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The relation between changes in respiratory quotient (RQ) following dietary interventions and clinical parameters and body fat pools remains unknown. In this randomized controlled trial, participants with moderate abdominal obesity or/and dyslipidemia (n = 159) were randomly assigned to a Mediterranean/low carbohydrate (MED/LC, n = 80) or a low fat (LF, n = 79) isocaloric weight loss diet and completed a metabolic assessment. Changes in RQ (measured by indirect calorimeter), adipose-tissue pools (MRI), and clinical measurements were assessed at baseline and after 6 months of intervention. An elevated RQ at baseline was significantly associated with increased visceral adipose tissue, hepatic fat, higher levels of insulin and homeostatic insulin resistance. After 6 months, body weight had decreased similarly between the diet groups (−6 ± 6 kg). However, the MED/LC diet, which greatly improved metabolic health, decreased RQ significantly more than the LF diet (−0.022 ± 0.007 vs. −0.002 ± 0.008, p = 0.005). Total cholesterol and diastolic blood pressure were independently associated with RQ changes (p = 0.045). RQ was positively associated with increased superficial subcutaneous-adipose-tissue but decreased renal sinus, pancreatic, and intramuscular fats after adjusting for confounders. Fasting RQ may reflect differences in metabolic characteristics between subjects affecting their potential individual response to the diet.

It is unclear if a reduction in hepatic fat content (HFC) is a major mediator of the cardiometabolic benefit of lifestyle intervention, and whether it has prognostic significance beyond the loss of visceral adipose tissue (VAT). In the present sub-study, we hypothesized that HFC loss in response to dietary interventions induces specific beneficial effects independently of VAT changes.In an 18-month weight-loss trial, 278 participants with abdominal obesity/dyslipidemia were randomized to low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC + 28 g walnuts/day) diets with/without moderate physical activity. HFC and abdominal fat-depots were measured using magnetic resonance imaging at baseline, after 6 (sub-study, n = 158) and 18 months.Of 278 participants (mean HFC 10.2% [range: 0.01%-50.4%]), the retention rate was 86.3%. The %HFC substantially decreased after 6 months (-6.6% absolute units [-41% relatively]) and 18 months (-4.0% absolute units [-29% relatively]; p 0.001 vs. baseline). Reductions of HFC were associated with decreases in VAT beyond weight loss. After controlling for VAT loss, decreased %HFC remained independently associated with reductions in serum gamma glutamyltransferase and alanine aminotransferase, circulating chemerin, and glycated hemoglobin (p 0.05). While the reduction in HFC was similar between physical activity groups, MED/LC induced a greater %HFC decrease (p = 0.036) and greater improvements in cardiometabolic risk parameters (p 0.05) than the LF diet, even after controlling for VAT changes. Yet, the greater improvements in cardiometabolic risk parameters induced by MED/LC were all markedly attenuated when controlling for HFC changes.%HFC is substantially reduced by diet-induced moderate weight loss and is more effectively reduced by the MED/LC diet than the LF diet, independently of VAT changes. The beneficial effects of the MED/LC diet on specific cardiometabolic parameters appear to be mediated more by decreases in %HFC than VAT loss.High hepatic fat content is associated with metabolic syndrome, type 2 diabetes mellitus, and coronary heart disease. In the CENTRAL 18-month intervention trial, a Mediterranean/low-carbohydrate diet induced a greater decrease in hepatic fat content than a low-fat diet, conferring beneficial health effects that were beyond the favorable effects of visceral fat loss. ClinicalTrials.gov Identifier: NCT01530724.

