Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, ß-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease.

This study assessed the extent to which high fat diet (HFD)-induced ß-amyloid accumulation and cognitive decline in APP/PSEN1 mice are reversible through control of fat intake. Ten months of HFD (60% calories from fat) led to significant deficits in a 2-trial Y maze task, and nest building assay, and decreased voluntary locomotor activity. The HFD induced an inflammatory response, indicated by increased expression of several inflammatory markers. Substituting a low fat diet led to pronounced weight loss and correction of glucose intolerance, decreases in the inflammatory response, and improved performance on behavioral tasks in both wild-type and APP/PSEN1 transgenic mice. Insoluble ß-amyloid levels, and extent of tau phosphorylation were also lower following dietary reversal in APP/PSEN1 mice compared to high fat-fed animals, indicating that the inflammatory response may have contributed to key pathogenic pathways in the Alzheimer's disease model. The data suggest that weight loss can be a vital strategy for cognitive protection, but also highlight potential mechanisms for intervention when sustained weight loss is not possible.

Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer's Disease: Impacts on Cognitive Decline.

In the past few decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM), as well as older individuals at risk for Alzheimer's disease (AD), has increased. While the consumption of diets high in fat (total and saturated) have been linked to increased risk of AD, diets rich in antioxidants, polyunsaturated fats, and omega-3 fatty acids are associated with decreased risk. Additionally, AD patients are at increased risk for developing T2DM. Recent research suggests that there are stronger similarities between AD and T2DM than have previously been considered. Here we review the neurocognitive and inflammatory effects of high-fat diet consumption, its relationship to AD, and the treatment potential of dietary interventions that may decrease risk of cognitive decline and other associated neuropathological changes, such as insulin resistance, oxidative stress, and chronic inflammatory processes.

Beneficial effects of dietary EGCG and voluntary exercise on behavior in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: (1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and (2) soluble amyloid-ß (Aß) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aß1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD.

Selective inhibition of matrix metalloproteinase-9 attenuates secondary damage resulting from severe traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Following the initial insult, severe TBI progresses to a secondary injury phase associated with biochemical and cellular changes. The secondary injury is thought to be responsible for the development of many of the neurological deficits observed after TBI and also provides a window of opportunity for therapeutic intervention. Matrix metalloproteinase-9 (MMP-9 or gelatinase B) expression is elevated in neurological diseases and its activation is an important factor in detrimental outcomes including excitotoxicity, mitochondrial dysfunction and apoptosis, and increases in inflammatory responses and astrogliosis. In this study, we used an experimental mouse model of TBI to examine the role of MMP-9 and the therapeutic potential of SB-3CT, a mechanism-based gelatinase selective inhibitor, in ameliorating the secondary injury. We observed that activation of MMP-9 occurred within one day following TBI, and remained elevated for 7 days after the initial insult. SB-3CT effectively attenuated MMP-9 activity, reduced brain lesion volumes and prevented neuronal loss and dendritic degeneration. Pharmacokinetic studies revealed that SB-3CT and its active metabolite, p-OH SB-3CT, were rapidly absorbed and distributed to the brain. Moreover, SB-3CT treatment mitigated microglial activation and astrogliosis after TBI. Importantly, SB-3CT treatment improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. These results demonstrate that MMP-9 is a key target for therapy to attenuate secondary injury cascades and that this class of mechanism-based gelatinase inhibitor-with such desirable pharmacokinetic properties-holds considerable promise as a potential pharmacological treatment of TBI.

Life events, chronic stressors, and depressive symptoms in low-income urban mothers with asthmatic children.

