Characterization of blood-borne transmission of simian foamy virus

BACKGROUND: Simian foamy virus (SFV) is an endemic, nonhuman primate (NHP) retrovirus that is transmitted to individuals who work with or hunt NHPs. The cross-species transmission of simian retroviruses is believed to be the etiology of human immunodeficiency virus and human T-lymphotropic virus infections in humans. Although SFV is not pathogenic in the native host, the shared ancestry with other simian retroviruses has brought into question the potential for acquired pathogenicity after cross-species transmission. This study examines whether SFV also shares the traits of transmissibility through the blood supply. STUDY DESIGN AND METHODS: Within a controlled environment, blood from an SFV-infected monkey was transfused into an SFV-uninfected monkey. Evidence of infection, pathogenic effects, immune correlates, and viral shedding were followed for 6 months after transfusion. RESULTS: Molecular evidence of SFV infection manifested 8 weeks after transfusion followed by seroconversion 1 week later. Quantitative analysis demonstrated that the highest level of detectable virus was concomitant with seroconversion followed by establishment of a viral "set-point." Analysis of circulating lymphocytes revealed changes early in infection. Potential routes of transmission of SFV and roles of site-specific immune response are suggested by the late appearance of SFV shedding in the saliva of the transfused animal. CONCLUSION: The blood supply has historically provided a portal through which novel, occult viruses can become disseminated among humans. The demonstration of transmissibility of SFV through whole-blood transfusion, in an NHP model, contributes to the understanding of potential risks associated with blood donation by SFV-infected humans.     

Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing

MDMA (±3,4-methylenedioxymethamphetamine, ‘ecstasy'') is used recreationally, reportedly because it increases feelings of empathy, sociability, and interpersonal closeness. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. MDMA users (N=65) participated in a 4-session, within-between-subjects study in which they received oral MDMA (0.75, 1.5 mg/kg), intranasal oxytocin (20 or 40 IU), or placebo under double-blind conditions. The primary outcomes included measures of emotion recognition and sociability (desire to be with others). Cardiovascular and subjective effects were also assessed. As expected, MDMA dose-dependently increased heart rate and blood pressure and feelings of euphoria (eg, ‘High'' and ‘Like Drug''). On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose (1.5 mg/kg) increased desire to be with others, compared with placebo. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.     

DNA/MVA vaccine for HIV type 1: effects of codon-optimization and the expression of aggregates or virus-like particles on the immunogenicity of the DNA prime

Recently, a vaccine consisting of DNA priming followed by boosting with modified vaccinia Ankara (MVA) has provided long-term protection of rhesus macaques against a virulent challenge with a chimera of simian and human immunodeficiency viruses. Here, we report studies on the development of the DNA component for a DNA/MVA HIV vaccine for humans. Specifically, we assess the ability of a codon-optimized Gag-expressing DNA and two noncodon-optimized Gag-Pol-Env-expressing DNAs to prime the MVA booster dose. The codon-optimized DNA expressed virus-like particles (VLPs), whereas one of the noncodon-optimized DNAs expressed VLPs and the other expressed aggregates of HIV proteins. The MVA boost expressed Gag-Pol and Env and produced VLPs. Immunogenicity studies in macaques used one intramuscular prime with 600 microg of DNA and two intramuscular boosts with 1 x 10(8) pfu of MVA at weeks 8 and 30. The codon-optimized and noncodon-optimized DNAs proved similar in their ability to prime anti-Gag T cell responses. The aggregate and VLP-expressing Gag-Pol-Env DNAs also showed no significant differences in their ability to prime anti-Env Ab responses. The second MVA booster dose did not increase the peak CD4 and CD8 T cell responses, but increased anti-Env Ab titers by 40- to 90-fold. MVA-only immunizations elicited 10-100 times lower frequencies of T cells and 2-4 lower titers of anti-Env Ab than the Gag-Pol-Env DNA/MVA immunizations. Based on the breadth of the T cell response and a trend toward higher titers of anti-Env Ab, we are moving forward with human trials of the noncodon-optimized VLP-expressing DNA.     

Prevalence and Correlates of Hearing and Visual Impairments in European Nursing Homes: Results From the SHELTER Study

Background

Visual and hearing impairments are known to be related to functional disability, cognitive impairment, and depression in community-dwelling older people. The aim of this study was to examine the prevalence of sensory impairment in nursing home residents, and whether sensory impairment is related to other common clinical problems in nursing homes, mediated by functional disability, cognitive impairment, and depressive symptoms.

Methods

Cross-sectional data of 4007 nursing home residents in 59 facilities in 8 countries from the SHELTER study were analyzed. Visual and hearing impairments were assessed by trained staff using the interRAI instrument for Long-Term Care Facilities. Generalized linear mixed models adjusted for functional disability, cognitive impairment, and depressive symptoms were used to analyze associations of sensory impairments with prevalence of clinical problems, including behavioral symptoms, incontinence, fatigue, falls, problems with balance, sleep, nutrition, and communication.

Results

Of the participants, 32% had vision or hearing impairment (single impairment) and another 32% had both vision and hearing impairments (dual impairment). Residents with single impairment had significantly higher rates of communication problems, fatigue, balance problems, and sleep problems, as compared with residents without any sensory impairment. Those with dual impairment had significantly higher rates of all clinical problems assessed in this study as compared with those without sensory impairment. For each clinical problem, the magnitude of the odds ratio for specific clinical problems was higher for dual impairment than for single impairment.

Conclusion

Visual and hearing impairments are associated with higher rates of common clinical problems among nursing home residents, independent of functional disability, cognitive impairment, and depressive symptoms.     

The efficacy and safety of venetoclax therapy in elderly patients with relapsed,refractory chronic lymphocytic leukaemia

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.     

Mouse intracerebral hemorrhage models produce different degrees of initial and delayed damage,axonal sprouting,and recovery

The mechanisms of delayed damage and recovery after intracerebral hemorrhage (ICH) remain poorly defined. Two rodent models of ICH are commonly used: injection of the enzyme collagenase (cICH) and injection of autologous blood (bICH). In mice, we compared the effects of these two models on initial and delayed tissue damage, motor system connections, and behavioral recovery. There is no difference in lesion size between models. Injection of autologous blood causes greater mass effect and early mortality. However, cICH produces greater edema, inflammation, and cell death. Injection of the enzyme collagenase causes greater loss of cortical connections and secondary shrinkage of the striatum. Intracerebral hemorrhage occurs within the motor system connections of the striatum. Mapping of the projections of the forelimb motor area shows a significant sprouting in motor cortex projections only in cICH. Both models of ICH produce deficits in forelimb motor control. Behavioral recovery occurs by 5 weeks in cICH and 9 weeks in bICH. In summary, cICH and bICH differ in almost every facet of initial and delayed stroke pathophysiology, with cICH producing greater initial and secondary tissue damage and greater motor system axonal sprouting than bICH. Motor recovery occurs in both models, suggesting that motor system axonal sprouting in cICH is not causally associated with recovery.