Lethal Staphylococcus aureus-induced shock in primates: prevention of death with anti-TNF antibody.

A successful experimental treatment for gram-positive sepsis to our knowledge has not been achieved. The objectives of this study were to develop a nonhuman primate model of lethal gram-positive sepsis employing the micro-organism Staphylococcus aureus and to determine the efficacy of treatment using monoclonal antibody (MAb) to tumor necrosis factor alpha (TNF). The antibody was administered intravenously, 15 mg/kg, 30 minutes after the beginning of a 2-hour infusion of S. aureus, 4 x 10(10) colony forming units/kilogram. The baboons infused with S. aureus demonstrated the release of the cytokines TNF and interleukin-6 (IL-6), but endotoxin was not observed in the plasma at any time. Treatment with antibody to TNF abolished the rise in serum TNF levels and reduced the increased levels of IL-6. Treatment with MAb to TNF prevented multiple organ failure and achieved permanent (> 7 day) survival of all baboons.     

Gene conversion is a likely cause of mutation in PKD1

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.      

Predictors of low CD4 count in resource-limited settings: based on an antiretroviral-naive heterosexual thai population

A barrier to the appropriate provision of antiretroviral therapy to treat immunosuppressed HIV-infected persons in resource-poor countries is identifying who requires treatment. The World Health Organization (WHO) has suggested using a clinical algorithm combined with a total lymphocyte count (TLC) < 1200 cells/mm as a surrogate for a CD4 count less than 200 cells/mm when it is not possible to measure the CD4 count. We evaluated various TLC levels, anemia, and body mass index and compared our data with the WHO criteria to develop a more sensitive algorithm to predict CD4 counts of < 200 cells/mm and < 350 cells/mm in 839 men and women from Thailand infected with HIV-1 subtype E (CRF01_AE). The December 2003 WHO guidelines had a sensitivity of 34.1% in men and 31.8% in women to detect persons with a CD4 count < 200 cells/mm in this HIV-infected population from Thailand. The use of a TLC < 1500 cells/mm or TLC < 2000 cells/mm combined with anemia or WHO stage II infection doubled the sensitivity to detect persons with a CD4 count < 200 (63.0% in men, 68.2% in women) with less than a 6% decrease in specificity.     

Participant retention in clinical trials of candidate HIV vaccines

OBJECTIVE:: To determine predictors of loss to follow-up (LTFU) in trials of candidate HIV vaccines. METHODS:: Data were obtained from trials of candidate preventive HIV vaccines conducted by the AIDS Vaccine Evaluation Group (AVEG) and HIV Network for Prevention Trials (HIVNET) that enrolled HIV-negative volunteers. Analytic models included multiple logistic regression and generalized estimating equations. RESULTS:: Of 3033 volunteers enrolled in 48 trials, 282 (9.3%) persons did not complete follow-up. In univariate analyses, age, trial duration, and number of immunizations were associated with LTFU. In a multivariate logistic model, age (per year) (adjusted odds ratio [AOR] = 0.96, 95% confidence interval [CI]: 0.95, 0.98) and study duration (per month) (AOR = 1.04, 95% CI: 1.01, 1.08) remained significantly associated with LTFU. CONCLUSIONS:: Younger age and increasing trial duration predicted LTFU. Limiting enrollment in trials of novel products to those less than 40 years of age may exclude participants shown to have improved retention. Trials should be designed to last only as long as required to address the scientific question. Retention efforts in future trials should especially address younger persons.     

Dynamic and static phantoms for evaluation of digital subtraction angiographic systems

Two types of phantoms were developed with which to evaluate the overall performance of digital subtraction angiography (DSA) systems. A dynamic phantom, called a "fish bone" phantom, consists of polyethylene tubes that simulate blood vessels with various lesions, such as stenoses, ulcers, and aneurysms. With this phantom, washout curves were obtained representing the relationship between iodine content and time. It will be useful for qualitative assessment of DSA images, evaluation of different image-processing schemes, and studies of blood flow analysis. A static phantom, called a "C-D" phantom, can be used for measurement of quantitative contrast-detail (C-D) diagrams and for daily monitoring of DSA systems. This was constructed of tubes of seven different diameters (2.15-0.28 mm) and 14 different concentrations of contrast medium (100%-1.1% Renografin-76 [meglumine and sodium diatrizoate]). The C-D diagrams were determined from an observer performance study using C-D phantom images obtained at four different DSA settings.