Disruption of the Hippocampal and Hypothalamic Blood-Brain Barrier in a Diet-Induced Obese Model of Type II Diabetes: Prevention and Treatment by the Mitochondrial Carbonic Anhydrase Inhibitor, Topiramate

Background: Type II diabetes is a vascular risk factor for cognitive impairment and increased risk of dementia. Disruption of the blood–retinal barrier (BRB) and blood–brain barrier (BBB) are hallmarks of subsequent retinal edema and central nervous system dysfunction. However, the mechanisms by which diet or metabolic syndrome induces dysfunction are not understood. A proposed mechanism is an increase in reactive oxygen species (ROS) and oxidative stress. Inhibition of mitochondrial carbonic anhydrase (mCA) decreases ROS and oxidative stress. In this study, topiramate, a mCA inhibitor, was examined for its ability to protect the BRB and BBB in diet-induced obese type II diabetic mice. Methods: BBB and BRB permeability were assessed using 14C-sucrose and 99mTc-albumin in CD-1 mice fed a low-fat (control) or a high-fat diet. Topiramate administration was compared to saline controls in both preventative and efficacy arms examining BRB and BBB disruption. Body weight and blood glucose were measured weekly and body composition was assessed using EchoMRI. Metabolic activity was measured using a comprehensive laboratory animal monitoring system. Brain tissues collected from the mice were assessed for changes in oxidative stress and tight junction proteins. Results: High-fat feeding caused increased entry of 14C-sucrose and 99mTc-albumin into the brains of diet-induced obese type II diabetic mice. Increased permeability to 14C-sucrose was observed in the hypothalamus and hippocampus, and attenuated by topiramate treatment, while increased permeability to 99mTc-albumin occurred in the whole brain and was also attenuated by topiramate. Treatment with topiramate decreased measures of oxidative stress and increased expression of the tight junction proteins ZO-1 and claudin-12. In the retina, we observed increased entry of 99mTc-albumin simultaneously with increased entry into the whole brain during the preventative arm. This occurred prior to increased entry to the retina for 14C-sucrose which occurred during the efficacy arm. Treatment with topiramate had no effect on the retina. Conclusions: Blood–brain barrier and blood–retinal barrier dysfunction were examined in a mouse model of diet-induced obese type II diabetes. These studies demonstrate that there are spatial and temporal differences in 14C-sucrose and 99mTc-albumin permeability in the brain and retina of diet-induced obese type II diabetic mice. Topiramate, a mitochondrial carbonic anhydrase inhibitor, is efficacious at both preventing and treating BBB disruption in this diet-induced obese type II diabetic mouse model

Intranasal Administration as a Route for Drug Delivery to the Brain: Evidence for a Unique Pathway for Albumin

A variety of compounds will distribute into the brain when placed at the cribriform plate by intranasal (i.n.) administration. In this study, we investigated the ability of albumin, a protein that can act as a drug carrier but is excluded from brain by the blood-brain barrier, to distribute into the brain after i.n. administration. We labeled bovine serum albumin with [125I] ([125I]Alb) and studied its uptake into 11 brain regions and its entry into the blood from 5 minutes to 6 hours after i.n. administration. [125I]Alb was present throughout the brain at 5 minutes. Several regions showed distinct peaks in uptake that ranged from 5 minutes (parietal cortex) to 60 minutes (midbrain). About 2–4% of the i.n. [125I]Alb entered the bloodstream. The highest levels occurred in the olfactory bulb and striatum. Distribution was dose-dependent, with less taken up by whole brain, cortex, and blood at the higher dose of albumin. Uptake was selectively increased into the olfactory bulb and cortex by the fluid-phase stimulator PMA (phorbol 12-myristate 13-acetate), but inhibitors to receptor-mediated transcytosis, caveolae, and phosphoinositide 3-kinase were without effect. Albumin altered the distribution of radioactive leptin given by i.n. administration, decreasing uptake into the blood and by the cerebellum and increasing uptake by the hypothalamus. We conclude that [125I]Alb administered i.n. reaches all parts of the brain through a dose-dependent mechanism that may involve fluid-phase transcytosis and, as illustrated by leptin, can affect the delivery of other substances to the brain after their i.n. administration

