Neuropathogenesis of Chimeric Simian/Human Immunodeficiency Virus infection In Pig-tailed and Rhesus Macaques

We recently reported that a chimeric simian/human immunodeficiency virus (SHIV_KU-1) developed in our laboratory caused progressive depletion of CD4⁺T lymphocytes and AIDS within 6 months of inoculation into pig-tailed macaques (M.nemestrina). None of the pig-tailed macaques showed productive SHIV infection in the central nervous system (CNS). In this report, we show that by further passage of the pathogenic virus in rhesus macaques [M. mulatta], we have derived a new strain of SHIV (SHIV_KU-2) that has caused AIDS and productive CNS infection in 3 of 5 rhesus macaques infected with the virus. Productive replication of SHIV in the CNS was clearly shown by high infectivity titers and p27 protein levels in brain homogenates, and in 2 of the 3 rhesus macaques this was associated with disseminated, nodular, demyelinating lesions, including focal multinucleated giant cell reaction, largely confined to the white matter. These findings were reminiscent of HIV-1 associated neurological disease, and our immunohistochemical and in situ hybridization data indicated that the neuropathological lesions were associated with the presence of SHIV-specific viral antigens and nucleic acid respectively. However, the concomitant reactivation of opportunistic infections in these macaques suggested that such pathogens may have influenced the replication of SHIV in the CNS, or modified the neuropathological sequelae of SHIV infection in the rhesus species, but not in pig-tailed macaques. Our findings in the two species of macaques highlight the complexities of lentiviral neuropathogenesis, the precise mechanisms of which are still elusive.     

Exposure to Tobacco Retail Outlets and Smoking Initiation among New York City Adolescents

This study was designed to estimate the relationship between exposure to tobacco retail outlets and smoking initiation in a racially diverse urban setting. Using data from the 2011 NYC Youth Risk Behavior Survey, multivariable logistic regression analyses were conducted to estimate the exposure–initiation relationship and test for effect modification, while controlling for covariates. The predicted probability of smoking initiation from the multivariable model increased from 7.7 % for zero times a week exposed to tobacco retailers to 16.0 % for exposure seven times or more per week. The odds of initiation were significantly higher among adolescents exposed to tobacco retail outlets two times or more a week compared with those exposed less often (AOR = 1.41; 95 % CI: 1.08, 1.84). Risk-taking behavior modified the relationship between exposure and initiation, with the odds of initiation highest among those low in risk-taking (AOR = 1.78; 95 % CI: 1.14, 1.56). These results are consistent with past research, showing that frequent exposure to tobacco marketing in retail settings is associated with increased odds of initiation. Reducing exposure to tobacco retail marketing could play an important role in curtailing smoking among adolescents, especially those less prone to risk-taking.     

Sensory evoked potentials in SIV-infected monkeys with rapidly and slowly progressing disease

Human immunodeficiency virus (HIV-1) infects the central nervous system (CNS) early in the course of disease progression and leads to some form of neurological disease in 40-60% of cases. Both symptomatic and asymptomatic HIV-infected subjects also show abnormalities in evoked potentials. As part of an effort to further validate an animal model of the neurological disease associated with lentiviral infection, we recorded multimodal sensory evoked potentials (EPs) from nine rhesus macaques infected with passaged strains of SIVmac (R71/E17), prior to and at 1 month intervals following inoculation. The latencies of forelimb and hindlimb somatosensory evoked potentials (SEP) and flash visual evoked potentials (VEP) were measured. Within 14 weeks of inoculation, all but two animals had progressed to end-stage disease (rapid progressors). The two animals with slowly progressing disease (AQ15 and AQ94) had postinoculation life spans of 109 and 87 weeks, respectively. No significant changes were observed in evoked potentials recorded during the control period or at any time in the animals with slowly progressing disease. However, all of the monkeys with rapidly progressing disease exhibited increases in latency for at least one evoked potential type. The overall mean increases in somatosensory and visual evoked potential peak latencies for the rapid progressors were 22.4 and 25.3%, respectively. For comparison, the changes in slow progressors were not significant (1.8 and -1.9%, respectively). These results, coupled with our previous finding of slowed motor evoked potentials in the same cohort of macaques (Raymond et al.: J Neurovirol 1999;5:217-231), demonstrate a broad and somewhat variable pattern of viral injury to both sensory and motor system structures, resembling the findings in HIV-infected humans. These results coupled with our earlier work demonstrating cognitive and motor behavioral impairments in the same monkeys support the use of the SIVmac-infected rhesus macaque as a model of AIDS-related neurological disease.     

