Impairment of brain redox homeostasis caused by the major metabolites accumulating in hyperornithinemia–hyperammonemia–homocitrullinuria syndrome in vivo

Ornithine, ammonia and homocitrulline are the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.     

Drug trajectories among youth undergoing treatment: The influence of psychological problems and delinquency

Previous research has documented associations of addiction with delinquency and psychological problems. However, few studies have evaluated their influence on adolescent's drug use trajectories. The current study aims to examine the influence of these factors on the recovery trajectories of 199 youths aged 15.6 years on average admitted to inpatient and outpatient addiction treatment centers, followed up three and six months later. Results indicate that youth who show higher severity of drug abuse exhibit greater improvement than youth with a lower severity of drug abuse at the onset of treatment. Although psychological problems were associated with baseline drug use, they did not influence drug use trajectory over time. Only delinquency influenced the recovery trajectories of these youth. Results suggest that a high level of delinquency can have a significant effect on the drug recovery process of adolescents and that interventions should attempt to reduce both drug use and delinquency.     

Chronic exposure to Helicobacter pylori impairs dendritic cell function and inhibits Th1 development

Helicobacter pylori causes chronic gastric infection that affects the majority of the world's population. Despite generating an inflammatory response, the immune system usually fails to clear the infection. Since dendritic cells (DCs) play a pivotal role in shaping the immune response, we investigated the effects of H. pylori on DC function. We have demonstrated that H. pylori increased the expression of activation markers on DCs while upregulating the inhibitory B7 family molecule, PD-L1. Functionally, H. pylori-treated DCs resulted in the production of interleukin-10 (IL-10) and IL-23 but not of alpha interferon (IFN-alpha). While very little or no IL-12 was produced to H. pylori alone, simultaneous ligation of CD40 on DCs induced IL-12 release. We also demonstrated that DCs treated with H. pylori-induced IFN-gamma production by allogeneic naive T cells. However, stimulation of DCs with H. pylori for an extended period of time impaired their ability to produce cytokines after CD40 ligation and limited their ability to promote IFN-gamma release, suggesting that the DCs had become exhausted by the prolonged stimulation. The effect of chronic infection with H. pylori on DC function was further investigated by focusing on DC development. Demonstrating that monocytes differentiated into DCs in the presence of H. pylori exhibited an exhausted phenotype with an impaired ability to produce IL-12 and a downregulation of CD1a. Our results raise the possibility that in chronic H. pylori infection DCs become exhausted after prolonged antigen exposure leading to suboptimal Th1 development. This effect may contribute to persistence of H. pylori infection.     

Morphological signs of apoptosis in axotomized ganglion cells of the rabbit retina

Optic nerve section in mammals induces apoptotic death of retinal ganglion cells (RGCs). However, a small population of RGCs survives for a relatively long time. These cells experience significant morphological changes due to the apoptotic process, but some of these changes are not clearly differentiated from those experienced in necrotic cells. In the present work, rabbit RGCs were studied 1 month after optic nerve section using light microscopy after neurobiotin injection, transmission electron microscopy (EM) and scanning electron microscopy (SEM). Apoptosis was identified by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling and characteristic signs of apoptosis were observed in the EM images. Ultrastructural analyses showed vacuolar degeneration in the cytoplasm and normal cellular structure loss. Signs of membrane changes were observed in axotomized RGCs by SEM. Early changes seen in the cell membrane suggest that axotomy may cause important changes in the cytoskeleton. We conclude that characteristic signs of apoptosis at the cell membrane level are clearly observed in rabbit RGCs after axotomy and they may be responsible for the cellular death.     

Seeing is believing: a focus on the contribution of microscopic imaging to our understanding of immune system function

Many cells of the immune system do not occupy fixed tissue locations, but circulate in the blood, traffic through the lymph, and migrate within organized lymphoid organs and periphery tissues. Rare antigen-specific lymphocytes must find one another for productive adaptive immune responses and the different phases of cell-mediated and humoral immune response development take place in distinct sites. This historical feature examines how we have reached our current understanding of these aspects of immune system function. It emphasizes the critical role of ever-improving imaging techniques in determining where immune cells reside and interact and stresses the key past contribution of sequential static immunohistochemical analysis using monoclonal reagents. In combination with genetic studies, these imaging experiments resulted in our current paradigm that views activation-dependent changes in chemokine sensitivity as central to effective cell co-operation. We also highlight the very recent application of two-photon imaging to the direct observation of immune cell dynamics in a natural tissue environment, noting how the application of this technology has reinforced some existing ideas and is changing other long-held views. We conclude with some speculations about the opportunities for further advances using ever more powerful imaging methods.     

Ethnic differences in all-cause and cardiovascular mortality by physical activity levels among older adults in the US

Aims: This study sought to determine whether the association between varying levels of physical activity (PA) and all-cause and cardiovascular mortality differ by race/ethnicity in older adults.

Methods: The sample comprised 2520 women and 2398 men drawn from National Health and Nutrition Examination Survey III (1988–1994) aged?≥?60 years. We used the metabolic equivalent (MET) of self-reported PA levels to define activity groups (inactive: those who did not report any PA; active: those who reported 3–6 METs for ≥5 times/week or >6 METs, ≥3 times/week; insufficiently active: those meeting neither criteria). Racial/Ethnic differences were modeled using proportional hazard regression (HR) adjusting for age, education, smoking, diabetes, and hypertension.

Results: Among those classified as inactive, Non-Hispanic Blacks (NHB) (HR: 0.72, 95% CI: 0.58–0.90) and Mexican Americans (HR: 0.59, 95%CI: 0.45–0.78) had a lower risk of all-cause mortality when compared to non-Hispanic Whites (NHW). Among those classified as insufficiently active, Mexican Americans (HR: 0.63, 95% CI: 0.51–0.77), but not NHB (HR: 0.81, (95% CI: 0.64–1.02) had a lower risk of all-cause mortality when compared to NHWs Similar results were observed for cardiovascular mortality.

Conclusion: Overall, PA in the elderly (either insufficient or active) is associated with a lower all-cause mortality across all race/ethnic groups as compared to NHW. Further investigation, including studies with larger sample, is needed to address the health consequences of varying degrees of PA in ethnically diverse populations.