Publications

APOBEC3G (A3G), a deoxycytidine deaminase, is a powerful host antiretroviral factor that can restrict HIV-1 infection. This restriction is counteracted by the HIV-1 virion infectivity factor (Vif) protein, whose activity culminates in depletion of A3G from infected cells. In the absence of Vif, viruses encapsidate A3G, which acts in part to mutate viral DNA formed during reverse transcription upon subsequent infection of a new cell. Cellular A3G also functions as a post-entry restriction factor for HIV in resting CD4 T cells, where it resides in a low molecular mass form. Unfortunately, this barrier is forfeited when CD4 T cells are activated because A3G is recruited into inactive high molecular mass ribonucleoprotein complexes. In addition to restricting HIV, A3G and related deaminases may counter other retroviruses and protect the cell from endogenous mobile retroelements. Understanding A3G complex assembly and its interplay with HIV Vif may make possible future development of a new class of HIV therapeutic agents.

To assess malaria-related prevention and treatment strategies in an urban parish of Kampala, Uganda, a questionnaire was administered to 339 randomly selected primary caregivers of children 1-10 years of age. Our study population was relatively stable and well educated, with better access to health services than many in Africa. Ownership of an insecticide-treated net (ITN) was reported by 11% of households and was predicted only by greater household wealth (highest quartile versus lowest quartile: odds ratio [OR] 21.8; 95% confidence interval [CI], 2.74-173). Among women, 5% reported use of an ITN and 11% used intermittent preventive therapy (IPT) during their last pregnancy. Use of appropriate IPT during pregnancy was predicted only by completion of secondary education or higher (OR, 2.87; 95% CI, 1.13-7.21). Children of 123 (36%) caregivers had experienced an episode of fever in the past 2 weeks. Of these, 22% received an anti-malarial that could be considered "adequate" (combination therapy or quinine). Only 1% of febrile children received adequate treatment at the correct dose within 24 hours of onset of fever. The only independent predictor of treatment with an adequate anti-malarial was accessing a clinic or hospital as the first source of care. In this urban area, use of appropriate malaria control measures occurs uncommonly.

OBJECTIVE

To compare the efficacies against uncomplicated falciparum malaria of chloroquine (CQ), amodiaquine (AQ), sulfadoxine-pyrimethamine (SP) and combinations of these inexpensive drugs.

METHODS

We searched Medline, Embase, Cochrane CENTRAL Register of Controlled Trials, BIOSIS, Web of Science, African Index Medicus, DARE, Digital Dissertations and Current Controlled Trials for randomised or quasi-randomised controlled trials conducted between 1991 and June 2004 regardless of language and geography. We also contacted malaria experts, searched reference lists, and contacted individual authors for unreported study characteristics and additional data. Unpublished data were sought and included in the analyses.

RESULTS

Thirteen randomised trials (n = 4248) were identified and the summary relative risks of treatment failure at 28 days were calculated. There was marginal benefit in adding CQ to SP, compared with SP monotherapy (RR = 0.74, 95% CI 0.54-1.02). Combining AQ with SP was associated with a significantly lower risk of treatment failure than SP monotherapy (RR = 0.35, 95% CI 0.15-0.82) and AQ monotherapy (RR = 0.59, 95% CI 0.42-0.83). AQ plus SP was associated with a significantly lower risk of treatment failure than CQ plus SP (RR = 0.42, 95% CI 0.25-0.72). Serious adverse events were rare and did not increase with combination therapy.

CONCLUSION

Amodiaquine plus SP remains an efficacious, affordable and safe option for treating malaria in certain settings.

In this study we investigated whether hyaluronan (HA)-CD44 interaction influences epidermal structure and function. Our data show that CD44 deficiency is accompanied by reduction in HA staining in CD44 knockout (k/o) mouse skin leading to a marked thinning of epidermis versus wild-type mouse skin. A significant delay in the early barrier recovery (following acute barrier disruption) occurs in CD44 k/o versus wild-type mouse skin. To assess the basis for these alterations in CD44 k/o mouse epidermis, we determined that differentiation markers are greatly reduced in the epidermis of CD44 k/o versus wild-type mice, while conversely HA binding to CD44 triggers differentiation in cultured human keratinocytes. CD44 downregulation (using CD44 small interfering RNAs) also inhibits HA-mediated keratinocyte differentiation. Slower barrier recovery in CD44 k/o mice could be further attributed to reduced lamellar body formation, loss of apical polarization of LB secretion, and downregulation of cholesterol synthesis. Accordingly, HA-CD44 binding stimulates both LB formation and secretion. Together, these observations demonstrate new roles for HA-CD44 interaction in regulating both epidermal differentiation and lipid synthesis/secretion, which in turn influence permeability barrier homeostasis. HA-CD44 signaling could comprise a novel approach to treat skin disorders characterized by abnormalities in differentiation, lipid synthesis, and/or barrier function.