OBJECTIVE: This secondary data analysis study examines the relationship between maternal sociodemographic variables, life events, chronic stressors, including asthma control and management and environmental stressors, and maternal depression. DESIGN: Cross-sectional descriptive design study consisting of baseline data from participants enrolled in a randomized asthma communication educational intervention trial. SAMPLE: 201 mothers of children with asthma (ages 6-12), recruited from community pediatric practices and emergency departments of 2 urban university hospitals. MEASUREMENT: Life events were measured using standardized items. Chronic stressors were measured using items from the International Asthma and Allergies in Childhood study and maternal and child exposure to violence. Depressive symptoms were assessed with the Center for Epidemiologic Studies-Depression scale. RESULTS: Close to 25% of the mothers had high depressive symptoms. In separate multiple logistic regression models, education (adjusted odds ratio [AOR]=2.62; 95% confidence interval [CI]=1.07, 6.39) or unemployment (AOR=2.38; 95% CI=1.16, 4.90) and the use of quick relief medications (AOR=2.74; 95% CI=1.33, 5.66) for asthma were positively associated with depressive symptoms. CONCLUSIONS: Implications include the need to assess maternal depressive symptoms of mothers of children with asthma, in order to improve asthma management for low-income urban children.

Extreme primary and secondary protein structure variability in the chimeric male-transmitted cytochrome c oxidase subunit II protein in freshwater mussels: evidence for an elevated amino acid substitution rate in the face of domain-specific purifying selection.

BACKGROUND: Freshwater unionoidean bivalves, and species representing two marine bivalve orders (Mytiloida and Veneroida), exhibit a mode of mtDNA inheritance involving distinct maternal (F) and paternal (M) transmission routes concomitant with highly divergent gender-associated mtDNA genomes. Additionally, male unionoidean bivalves have a approximately 550 bp 3' coding extension to the cox2 gene (Mcox2e), that is apparently absent from all other metazoan taxa. RESULTS: Our molecular sequence analyses of MCOX2e indicate that both the primary and secondary structures of the MCOX2e region are evolving much faster than other regions of the F and M COX2-COX1 gene junction. The near N-terminus approximately 2/3 of the MCOX2e region contains an interspecifically variable number of predicted transmembrane helices (TMH) and interhelical loops (IHL) whereas the C-terminus approximately 1/3 is relatively conserved and hydrophilic while containing conserved functional motifs. MCOX2e displays an overall pattern of purifying selection that leads to the preservation of TMH/IHL and C-terminus tail sub-regions. However, 14 amino acid positions in the MCOX2e TMH/IHL sub-region might be targeted by diversifying selection, each representing a site where there exists interspecific variation for the constituent amino acids residing in a TMH or IHL. CONCLUSION: Our results indicate that Mcox2e is unique to unionoidean bivalves, likely the result of a single insertion event that took place over 65 MYA and that MCOX2e is functional. The predicted TMH number, length and position variability likely stems from substitution-based processes rather than the typically implicated insertion/deletion events. MCOX2e has relatively high rates of primary and secondary structure evolution, with some amino acid residues potentially subjected to site-specific positive selection, yet an overall pattern of purifying selection leading to the preservation of the TMH/IHL and hydrophilic C-terminus tail subregions. The more conserved C-terminus tail (relative to the TMH/IHL sub-region of MCOX2e) is likely biologically active because it contains functional motifs. The rapid evolution of primary and secondary structure in MCOX2e, combined with the action of both positive and purifying selection, provide supporting evidence for the hypothesis that MCOX2e has a novel reproductive function within unionoidean bivalves. All tolled, our data indicate that unionoidean bivalve MCOX2 is the first reported chimeric animal mtDNA-encoded protein.

Infantile seizures: infants are not just little children.

Seizure semiology in infants defies the typical characteristics and classification schemata that have been developed for older children and adults. A clear classification system is a necessary first step to facilitate proper diagnosis, choice of treatment, and determination of prognosis. This is an especially challenging task with seizures in infants. A semiologic system based upon simple descriptive terms has been proposed, which the neurologist and pediatrician will recognize as closer to clinical experience.

Shared decision making in school age children with asthma.

Shared decision making in health care is a mutual partnership between the health care provider and the patient. Traditionally, children have had little involvement during their medical care visits or in decisions regarding their health care. Shared decision making in children with asthma may enhance their self-confidence as well as improve their self-management skills. Allowing the child to participate during the visit requires assessing the child's competence at different ages and abilities. Specific communication techniques to use with children during medical encounters include visual aids, turn-taking, clarifying communication, and role modeling. Providers additionally can offer strategies to parents on how to provide general information about asthma and treatments based on the child's questions and interest. The goal for school age children with asthma is to change dyadic interactions between the provider and parent into triadic interactions to improve the child's asthma management.