ABSTRACT
The efflux pump, p-glycoprotein, controls bioavailability and excretion of pharmaceutical compounds. In the blood-brain barrier, p-glycoprotein regulates the delivery of pharmaceutical substances to the brain, influencing efficacy and side effects for some drugs notably antipsychotics. Common side effects to antipsychotics include obesity and metabolic disease. Polymorphisms in the ABCB1 gene coding for p-glycoprotein are associated with more severe side effects to neuro-pharmaceuticals as well as weight gain, indicating a potential link between p-glycoprotein function and metabolic regulation. Using microarray data analysis from 145 neurologically sound adults, this study investigated the association between body mass index (BMI) and ABCB1 expression in the frontal cortex. Increasing BMI values were associated with a statistically significantly reduced expression of ABCB1. Investigation of DNA methylation patterns in a subgroup of 52 individuals found that the methylation/expression ratios of ABCB1 were unaffected by increasing BMI values. Interestingly, the effect of BMI on ABCB1 expression appeared stronger in African Americans than in Caucasians.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Black or African American/genetics , Brain/metabolism , White People/genetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Adolescent , Adult , Antipsychotic Agents/therapeutic use , Blood-Brain Barrier/metabolism , Body Mass Index , Brain/drug effects , DNA Methylation/drug effects , DNA Methylation/genetics , Female , Humans , Male , Middle Aged , Obesity/genetics , Polymorphism, Genetic/genetics , Weight Gain/drug effects , Weight Gain/genetics , Young AdultABSTRACT
Several studies link increasing body mass index (BMI) to cognitive decline both as a consequence of obesity per se and as a sequela of obesity-induced type 2 diabetes. Obese individuals are prone to a chronic low-grade inflammation as the metabolically active visceral fat produces proinflammatory cytokines. Animal studies indicate that these cytokines can cross the blood-brain barrier. Such crossover could potentially affect the immune system in the brain by inducing gene expression of proinflammatory genes. The relationship between obesity and neuroinflammation in the human brain is currently unknown. Therefore we aim to examine the relationship between BMI and gene expression of central inflammatory markers in the human frontal cortex. Microarray data of 141 neurologically and psychiatrically healthy individuals were obtained through the BrainCloud database. A simple linear regression analysis was performed with BMI as variable on data on IL10, IL1ß, IL6, PTGS2 (COX2) and NOS2 (iNOS). Increasing BMI is associated with a decrease in the mRNA expression of IL10 (P=0.014) and an increase in the expression of NOS2 (iNOS; P=0.040). Expressions of IL10 and NOS2 (iNOS) were negatively correlated (P<0.001). The expression of IL10 was mostly affected by individuals with BMI ⩾40. Multiple linear regression analyses with BMI, age, sex and race as variables were performed in order to identify potential confounders. In conclusion, increasing BMI could affect the IL10-mediated anti-inflammatory defense in the brain and induce iNOS-mediated inflammatory activity.
Subject(s)
Frontal Lobe/metabolism , Interleukin-10/genetics , Nitric Oxide Synthase Type II/genetics , Obesity/metabolism , RNA, Messenger/metabolism , Thinness/metabolism , Adolescent , Adult , Aged , Body Mass Index , Child , Child, Preschool , Cyclooxygenase 2/genetics , Female , Humans , Infant , Infant, Newborn , Interleukin-1beta/genetics , Interleukin-6/genetics , Linear Models , Male , Middle Aged , Overweight/metabolism , Young AdultABSTRACT
REASONS FOR PERFORMING STUDY: Previous studies indicate similar overall survival of horses with nephrosplenic entrapment of the large colon (NSE), regardless of treatment strategy. Short-term survival of a primarily conservative treatment strategy without rolling under general anaesthesia (GA) and a low proportion of surgical intervention as well as indicators of short-term nonsurvival has not been documented. OBJECTIVES: To document short-term survival of horses with NSE treated in a university referral hospital with a low rate of surgical interventions and to determine factors associated with the decision of treatment and short-term nonsurvival. METHODS: A retrospective review of medical records of 142 horses diagnosed with NSE between January 2000 and October 2009 was undertaken. Case details and clinical parameters from the initial examination, treatment and outcome were recorded. Factors associated with decision of treatment and short-term survival were identified by multiple logistic regression analysis. RESULTS: Warmblood breeds were over-represented in comparison to the general colic population. Overall short-term survival was 91.5% (130/142) which is similar to previous studies. Three horses considered to be in need of surgery were subjected to euthanasia for economical reasons before treatment. Of 114 conservatively treated horses, 110 (96.5%) survived, as did 20/25 (80%) of surgically treated horses. Nine conservatively managed horses were treated with phenylephrine. Gastric reflux (P = 0.0077), pain (P = 0.024) and abdominal distension (P = 0.05) were associated with the decision to treat surgically. Increased heart rate (P<0.001), and surgery (P = 0.032) were associated with reduced likelihood of short-term survival. CONCLUSIONS AND POTENTIAL RELEVANCE: Overall short-term survival was similar to that reported in previous studies with higher proportions of surgically managed cases. Consequently, horses with NSE should be managed by a primarily conservative treatment strategy, with the decision to treat surgically based on specific evidence based criteria.