Novel CD3Z and CD3E Deficiency in Two Unrelated Females

Journal of Clinical Immunology -     

Predictors of mortality in children due to severe and very severe pneumonia

Background:

Mortality due to pneumonia in children is more than any other illness. Limited data is available to predict mortality in children with pneumonia from central India.

Aim:

To study predictors of mortality in children aged 1-59 months hospitalised with severe and very severe pneumonia.

Materials and Methods:

Present study was observational longitudinal study that was done in a tertiary care hospital of central India. Two hundred and ninety children, aged 1-59 months, presented with severe and very severe pneumonia were enrolled in this study. Outcome and predictors of mortality were studied. Data was analysed with Chi-square test, univariate and multivariate regression analysis.

Results:

Out of 270 enrolled study subjects, maximum (108, 37.24%) were belonged to 1-6-months age group. Proportion of mortality was maximum (16, 64.00%) in that age group. Overall case fatality rate was 8.62%. Among significant variables, delayed hospital referral [adjusted odds ratio (OR)-52.09, 95% confidence interval (CI)- 6.74-402.39], incomplete immunisation (OR-12.28, 95% CI-2.15-69.93), severe malnutrition (Z score < −3) (OR-15.51, 95% CI- 2.04-117.83), refusal to feed (OR- 30.57, 95% CI- 2.47-378.26), and hypoglycaemia (OR- 6.98, 95% CI- 1.05-46.30) were found significant independently on multivariate regression analysis. Conclusion: Delayed hospital referral, incomplete immunisation, severe malnutrition, refusal to feed, and hypoglycaemia were independent predictors of mortality in children with severe and very severe pneumonia.     

Novel Endogenous Glycan Therapy for Retinal Diseases: Safety,In Vitro Stability,Ocular Pharmacokinetic Modeling,and Biodistribution

Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [³H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous > retina > sclera/choroid > aqueous humor > cornea > lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [³H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9563-1) contains supplementary material, which is available to authorized users.Key words: age-related macular degeneration (AMD), NA3 glycan, pharmacokinetics, safety     

Gradient of microglial activation in the brain of SIV infected macaques

Brains of macaques inoculated with macrophage-tropic, neurovirulent virus 7F, with lymphocyte-tropic SIV mac239, or with dual-tropic SIVmac239/1yE, were examined for microglial activation, astrocyte activation, apoptosis and neuron loss. The brain one animal inoculated with neurovirulent virus 7f showed massive microglial activation as assessed by expression of the major histo-compatibility complex class II (MHC-II). In this animal very numerous, large microglial nodules expressing MHC-II were concentrated in the basal pons and internal capsule. These microglial nodules contained cells undergoing apoptosis detected by in situ end labeling of fragmented DNA. In this animal, neuron loss was apparent near the microglial nodules. In the animals inoculated with SIVmac239 or SIVmac239/17E, pathologic changes such as perivascular cuffing and formation of microglial nodules were absent. However, increased expression of MHC-11 by microglial cells was also concentrated in white matter of the basal pons, midbrain and internal capsule. These results indicate the microglial activation in SIV-infected macaques follows a ventral to dorsal gradient regardless of viral tropism. These results also show that the type and severity of neuropathological changes in SIV-infected macaques is highly dependent on the tropism of the inoculated virus.