The ability to mobilize pancreatic-fat and the meaning of decreased fat in the pancreas remain controversial. We followed the dynamics of pancreatic-fat and its morphology during various long weight-loss induced lifestyle-interventions.In isolated workplace with monitored/provided lunch, we randomly assigned healthy persons with abdominal obesity or dyslipidemia for one of two 18-month equal-caloric diets: low-fat (LF) or Mediterranean/low-carbohydrate (Med/LC, with provided 1oz walnuts/day), with or without added moderate exercise (supervised gym membership). We used magnetic-resonance-imaging to quantify pancreatic-fat and morphology.At baseline, 277 eligible participants (mean age = 48 years; 88% men; pancreatic-fat = 17.4 ± 5.1%) had higher pancreatic-fat in men (17.7 ± 4.9% vs 14.9 ± 5.5% in women; p = 0.004). Following 18-month intervention (adherence = 86.3%) and moderate weight-loss (mean = -3.0 ± 5.5 kg), pancreatic-fat decreased moderately but significantly (-0.26 ± 2.18% units; p = 0.049). Med/LC diet induced a greater decrease in pancreatic-fat compared to LF (p = 0.043), and the combination of Med/LC diet + exercise exhibited the highest reduction (-0.69% units) as compared to LF diet without exercise (+0.12%units; p = 0.027 between groups). In multivariate regression models, after further adjusted for visceral adipose-tissue (ΔVAT), pancreatic-fat loss associated with both decreases in pancreatic-morphology ratio (perimeter divided by area; beta = 0.361; p 0.001) and superficial-subcutaneous adipose-tissue loss (beta = 0.242; p = 0.001), but not with changes in intrahepatic-fat (beta = -0.034; p = 0.638). Pancreatic-fat loss associated with increased intake of polyunsaturated-fat (beta = -0.137; p = 0.032), as with improved high-density lipoprotein-cholesterol (HDL; beta = -0.156; p = 0.023) and triglycerides/HDL ratio (beta = 0.162; p = 0.015), independently of ΔVAT, but not with glycemic-control parameters (e.g. HbA1c, HOMA-IR and HOMA-beta; p 0.2 for all).Pancreatic-fat loss is mainly associated with improved lipid, rather than glycemic profiles. Med/LC diet, mostly with exercise, may benefit pancreatic-fat loss. Pancreatic-morphology could serve as a biomarker of pancreatic-fat state. (ClinicalTrials.gov identifier: NCT01530724).

Accumulation of cervical and chin subcutaneous adipose tissues (SAT) represent known phenotypes of obesity. We aimed to evaluate the sensitivity of these fat storages to long-term weight-loss directed lifestyle-intervention and to assess their relations to bodily-adiposity, insulin-resistance, and cardiometabolic risk; We randomly assigned 278 participants with abdominal-obesity/dyslipidemia to low-fat or Mediterranean/low-carbohydrate diets +/− physical-activity. All participants underwent an 18 month whole-body magnetic resonance imaging follow-up, from which we assessed cervical and chin SAT-areas; Participants (age = 48 years; 90% men; body-mass-index = 30.9 kg/m2) had an 18-month adherence-rate of 86%. Cervical-SAT and chin-SAT decreased after 6-months (−13.1% and −5.3%, respectively, p < 0.001). After 18-months only cervical-SAT remained decreased compared to baseline (−5%, p < 0.001). Cervical and chin-SAT 18-month changes were associated with changes in weight (r = 0.70, r = 0.66 respectively; p = 0.05), HbA1c (β = 0.12; p = 0.03), and homeostasis-model-assessment-of-insulin-resistance (β = 0.12; p = 0.03). Cervical-SAT 18-month reduction was associated with decreased triglycerides (β = 0.16; p = 0.02) and leptin (β = 0.19; p = 0.01) independent of VAT; Cervical and chin-SATs are dynamic fat depots that correspond with weight-loss and are associated with changes in cardiometabolic profile. In long-term, chin-SAT displays a larger rebound compared with cervical-SAT. Chin-SAT accumulation is associated with in insulin-resistance, independent of central obesity. (ClinicalTrials identifier NCT01530724)

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.