Micro-Ethical Decision Making Among Baccalaureate Nursing Students: A Qualitative Investigation

Nursing students frequently encounter micro-ethical nursing practice problems during their clinical experience. The purpose of this study was to understand the lived experiences of senior-level baccalaureate students faced with making micro-ethical clinical decisions in practice settings. A descriptive qualitative design was used, and five central themes emerged. A dominant finding was the experience of unapplied and forgotten ethics education revealing a mismatch between what faculty perceived was taught and students’ experiences of that education. When faced with micro-ethical decisions, participants trusted and deferred to staff nurse recommendations, even if the advice contradicted best-practice standards. Contextual naivete was brought out of concealment, contributing to the experience of moral disequilibrium (i.e., students felt conflicted about what they learned in school as best practice and what they observed being role modeled in the clinical environment). This study resulted in theory-guided implications for nursing education and recommendations for future study

Catalytic living ring-opening metathesis polymerization

In living ring-opening metathesis polymerization (ROMP), a transition-metal–carbene complex polymerizes ring-strained olefins with very good control of the molecular weight of the resulting polymers. Because one molecule of the initiator is required for each polymer chain, however, this type of polymerization is expensive for widespread use. We have now designed a chain-transfer agent (CTA) capable of reducing the required amount of metal complex while still maintaining full control over the living polymerization process. This new method introduces a degenerative transfer process to ROMP. We demonstrate that substituted cyclohexene rings are good CTAs, and thereby preserve the ‘living’ character of the polymerization using catalytic quantities of the metal complex. The resulting polymers show characteristics of a living polymerization, namely narrow molecular-weight distribution, controlled molecular weights and block copolymer formation. This new technique provides access to well- defined polymers for industrial, biomedical and academic use at a fraction of the current costs and significantly reduced levels of residual ruthenium catalyst

A UK wide cohort study describing management and outcomes for infants with surgical Necrotising Enterocolitis

The Royal College of Surgeons have proposed using outcomes from necrotising enterocolitis (NEC) surgery for revalidation of neonatal surgeons. The aim of this study was therefore to calculate the number of infants in the UK/Ireland with surgical NEC and describe outcomes that could be used for national benchmarking and counselling of parents. A prospective nationwide cohort study of every infant requiring surgical intervention for NEC in the UK was conducted between 01/03/13 and 28/02/14. Primary outcome was mortality at 28-days. Secondary outcomes included discharge, post-operative complication, and TPN requirement. 236 infants were included, 43(18%) of whom died, and eight(3%) of whom were discharged prior to 28-days post decision to intervene surgically. Sixty infants who underwent laparotomy (27%) experienced a complication, and 67(35%) of those who were alive at 28 days were parenteral nutrition free. Following multi-variable modelling, presence of a non-cardiac congenital anomaly (aOR 5.17, 95% CI 1.9-14.1), abdominal wall erythema or discolouration at presentation (aOR 2.51, 95% CI 1.23-5.1), diagnosis of single intestinal perforation at laparotomy (aOR 3.1 95% CI 1.05-9.3), and necessity to perform a clip and drop procedure (aOR 30, 95% CI 3.9-237) were associated with increased 28-day mortality. These results can be used for national benchmarking and counselling of parents

Congenital diaphragmatic hernia and retinoids: searching for an etiology

Congenital diaphragmatic hernia (CDH) is a major life-threatening cause of respiratory failure in the newborn. Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the epidemiology and pathophysiology of human CDH, the metabolism of retinoids and the implications of retinoids in the development of the diaphragm and lung. Finally, we describe the existing evidence of a disruption of the retinoid-signaling pathway in CDH