Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome

IntroductionSubjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis.Results22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT.ConclusionA shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.     

Hydrogenated fat consumption affects acylation-stimulating protein levels and cholesterol esterification rates in moderately hypercholesterolemic women.

To determine whether hydrogenated fat consumption alters triglyceride metabolism and cholesterol esterification rates, 14 women (65-71 years of age) were provided with each of four diets for 5-week periods according to a randomized cross-over design. The experimental diets contained either soybean oil (SO), low trans squeeze (SQM), medium trans tub (TM), or high trans stick (SM) margarines. Triglyceride uptake by adipose tissue was determined by measuring plasma acylation-stimulating protein (ASP), FFA, glucose, and insulin levels, while rates of transfer and esterification rate of newly synthesized cholesterol (ER) were derived by using plasma CETP levels and the deuterium incorporation methodology. Plasma ASP levels were lowest (P < 0.05) in subjects on the SM diet (33.4 +/- 12.7 nM) compared with the SO (48.7 +/- 17.0 nM) and SQM (50.7 +/- 15.7 nM) diets. Conversely, FFA were highest (P < 0.05) on the SM diet (0.86 +/- 0.45 mM) relative to all the other diets. No differences were observed in plasma glucose and insulin levels among diets. A trend toward higher CETP levels after consumption of the SM diet was observed. However, the ER was lowest (P < 0.05) after the SM (0.111 +/- 0.062 g x day(-1)) diet and highest after consumption of the SQM (0.216 +/- 0.123 g x day(-1)) diet. In addition, ASP levels were negatively correlated with FFA (r = -0.63, P < 0.05), LDL cholesterol (r = -0.56, P < 0.05), and TG (r = -0.41, P < 0.05), whereas FFA was positively correlated with apolipoprotein B-containing lipoproteins (r = 0.58 and 0.47, for VLDL and LDL cholesterol, P < 0.05), and negatively correlated with HDL cholesterol (r = -0.51, P < 0.05). The ER was found to positively correlate with HDL cholesterol and HDL2 subfraction (r = 0.53 and 0.45, respectively, P < 0.05). Taken together, these data demonstrate that the alterations in circulating lipid levels, commonly observed with consumption of hydrogenated fat-rich diets, can be explained in part by changes in ASP activity as well as newly synthesized cholesterol ER.     

Regulation of phenylacetic acid degradation genes of Burkholderia cenocepacia K56-2

Background  

Metabolically versatile soil bacteria Burkholderia cepacia complex (Bcc) have emerged as opportunistic pathogens, especially of cystic fibrosis (CF). Previously, we initiated the characterization of the phenylacetic acid (PA) degradation pathway in B. cenocepacia, a member of the Bcc, and demonstrated the necessity of a functional PA catabolic pathway for full virulence in Caenorhabditis elegans. In this study, we aimed to characterize regulatory elements and nutritional requirements that control the PA catabolic genes in B. cenocepacia K56-2.     

Higher plasma docosahexaenoic acid is associated with reduced progression of coronary atherosclerosis in women with CAD

Fish intake, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and in some cases alpha-linolenic acid (ALA) have been associated with reduced risk of cardiovascular events and death. The association between n-3 fatty acids in plasma lipids and the progression of coronary artery atherosclerosis was assessed among women with established coronary artery disease (CAD). A prospective cohort study involved postmenopausal women (n = 228) participating in the Estrogen Replacement and Atherosclerosis Trial. Quantitative coronary angiography was performed at baseline and after 3.2 +/- 0.6 (mean +/- SD) years. Women with plasma phospholipid (PL) DHA levels above the median, compared with below, exhibited less atherosclerosis progression, as expressed by decline in minimum coronary artery diameter (-0.04 +/- 0.02 and -0.10 +/- 0.02 mm, respectively; P = 0.007) or increase in percentage stenosis (1.34 +/- 0.76% and 3.75 +/- 0.74%, respectively; P = 0.006), and had fewer new lesions [2.0% (0.5-3.5%) of measured segments (95% confidence interval) and 4.2% (2.8-5.6%), respectively; P = 0.009] after adjustments for cardiovascular risk factors. Similar results were observed for DHA in the triglycerides (TGs). EPA and ALA in plasma lipids were not significantly associated with atherosclerosis progression. Consistent with higher reported fish intake, higher levels of plasma TG and PL DHA are associated with less progression of coronary atherosclerosis in postmenopausal women with CAD.     