Background: In view of evidence linking pericardial fat accumulation with increased cardiovascular disease risk, strategies to reduce its burden are needed. Data comparing the effects of specific long-term dietary interventions on pericardial fat tissue mobilization are sparse.Objective: We sought to evaluate intrapericardial-fat (IPF) and extrapericardial-fat (EPF) changes during weight-loss interventions by different dietary regimens.Design: During 18 mo of a randomized controlled trial, we compared a Mediterranean/low-carbohydrate (MED/LC) diet plus 28 g walnuts/d with a calorically equal low-fat (LF) diet among randomly assigned participants with moderate abdominal obesity. We performed whole-body MRI and volumetrically quantified IPF and EPF among 80 participants to follow the 18-mo changes.Results: The participants [mean age: 48.6 y; mean body mass index (BMI; in kg/m2); 31.7; 90% men] had baseline IPF and EPF (mean ± SD) volumes of 172.4 ± 53.3 mL and 194.9 ± 71.5 mL, respectively. The 18-mo moderate weight loss of 3.7 kg was similar in both groups, but the reduction in waist circumference was higher in the MED/LC group (-6.9 ± 6.6 cm) than in the LF diet group (-2.3 ± 6.5 cm; P = 0.01). After 18 mo, the IPF volume had reduced twice as much in the MED/LC group compared with the LF group [-37 ± 26.2 mL (-22% ± 15%) compared with -15.5 ± 26.2 mL (-8% ± 15%), respectively; P 0.1]. After controlling for weight loss, IPF and EPF volume reduction paralleled changes in lipid profile but not with improved glycemic profile variables: the IPF relative reduction was associated with a decrease in triglycerides (TGs) (β = 0.090; 95% CI: 0.026, 0.154; P = 0.007) and the ratio of TGs to high-density lipoprotein (HDL) cholesterol (β = 2.689; 95% CI: 0.373, 5.003; P = 0.024), and the EPF relative reduction was associated with an increase in HDL cholesterol (β = -0.452; 95% CI: -0.880, -0.023; P = 0.039) and a decrease in total cholesterol and HDL cholesterol (β = 3.766; 95% CI: 1.092, 6.440; P = 0.007).Conclusions: Moderate but persistent dietary-induced weight loss substantially decreased both IPF and EPF volumes. Reduction of pericardial adipose tissues is independently associated with an improved lipid profile. The Mediterranean diet, rich in unsaturated fats and restricted carbohydrates, is superior to an LF diet in terms of the IPF burden reduction. This trial was registered at clinicaltrials.gov as NCT01530724.

ObjectiveTo generate evidence-based conclusions about the effect of wine consumption on weight gain and abdominal fat accumulation and distribution in patients with type 2 diabetes.DesignIn the 2-year randomized controlled CASCADE (CArdiovaSCulAr Diabetes & Ethanol) trial, patients following a Mediterranean diet were randomly assigned to drink 150 ml of mineral water, white wine or red wine with dinner for 2 years. Visceral adiposity and abdominal fat distribution were measured in a subgroup of sixty-five participants, using abdominal MRI.SettingBen-Gurion University of the Negev, Soroka-Medical Center and the Nuclear Research Center Negev, Israel.SubjectsAlcohol-abstaining adults with well-controlled type 2 diabetes.ResultsForty-eight participants (red wine, n 27; mineral water, n 21) who completed a second MRI measurement were included in the 2-year analysis. Similar weight losses (sd) were observed: red wine 1·3 (3·9) kg; water 1·0 (4·2) kg (P=0·8 between groups). Changes (95 % CI) in abdominal adipose-tissue distribution were similar: red wine, visceral adipose tissue (VAT) −3·0 (−8·0, 2·0) %, deep subcutaneous adipose tissue (DSAT) +5·2 (−1·1, 11·6) %, superficial subcutaneous adipose tissue (SSAT) −1·9 (−5·0, 1·2) %; water, VAT −3·2 (−8·9, 2·5) %, DSAT +2·9 (−2·8, 8·6) %, SSAT −0·15 (−3·3, 2·9) %. No changes in antidiabetic medication and no substantial changes in energy intake (+126 (sd 2889) kJ/d (+30·2 (sd 690) kcal/d), P=0·8) were recorded. A 2-year decrease in glycated Hb (β=0·28, P=0·05) was associated with a decrease in VAT.ConclusionsModerate wine consumption, as part of a Mediterranean diet, in persons with controlled diabetes did not promote weight gain or abdominal adiposity.