Irritation of the eyes, nose, and throat by airborne chemicals--also referred to as "sensory irritation"--is an important endpoint in both occupational and environmental toxicology. Modeling of human sensory irritation relies on knowledge of the physical chemistry of the compound(s) involved, as well as the exposure parameters (concentration and duration). A reciprocal relationship between these two exposure variables is postulated under Haber's law, implying that protracted, low-level exposures may be toxicologically equivalent to brief, high-level exposures. Although time is recognized as having an influence on sensory irritation, the quantitative predictions of Haber's Law have been addressed for only a handful of compounds in human experimental studies. We have conducted a systematic literature review that includes a semiquantitative comparison of psychophysical data extracted from controlled human exposure studies versus. the predictions of Haber's law. Studies containing relevant data involved exposures to ammonia (2), chlorine (2), formaldehyde (1), inorganic dusts such as calcium oxide (1), and the volatile organic compound 1-octene (1). With the exception of dust exposure, varying exposure concentration has a proportionally greater effect on sensory irritation than does changing exposure duration. For selected time windows, a more generalized power law model (c(n) x t = k) rather than Haber's law per se (c x t = k) yields reasonably robust predictions. Complicating this picture, however, is the frequent observation of intensity-time "plateauing," with time effects disappearing, or even reversing, after a relatively short period, depending on the test compound. The implications of these complex temporal dynamics for risk assessment and standard setting have been incompletely explored to date.

BACKGROUND

The Airways Questionnaire 20 (AQ20) is a concise measure of health-related quality of life (HRQL) in obstructive airway disease; however, its original format may underestimate impairment due to the complete cessation of certain activities.

METHODS

We revised seven items of the original AQ20 (revised AQ20 [AQ20-R]), adding response options for inability to perform certain activities. We assessed the performance of the AQ20-R among 352 adults with various airway conditions identified through a random telephone sample. Concurrent validity of the AQ20-R was assessed relative to the Short Form-12 (SF-12) physical component summary (PCS), FEV(1), and medication use. Predictive validity was assessed relative to health-care utilization among 278 subjects studied longitudinally.

RESULTS

Twenty-one of 352 subjects were unable to perform at least one activity. These subjects demonstrated higher AQ20-R scores (p < 0.001) indicating worse HRQL. Mean (+/- SD) AQ20-R scores differed significantly (p < 0.001) among subjects with COPD (8.9 +/- 5.2), asthma (6.7 +/- 5.0), and chronic bronchitis (4.7 +/- 4.2). At baseline, the AQ20-R correlated with the SF-12 PCS (r = - 0.55, p < 0.001) and FEV(1) (r = - 0.43, p < 0.001), and was associated with the use of respiratory-specific therapies (p

CONCLUSIONS

The AQ20-R is a valid respiratory-specific HRQL measure that accounts for activity cessation among the most impaired and can be used across various airway conditions.

Inflammation and inflammatory diseases are sexually dimorphic, but the underlying causes for this observed sexual dimorphism are poorly understood. We discuss neural-immune mechanisms that underlie sexual dimorphism in three critical aspects of the inflammatory process-plasma extravasation, neutrophil function, and inflammatory hyperalgesia. Plasma extravasation and accumulation/activation of leukocytes into tissues are critical components in inflammation and are required for several other aspects of the inflammatory response. Pain (hyperalgesia) also markedly influences the magnitude of other components of the inflammatory response and induces a feedback control of plasma extravasation and neutrophil function. More important, this feedback control itself is powerfully modulated by vagal afferent activity and both the function of the primary afferent nociceptor and the modulation of inflammatory hyperalgesia by vagal afferent activity are highly sexually dimorphic.

Acute human immunodeficiency virus (HIV) infection is associated with the rapid development of neutralization escape mutations. The degree to which viral evolution persists in chronic infection has not been well characterized, nor is it clear if all patients develop high-level neutralization antibody escape. We therefore measured neutralizing antibody responses against autologous and heterologous viruses in a cohort of acutely and chronically infected subjects (n = 65). Neutralizing antibody responses against both autologous virus and heterologous viruses were lower among individuals with acute infection than among those with chronic infection. Among chronically infected individuals, there was a negative correlation between the level of neutralizing antibodies against autologous virus and the level of viremia. In contrast, there was a positive correlation between the level of neutralizing antibodies against a panel of heterologous viruses and the level of viremia. Viral evolution, as defined by the presence of higher neutralizing titers directed against earlier viruses than against contemporaneous viruses, was evident for subjects with recent infection but absent for those with chronic infection. In summary, neutralizing antibody responses against contemporaneous autologous viruses are absent in early HIV infection but can be detected at low levels in chronic infection, particularly among those controlling HIV in the absence of therapy. HIV replication either directly or indirectly drives the production of increasing levels of antibodies that cross-neutralize heterologous primary isolates. Collectively, these observations indicate that although HIV continuously drives the production of neutralizing antibodies, there may be limits to the capacity of the virus to evolve continuously in response to these antibodies. These observations also suggest that the neutralizing antibody response may contribute to the long-term control of HIV in some patients while protecting against HIV superinfection in most patients.

Pharmacogenomics (PGx), the use of genetic information to individualize drug therapy, is an immediate and important application of the Human Genome Project. The advent of PGx presents challenges to the U.S. Food and Drug Administration (FDA) in pursuing its mandate of protecting public health and safety. The authors conducted a review of academic, industry, and government literature using a technology diffusion framework to identify issues faced by the FDA relevant to the application of PGx. Two hundred and ten articles were reviewed. Key issues were categorized as rationale and structure for PGx regulation, regulation of PGx-based testing technologies, regulation of applications in clinical settings, regulation of data, and regulation of product life cycles. This review identifies issues faced by the FDA with respect to PGx, which the FDA is addressing through several initiatives. It also illustrates the complex issues involved in developing, implementing, and adopting new technologies.