Long-term fatty acid stability in human serum cholesteryl ester,triglyceride, and phospholipid fractions

Fatty acid profiles of biological specimens from epidemiological/clinical studies can serve as biomarkers to assess potential relationships between diet and chronic disease risk. However, data are limited regarding fatty acid stability in archived specimens following long-term storage, a variable that could affect result validity. Our objective was to determine the effect of prolonged storage at −80°C on the fatty acid profiles of serum cholesteryl ester (CE), triglyceride (TG), and phospholipid (PL) fractions. This was accomplished by determining the fatty acid profile of frozen, archived, previously unthawed serum samples from 22 subjects who participated in a controlled feeding trial. Initial analysis was performed after trial completion and the repeat analysis after 8–10 years of storage using GC. No significant differences were observed among the majority of fatty acids regardless of lipid fraction. Reliability coefficients were high for the fatty acid classes (saturated fatty acid : 0.70, MUFA : 0.90, PUFA : 0.80). When differences were identified, they were limited to low abundance fatty acids (≤1.5 mol%). These differences were quantitatively small and likely attributable to technical improvements in GC methodology rather than sample degradation. Thus, our data demonstrate that storage at −80°C up to 10 years does not significantly influence serum CE, TG, or PL fatty acid profiles.     

Alterations in cholesterol absorption/synthesis markers characterize Framingham Offspring Study participants with CHD

Data is limited on measures influencing cholesterol homeostasis in subjects at high risk of developing cardiovascular disease (CVD) relative to established risk factors. To address this, we quantified circulating indicators of cholesterol homeostasis (plasma phytosterols and cholesterol precursor concentrations as surrogate measures of cholesterol absorption and synthesis, respectively) in Framingham Offspring Study Cycle-6 participants diagnosed with established CVD and/or ≥50% carotid stenosis not taking lipid lowering medication (cases, N = 155) and matched controls (N = 414). Cases and controls had similar plasma LDL-cholesterol; HDL-cholesterol was significantly lower in males, while triglyceride concentrations were significantly higher in female cases relative to their respective controls. Cholesterol absorption markers were significantly higher (229 ± 7 vs. 196 ± 4, 169 ± 6 vs. 149 ± 3 and 144 ± 5 vs. 135 ± 3 for campesterol, sitosterol, and cholestanol, respectively), whereas cholesterol synthesis markers were significantly lower (116 ± 4 vs. 138 ± 3, 73 ± 3 vs. 75 ± 2 for lathosterol and desmosterol, respectively) in cases compared with controls, irrespective of sex. After controlling for standard risk factors, campesterol (2.47 [1.71-3.56]; P < 0.0001), sitosterol (1.86 [1.38-2.50]; P < 0.0001), cholestanol (1.57 [1.09-2.27]; P = 0.02), desmosterol (0.59 [0.42-0.84]; P = 0.003), and lathosterol (0.58 [0.43-0.77]; P = 0.0002) were significantly associated with CVD (odds ratio [95% confidence interval]). These data suggest that impaired cholesterol homeostasis, reflected by lower synthesis and higher absorption marker concentrations, are highly significant independent predictors of prevalent CVD in this study population.     

Type I interferon is required for T helper (Th) 2 induction by dendritic cells

Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN‐I) in enabling this process. An IFN‐I signature was evident in DCs responding to the helminth Schistosoma mansoni or the allergen house dust mite (HDM). Further, IFN‐I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from Ifnar1^?/? mice were incapable of initiating Th2 responses in vivo. These data demonstrate for the first time that the influence of IFN‐I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses.     

Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: insights from the PROSPER trial

Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy (40 mg/day), plasma markers of cholesterol synthesis (desmosterol, lathosterol) and fractional cholesterol absorption (campesterol, sitosterol) were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with (cases, n = 223) and without (controls, n = 257) a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers desmosterol (−12% and −11%) and lathosterol (−50% and −56%) and increased concentrations of the cholesterol absorption markers campesterol (48% and 51%) and sitosterol (25% and 26%) were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.     

Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 (apoB-100) in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with placebo, atorvastatin 20 mg/day was associated with significant reductions in TRL, IDL, and LDL apoB-100 pool size as a result of significant increases in fractional catabolic rate (FCR) without changes in production rate (PR). Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further significant reduction in the LDL apoB-100 pool size as a result of a further increase in FCR. ApoB-48 pool size was reduced significantly by both atorvastatin doses, and this reduction was associated with nonsignificant increases in FCR. The lathosterol-campesterol ratio was decreased by atorvastatin treatment, and changes in this ratio were inversely correlated with changes in TRL apoB-100 and apoB-48 PR. No significant effect on apoA-I kinetics was observed at either dose of atorvastatin. Our data indicate that atorvastatin reduces apoB-100- and apoB-48-containing lipoproteins by increasing their catabolism and has a dose-dependent effect on LDL apoB-100 kinetics. Atorvastatin-mediated changes in cholesterol homeostasis may contribute to apoB PR regulation.