It remains unclear whether intermuscular adipose tissue (IMAT) has any metabolic influence or whether it is merely a marker of abnormalities, as well as what are the effects of specific lifestyle strategies for weight loss on the dynamics of both IMAT and thigh muscle area (TMA). We followed the trajectory of IMAT and TMA during 18-mo lifestyle intervention among 278 sedentary participants with abdominal obesity, using magnetic resonance imaging. We measured the resting metabolic rate (RMR) by an indirect calorimeter. Among 273 eligible participants (47.8 ± 9.3 yr of age), the mean IMAT was 9.6 ± 4.6 cm2. Baseline IMAT levels were directly correlated with waist circumference, abdominal subdepots, C-reactive protein, and leptin and inversely correlated with baseline TMA and creatinine ( P < 0.05 for all). After 18 mo (86.3% adherence), both IMAT (−1.6%) and TMA (−3.3%) significantly decreased ( P < 0.01 vs. baseline). The changes in both IMAT and TMA were similar across the lifestyle intervention groups and directly corresponded with moderate weight loss ( P < 0.001). IMAT change did not remain independently associated with decreased abdominal subdepots or improved cardiometabolic parameters after adjustments for age, sex, and 18-mo weight loss. In similar models, 18-mo TMA loss remained associated with decreased RMR, decreased activity, and with increased fasting glucose levels and IMAT ( P < 0.05 for all). Unlike other fat depots, IMAT may not represent a unique or specific adipose tissue, instead largely reflecting body weight change per se. Moderate weight loss induced a significant decrease in thigh muscle area, suggesting the importance of resistance training to accompany weight loss programs.

The blood–brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood–brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood–brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo. Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood–brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood–brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT In this study, we reveal a new mechanism that governs blood–brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.

Background: We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots. Methods: We performed an 18-month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to isocaloric low-fat or Mediterranean/low-carbohydrate (MED/LC) diet+28 g walnuts/day with/without added moderate physical activity (PA; 80% aerobic; supervised/free gym membership). Overall primary outcome was body fat redistribution, and the main specific end point was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots (deep and superficial subcutaneous, liver, pericardial, muscle, pancreas, and renal sinus) by magnetic resonance imaging. Results: Of 278 participants (age, 48 years, 89% men, body mass index, 30.8 kg/m 2 ), 86% completed the trial with good adherence. The low-fat group preferentially decreased reported fat intake (−21.0% versus −11.5% for the MED/LC; P P + groups significantly increased the metabolic equivalents per week versus the PA − groups (19.0 versus 2.1; P =0.009). Whereas final moderate weight loss was indifferent, exercise attenuated the waist circumference rebound with the greatest effect in the MED/LC PA+ group ( P + with either diet had a significantly greater effect on decreasing VAT (mean of difference, −6.67cm 2 ; 95% confidence interval, −14.8 to −0.45) compared with PA − . The MED/LC diet was superior to the low-fat diet in decreasing intrahepatic, intrapericardial, and pancreatic fats ( P Conclusions: Moderate weight loss alone inadequately reflects the significant lifestyle effects on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle protocols may uniquely induce fat mobilization from specific anatomic sites. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01530724.

Focal cerebral ischemia is among the main causes of death and disability worldwide. The ischemic core often progresses, invading the peri-ischemic brain; however, assessing the propensity of the peri-ischemic brain to undergo secondary damage, understanding the underlying mechanisms, and adjusting treatment accordingly remain clinically unmet challenges. A significant hallmark of the peri-ischemic brain is dysfunction of the blood-brain barrier (BBB), yet the role of disturbed vascular permeability in stroke progression is unclear. Here we describe a longitudinal in vivo fluorescence imaging approach for the evaluation of cortical perfusion, BBB dysfunction, free radical formation and cellular injury using the photothrombosis vascular occlusion model in male Sprague Dawley rats. Blood-brain barrier dysfunction propagated within the peri-ischemic brain in the first hours after photothrombosis and was associated with free radical formation and cellular injury. Inhibiting free radical signaling significantly reduced progressive cellular damage after photothrombosis, with no significant effect on blood flow and BBB permeability. Our approach allows a dynamic follow-up of cellular events and their response to therapeutics in the acutely injured cerebral cortex.

