered. Predisposing factors explored in this article include genetics and the disturbance of skin function. Immunopathogenic factors reviewed include T cell dysfunction, biphasic cytokine expression and the role of immunoglobulin E. Provoking factors considered include microbial factors, psychosomatic interactions, contact allergens and irritants, inhalant allergens, food and climate. Immunosuppressive treatments reviewed include cyclosporin, azathioprine, methotrexate, tacrolimus, interferon-gamma, phosphodiesterase inhibitors and pimecrolimus (SDZ ASM 981).     

Isolation and characterization of lymphocyte-like cells from a lamprey

Lymphocyte-like cells in the intestine of the sea lamprey, Petromyzon marinus, were isolated by flow cytometry under light-scatter conditions used for the purification of mouse intestinal lymphocytes. The purified lamprey cells were morphologically indistinguishable from mammalian lymphocytes. A cDNA library was prepared from the lamprey lymphocyte-like cells, and more than 8,000 randomly selected clones were sequenced. Homology searches comparing these ESTs with sequences deposited in the databases led to the identification of numerous genes homologous to those predominantly or characteristically expressed in mammalian lymphocytes, which included genes controlling lymphopoiesis, intracellular signaling, proliferation, migration, and involvement of lymphocytes in innate immune responses. Genes closely related to those that in gnathostomes control antigen processing and transport of antigenic peptides could be ascertained, although no sequences with significant similarity to MHC, T cell receptor, or Ig genes were found. The data suggest that the evolution of lymphocytes in the lamprey has reached a stage poised for the emergence of adaptive immunity.     

Heritability of blood pressure in Nigerian families

OBJECTIVES: There are few studies of familial aggregation of blood pressure in African populations. This study was undertaken to provide estimates of heritability for four blood pressure phenotypes: systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure. METHODS : A population-based sample of 528 pedigrees or extended families, comprising 1825 measured individuals, was studied in a poor urban community in Ibadan, Nigeria. RESULTS : The mean SBP was 121.7 (SD 22.6) mmHg for men and 120.7 (SD 26.8) mmHg for women, while the mean DBP was 74.6 (SD 14.1) mmHg for men and 75.5 (SD 15.2) mm Hg for women. The study sample was lean [mean body mass index (BMI) approximately 21 kg/m2]. Maximum-likelihood heritability estimates were obtained under a polygenic model with simultaneous estimation of household effects using a variance components method, as implemented in the SOLAR software package. Heritability estimates of the traits were 34% for SBP, 29% for DBP, 36% for MAP and 13% for pulse pressure. Household effects were statistically significant for DBP (7.1%) and MAP (4.5%). Measured covariates (age, sex and BMI) accounted for 25, 24, 26 and 16% of the total variance, respectively, for SBP, DBP, MAP and pulse pressure. CONCLUSIONS : These figures suggest that, similar to that reported in other populations, blood pressure is a heritable trait. Studies similar to this are needed to describe the familial aggregation of other complex traits in sub-Saharan African populations and to serve as a prelude to the identification of susceptibility genes involved in the pathophysiology of common complex diseases, including blood pressure and hypertension.