Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose ...tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.
Purpose
To investigate a possible microvascular component of poppers maculopathy (PMP) using optical coherence tomography angiography (OCTA).
Methods
Twelve patients suffering from poppers ...maculopathy were included. Health records, optical coherence tomography (OCT), and OCTA data was gathered and compared to a healthy control group (HC). PMP lesion type was determined by manifestation in OCT. OCTA-based evaluation of retinal vascular plexus and choriocapillaris (CC) was executed. Vessel density (VD) and vessel length density (VLD) in superficial and deep capillary plexus (SCP, DCP), as well as flow deficits (FD), within the foveal avascular zone (FAZ) in CC were assessed.
Results
Median age of PMP patients was 40 (min 24; max 64) years, all male. Eleven patients presented with ellipsoid zone-type lesions; one patient showed a vitelliform-type lesion. No qualitative microvascular changes between PMP patients and HC were identified. Quantitative values for VD and VLD of SCP and DCP did not differ in between the two groups. The analysis of FDs in CC showed no deviation from PMP patients to HC.
Conclusions
No vascular anomalies in qualitative and quantitative analysis in OCTA were detected in PMP patients. The constitution of the CC within FAZ of PMP patients does not differ from HC when assessed as FD.
Identification of a novel catalyst–allenoate pair allows enantioselective 2+2 cycloaddition of α-methylstyrene. To understand the origin of selectivity, a detailed mechanistic investigation was ...conducted. Herein, two competing reaction pathways are proposed, which operate simultaneously and funnel the alkenes to the same axially chiral cyclobutanes. In agreement with the Woodward–Hoffmann rules, this mechanistic curiosity can be rationalized through a unique symmetry operation that was elucidated by deuteration experiments. In the case of 1,1-diarylalkenes, distal communication between the catalyst and alkene is achieved through subtle alteration of electronic properties and conformation. In this context, a Hammett study lends further credibility to a concerted mechanism. Thus, extended scope exploration, including β-substitution on the alkene to generate two adjacent stereocenters within the cyclobutane ring, is achieved in a highly stereospecific and enantioselective fashion (33 examples, up to >99:1 er).
The spectrum of nonalcoholic fatty liver disease (NAFLD) includes a nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The specific types and amounts of lipids that accumulate ...in NAFLD are not fully defined. The free fatty acid (FFA), diacylglycerol (DAG), triacylglycerol (TAG), free cholesterol (FC), cholesterol ester, and phospholipid contents in normal livers were quantified and compared to those of NAFL and NASH, and the distribution of fatty acids within these classes was compared across these groups. Hepatic lipids were quantified by capillary gas chromatography. The mean (nmol/g of tissue) DAG (normal/NAFL/NASH: 1922 versus 4947 versus 3304) and TAG (13,609 versus 128,585 versus 104,036) increased significantly in NAFLD, but FFA remained unaltered (5533 versus 5929 versus 6115). There was a stepwise increase in the mean TAG/DAG ratio from normal livers to NAFL to NASH (7 versus 26 versus 31, P < 0.001). There was also a similar stepwise increment in hepatic FC (7539 versus 10,383 versus 12,863, P < 0.05 for NASH). The total phosphatidylcholine (PC) decreased in both NAFL and NASH. The FC/PC ratio increased progressively (0.34 versus 0.69 versus 0.71, P < 0.008 for both). Although the levels for linoleic acid (18:2n‐6) and α‐linolenic acid (18:3n‐3) remained unaltered, there was a decrease in arachidonic acid (20:4n‐6) in FFA, TAG, and PC (P < 0.05 for all) in NASH. Eicosapentanoic acid (20:5n‐3) and docosahexanoic acid (22:6n‐3) were decreased in TAG in NASH. The n‐6:n‐3 FFA ratio increased in NASH (P < 0.05). Conclusions: NAFLD is associated with numerous changes in the lipid composition of the liver. The potential implications are discussed. (HEPATOLOGY 2007.)
Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global ...biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.
Specific alterations in hepatic lipid composition characterize the spectrum of nonalcoholic fatty liver disease (NAFLD), which extends from nonalcoholic fatty liver (NAFL) to nonalcoholic ...steatohepatitis (NASH). However, the plasma lipidome of NAFLD and whether NASH has a distinct plasma lipidomic signature are unknown. A comprehensive analysis of plasma lipids and eicosanoid metabolites quantified by mass spectrometry was performed in NAFL (n = 25) and NASH (n = 50) subjects and compared with lean normal controls (n = 50). The key findings include significantly increased total plasma monounsaturated fatty acids driven by palmitoleic (16:1 n7) and oleic (18:1 n9) acids content (P < 0.01 for both acids in both NAFL and NASH). The levels of palmitoleic acid, oleic acid, and palmitoleic acid to palmitic acid (16:0) ratio were significantly increased in NAFLD across multiple lipid classes. Linoleic acid (8:2n6) was decreased (P < 0.05), with a concomitant increase in γ‐linolenic (18:3n6) and dihomo γ‐linolenic (20:3n6) acids in both NAFL and NASH (P < 0.001 for most lipid classes). The docosahexanoic acid (22:6 n3) to docosapentenoic acid (22:5n3) ratio was significantly decreased within phosphatidylcholine (PC), and phosphatidylethanolamine (PE) pools, which was most marked in NASH subjects (P < 0.01 for PC and P < 0.001 for PE). The total plasmalogen levels were significantly decreased in NASH compared with controls (P < 0.05). A stepwise increase in lipoxygenase (LOX) metabolites 5(S)‐hydroxyeicosatetraenoic acid (5‐HETE), 8‐HETE, and 15‐HETE characterized progression from normal to NAFL to NASH. The level of 11‐HETE, a nonenzymatic oxidation product of arachidonic (20:4) acid, was significantly increased in NASH only. Conclusions: Although increased lipogenesis, desaturases, and LOX activities characterize NAFL and NASH, impaired peroxisomal polyunsaturated fatty acid (PUFA) metabolism and nonenzymatic oxidation is associated with progression to NASH. (HEPATOLOGY 2009;50:1827–1838.)
