Management of infectious intracranial aneurysms in the pediatric population

Introduction

Infectious intracranial aneurysms (IIAs) account for approximately 15 % of all pediatric intracranial aneurysms. Histologically, they are pseudoaneurysms that develop in response to an inflammatory reaction within the adventitia and muscularis layers, ultimately resulting in disruption of both the internal elastic membrane and the intima. The majority of pediatric IIAs are located within the anterior circulation, and they can be multiple in 15–25 % of cases.

Background

The most common presentation for an IIA is intracerebral and/or subarachnoid hemorrhage. In children with a known diagnosis of infective endocarditis who develop new neurological manifestations, it is imperative to exclude the existence of an IIA. The natural history of untreated infectious aneurysms is ominous; they demonstrate a high incidence of spontaneous rupture. High clinical suspicion, prompt diagnosis, and adequate treatment are of paramount importance to prevent devastating neurological consequences.

Discussion

The prompt initiation of intravenous broad-spectrum antibiotics represents the mainstay of treatment. Three questions should guide the management of pediatric patients with IIAs: (a) aneurysm rupture status, (b) the presence of intraparenchymal hemorrhage or elevated intracranial pressure, and (c) relationship of the parent vessel to eloquent brain tissue. Those three questions should orient the treating physician into either antibiotic therapy alone or in combination with microsurgical or endovascular interventions. This review discusses important aspects of the epidemiology, the diagnosis, and the management of IIAs in the pediatric population.

     

Lysosomal targeting strategies for design and delivery of bioactive for therapeutic interventions

Lysosomes are of particular interest for the design and delivery of pH-dependent pro-drugs, enhancing selectivity and developing strategies to inhibit drug degradation inside the cells. There is great potential to bring intracellular drug delivery and distribution using nanotherapeutic approaches to target lysosomes for therapeutic interventions. Lysosomal targeting strategies involve two contrasting facets. One aspect is to directly target therapeutics to the lysosome through receptor-mediated endocytosis and the other facet involves strategies, which ensure escape from the lysosome in order to prevent their degradation, so that therapeutics may remain intact and available in the cytosol for their further action. It provides a unique opportunity to explore novel treatment strategies and design future drugs for the effective treatment of lysosome-related diseases especially lysosomal storage disorders (LSD), cancer, inflammatory, neurodegenerative conditions (Parkinson's, Alzheimer's and Huntington's diseases) and autoimmune diseases. In this review, we illustrate the fundamentals of membrane trafficking, subcellular organisation, strategies to target lysosomes and its implications for the advance design of efficient drug delivery vectors for safe and effective therapies.     

Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats

There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl(4) (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl(4) bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl(4) hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0-96 h) of CCl(4) (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and (14)CCl(4) covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl(4) administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl(4) hepatotoxicity is potentiated due to inhibited tissue repair.     

Cytokine accumulation in stored red cell concentrates: effect of buffy-coat removal and leucoreduction

The accumulation of cytokines in stored red blood cell concentrates (RCCs) has been implicated as a potential cause of transfusion reactions associated with the use of such products. At present, it is unclear whether there is any link between residual leukocyte and/or platelet content with cytokine levels in various RCCs. In this study, we have therefore assessed cytokine levels of leukocyte (e.g., IL8) and platelet (e.g., RANTES, TGF-beta1) origin in supernatants of RCCs prepared by the plasma reduced method or by depletion of the buffy coat. We have also assessed whether the Duffy antigen receptor (DARC, a promiscuous receptor for some chemokines) has any role in the diminution of cytokine levels in stored blood components by comparing cytokine levels in stored plasma reduced RCCs derived from both DARC +ve and DARC -ve individuals. In addition, comparison of filtered and non-filtered products of the same origin has also been conducted. Results showed that supernatants from DARC -ve concentrates contained higher levels of IL-8 up to days 14/15 of storage compared with DARC +ve RCCs. However, at later time points, similar levels of IL-8 were observed in RCCs regardless of their Duffy receptor status. For TGF-beta1 and RANTES, no significant difference in the levels of these cytokines was detected between DARC +ve and DARC -ve concentrates. Removal of leukocytes and platelets by conventional leukocyte filtration significantly reduced the accumulation of cytokines. Buffy coat reduced RCCs contained minimal amounts of IL-8 and TGF-beta1 but no RANTES. We conclude therefore, that the levels of cytokines in the supernatants of RCCs stored at 4 degrees C are related mainly to their leucocyte and platelet content.     

Biomarkers for major depressive and bipolar disorders using metabolomics: A systematic review

Major depressive disorder (MDD) and bipolar disorder (BD) lack robust biomarkers useful for screening purposes in a clinical setting. A systematic review of the literature was conducted on metabolomic studies of patients with MDD or BD through the use of analytical platforms such as in vivo brain imaging, mass spectrometry, and nuclear magnetic resonance. Our search identified a total of 7,590 articles, of which 266 articles remained for full‐text revision. Overall, 249 metabolites were found to be dysregulated with 122 of these metabolites being reported in two or more of the studies included. A list of biomarkers for MDD and BD established from metabolites found to be abnormal, along with the number of studies supporting each metabolite and a comparison of which biological fluids they were reported in, is provided. Metabolic pathways that may be important in the pathophysiology of MDD and BD were identified and predominantly center on glutamatergic metabolism, energy metabolism, and neurotransmission. Using online drug registries, we also illustrate how metabolomics can facilitate the discovery of novel candidate drug targets.     

Training-induced plasticity in older adults: effects of training on hemispheric asymmetry

The extent to which cortical plasticity is retained in old age remains an understudied question, despite large social and scientific implications of such a result. Neuroimaging research reports individual differences in age-related activation, thereby educing speculation that some degree of plasticity may remain throughout life. We conducted a randomized longitudinal dual-task training study to investigate if performance improvements (a) change the magnitude or pattern of fMRI activation, thereby suggesting some plasticity retention in old age and (b) result in a reduction in asymmetry and an increase in age differences in fMRI activation as a compensatory model of performance-related activation predicts. Performance improvements were correlated with an increase in hemispheric asymmetry and a reduction in age differences in ventral and dorsal prefrontal activation. These results provide evidence for plasticity in old age and are discussed in relation to an alternative argument for the role of reduced asymmetry in performance improvements.