Summary Background & aims Data regarding the role of kidney adiposity, its clinical implications, and its dynamics during weight-loss are sparse. We investigated the effect of long-term weight-loss induced intervention diets on dynamics of renal-sinus-fat, an ectopic fat depot, and %renal-parenchymal-fat, lipid accumulation within the renal parenchyma. Methods We randomized 278 participants with abdominal obesity/dyslipidemia to low-fat or Mediterranean/low-carbohydrate diets, with or without exercise. We quantified renal-sinus-fat and %renal-parenchymal-fat by whole body magnetic-resonance-imaging. Results Participants (age = 48 years; 89% men; body-mass-index = 31 kg/m 2 ) had 86% retention to the trial after 18 months. Both increased renal-sinus-fat and %renal-parenchymal-fat were directly associated with hypertension, and with higher abdominal deep-subcutaneous-adipose-tissue and visceral-adipose-tissue (p of trend Conclusions Renal-sinus-fat and renal-parenchymal-fat are fairly related to weight-loss. Decreased renal-sinus-fat is associated with improved hepatic parameters, independent of changes in weight or hepatic fat, rather than with improved renal function or blood pressure parameters. ClinicalTrials.govIdentifier NCT01530724 .

Background Intrahepatic fat (IHF) is best known to associate with waist circumference (WC) and visceral adipose tissue (VAT), but its relation to abdominal subcutaneous adipose tissue is controversial. While IHF ≥ 5% dichotomously defines fatty liver, %IHF is rarely considered as a continuous variable that includes the normal range. In this study, we aimed to evaluate %IHF association with abdominal fat subdepots, pancreatic, and renal-sinus fats. Methods We evaluated %IHF, abdominal fat subdepots, %pancreatic, and renal-sinus fats, among individuals with moderate abdominal obesity, using 3-Tesla magnetic resonance imaging. Results Among 275 participants, %IHF widely ranged (0.01%-50.4%) and was lower in women (1.6%) than men (7.3%; P

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

The blood-brain barrier (BBB) is a highly complex structure, which separates the extracellular fluid of the central nervous system (CNS) from the blood of CNS vessels. A wide range of neurologic conditions, including stroke, epilepsy, Alzheimer's disease, and brain tumors, are associated with perturbations of the BBB that contribute to their pathology. The common consequence of a BBB dysfunction is increased permeability, leading to extravasation of plasma constituents and vasogenic brain edema. The BBB impairment can persist for long periods, being involved in secondary inflammation and neuronal dysfunction, thus contributing to disease pathogenesis. Therefore, reliable imaging of the BBB impairment is of major importance in both clinical management of brain diseases and in experimental research. From landmark studies by Ehrlich and Goldman, the use of dyes (probes) has played a critical role in understanding BBB functions. In recent years methodologic advances in morphologic and functional brain imaging have provided insight into cellular and molecular interactions underlying BBB dysfunction in animal disease models. These imaging techniques, which range from in situ staining to noninvasive in vivo imaging, have different spatial resolution, sensitivity, and capacity for quantitative and kinetic measures of the BBB impairment. Despite significant advances, the translation of these techniques into clinical applications remains slow. This review outlines key recent advances in imaging techniques that have contributed to the understanding of BBB dysfunction in disease and discusses major obstacles and opportunities to advance these techniques into the clinical realm.

OBJECTIVE Unlike visceral adipose tissue (VAT), the association between subcutaneous adipose tissue (SAT) and obesity-related morbidity is controversial. In patients with type 2 diabetes, we assessed whether this variability can be explained by a putative favorable, distinct association between abdominal superficial SAT (SSAT) (absolute amount or its proportion) and cardiometabolic parameters. RESEARCH DESIGN AND METHODS We performed abdominal magnetic resonance imaging (MRI) in 73 patients with diabetes (mean age 58 years, 83% were men) and cross-sectionally analyzed fat distribution at S1-L5, L5-L4, and L3-L2 levels. Patients completed food frequency questionnaires, and subgroups had 24-h ambulatory blood pressure monitoring and 24-h ambulatory electrocardiography. RESULTS Women had higher %SSAT (37 vs. 23% in men; P < 0.001) despite a similar mean waist circumference. Fasting plasma glucose (P = 0.046) and HbA1c (P = 0.006) were both lower with increased tertile of absolute SSAT. In regression models adjusted for age, waist circumference, and classes of medical treatments used in this patient population, increased %SSAT was significantly associated with decreased HbA1c (β = −0.317; P = 0.013), decreased daytime ambulatory blood pressure (β = −0.426; P = 0.008), and increased HDL cholesterol (β = 0.257; P = 0.042). In contrast, increased percent of deep SAT (DSAT) was associated with increased HbA1c (β = 0.266; P = 0.040) and poorer heart rate variability parameters (P = 0.030). Although total fat and energy intake were not correlated with fat tissue distribution, increased intake of trans fat tended to be associated with total SAT (r = 0.228; P = 0.05) and DSAT (r = 0.20; P = 0.093), but not with SSAT. CONCLUSIONS Abdominal SAT is composed of two subdepots that associate differently with cardiometabolic parameters. Higher absolute and relative distribution of fat in abdominal SSAT may signify beneficial cardiometabolic effects in patients with type 2 diabetes.