Neuromuscular electrical stimulation (NMES) can be delivered over a nerve trunk or muscle belly and both can generate contractions through peripheral and central pathways. Generating contractions ...through peripheral pathways is associated with a nonphysiological motor unit recruitment order, which may limit the efficacy of NMES rehabilitation. Presently, we compared recruitment through peripheral and central pathways for contractions of the knee extensors evoked by NMES applied over the femoral nerve vs. the quadriceps muscle. NMES was delivered to evoke 10 and 20% of maximum voluntary isometric contraction torque 2-3 s into the NMES (time(1)) in two patterns: 1) constant frequency (15 Hz for 8 s); and 2) step frequency (15-100-15 Hz and 25-100-25 Hz for 3-2-3 s, respectively). Torque and electromyographic activity recorded from vastus lateralis and medialis were quantified at the beginning (time(1)) and end (time(2); 6-7 s into the NMES) of each pattern. M-waves (peripheral pathway), H-reflexes, and asynchronous activity (central pathways) during NMES were quantified. Torque did not differ regardless of NMES location, pattern, or time. For both muscles, M-waves were ∼7-10 times smaller and H-reflexes ∼8-9 times larger during NMES over the nerve compared with over the muscle. However, unlike muscles studied previously, neither torque nor activity through central pathways were augmented following 100 Hz NMES, nor was any asynchronous activity evoked during NMES at either location. The coefficient of variation was also quantified at time(2) to determine the consistency of each dependent measure between three consecutive contractions. Torque, M-waves, and H-reflexes were most variable during NMES over the nerve. In summary, NMES over the nerve produced contractions with the greatest recruitment through central pathways; however, considering some of the limitations of NMES over the femoral nerve, it may be considered a good complement to, as opposed to a replacement for, NMES over the quadriceps muscle for maintaining muscle quality and reducing contraction fatigue during NMES rehabilitation.
Macrophages show endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological importance and the underlying mechanisms of this ...phenomenon remain unknown. Here we show that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid-binding protein-4 (aP2) expression. Using genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. The absence of lipid chaperones incites an increase in the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, the impact of aP2 on macrophage lipid metabolism and the ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and show that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.
Susac's syndrome (ScS) is a rare, potentially life-threatening auto-immune disease. Ophthalmic imaging can depict characteristic branch retinal arteriolar occlusions (BRAO) and arterial wall ...hyperfluorescences that form one of the three diagnostic pillars of this condition. We aim to demonstrate that ophthalmological ultrawide-field (UWF) imaging allows for a qualitative and quantitative assessment in ScS, with application in diagnostics, monitoring of treatment response, and titration of therapy.
In seven ScS patients (♀:♂ = 2:5), with a median age of 36 years, range 18 to 57 years, serial ultrawide-field fluoresceine angiography (UWF-FA) studies were performed, with adjunctive wide-field optical coherence tomography angiography analyses (WF-OCTA) in five patients. Mean follow-up was 12.5 months, range 1 to 46 months.
In all seven patients, BRAO and arterial wall hyperfluorescences were present in UWF-FA and calculated as a quantitative score of disease activity in fluorescein angiography (DA-FA) during follow-up visits. Treatment response was accessible in follow-up imaging as partial reperfusion of retinal vessels, resolution of arterial wall hyperfluorescences and consequently, in reduction of DA-FA score. While qualitative analysis of WF-OCTA provided further information about retinal micro-perfusion, quantitative analysis did not demonstrate a vectored treatment response as it was accessible in FA.
DA-FA score, as a comprehensive disease activity parameter in ScS has potential to facilitate optimal communication between subspecialties and thereby treatment success.
Students' use of working memory (WM) is a key to academic success, as many subject areas and various tasks school-aged children encounter require the ability to attend to, work with, and recall ...information. Children with poor WM ability typically struggle with academic work compared to similar-aged peers without WM deficits. Further, WM has been shown to be significantly correlated with inattention and disorganization in those with ADHD, and WM deficits have also been identified as a potential underpinning of specific learning disorder (SLD). As an intervention technique, the use of computerized cognitive training has demonstrated improved attention and working memory skills in children with WM deficits, and children that have completed cognitive training protocols have demonstrated performance improvements in reading and math. The current study aimed to examine the effectiveness of cognitive training (conducted in a clinical setting) for students diagnosed with ADHD and SLD. Using paired-samples t-tests and a psychometric network modeling technique, results from data obtained from a sample of 43 school-aged children showed (1) that attention and working memory improved following cognitive training and (2) that cognitive training might be related to cognitive structural changes found pre- to post-training among the variables being measured. Implications for clinical practice and school-based interventions are discussed.
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