The brain is characterized by an extremely rich blood supply, regulated by changes in blood vessel diameter and blood flow, depending on metabolic demands. The blood-brain barrier (BBB)-a functional and structural barrier separating the intravascular and neuropil compartments-characterizes the brain's vascular bed and is essential for normal brain functions. Disruptions to the regional cerebral blood supply, to blood drainage and to BBB properties have been described in most common neurological disorders, but there is a lack of quantitative methods for assessing blood flow dynamics and BBB permeability in small blood vessels under both physiological and pathological conditions. Here, we present a quantitative image analysis approach that allows the characterization of relative changes in the regional cerebral blood flow (rCBF) and BBB properties in small surface cortical vessels. In experiments conducted using the open window technique in rats, a fluorescent tracer was injected into the tail vein, and images of the small vessels at the surface of the cortex were taken using a fast CCD camera. Pixel-based image analysis included registration and characterization of the changes in fluorescent intensity, followed by cluster analysis. This analysis enabled the characterization of rCBF in small arterioles and venules and changes in BBB permeability. The method was implemented successfully under experimental conditions, including increased rCBF induced by neural stimulation, bile salt-induced BBB breakdown, and photothrombosis-mediated local ischemia. The new approach may be used to study changes in rCBF, neurovascular coupling and BBB permeability under normal and pathological brain conditions.

BACKGROUND Recommendations for moderate alcohol consumption remain controversial, particularly in type 2 diabetes mellitus (T2DM). Long-term randomized, controlled trials (RCTs) are lacking. OBJECTIVE To assess cardiometabolic effects of initiating moderate alcohol intake in persons with T2DM and whether the type of wine matters. DESIGN 2-year RCT (CASCADE [CArdiovaSCulAr Diabetes & Ethanol] trial). (ClinicalTrials.gov: NCT00784433). SETTING Ben-Gurion University of the Negev-Soroka Medical Center and Nuclear Research Center Negev, Israel. PATIENTS Alcohol-abstaining adults with well-controlled T2DM. INTERVENTION Patients were randomly assigned to 150 mL of mineral water, white wine, or red wine with dinner for 2 years. Wines and mineral water were provided. All groups followed a Mediterranean diet without caloric restriction. MEASUREMENTS Primary outcomes were lipid and glycemic control profiles. Genetic measurements were done, and patients were followed for blood pressure, liver biomarkers, medication use, symptoms, and quality of life. RESULTS Of the 224 patients who were randomly assigned, 94% had follow-up data at 1 year and 87% at 2 years. In addition to the changes in the water group (Mediterranean diet only), red wine significantly increased high-density lipoprotein cholesterol (HDL-C) level by 0.05 mmol/L (2.0 mg/dL) (95% CI, 0.04 to 0.06 mmol/L [1.6 to 2.2 mg/dL]; P < 0.001) and apolipoprotein(a)1 level by 0.03 g/L (CI, 0.01 to 0.06 g/L; P = 0.05) and decreased the total cholesterol-HDL-C ratio by 0.27 (CI, -0.52 to -0.01; P = 0.039). Only slow ethanol metabolizers (alcohol dehydrogenase alleles [ADH1B*1] carriers) significantly benefited from the effect of both wines on glycemic control (fasting plasma glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c) compared with fast ethanol metabolizers (persons homozygous for ADH1B*2). Across the 3 groups, no material differences were identified in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life, except that sleep quality improved in both wine groups compared with the water group (P = 0.040). Overall, compared with the changes in the water group, red wine further reduced the number of components of the metabolic syndrome by 0.34 (CI, -0.68 to -0.001; P = 0.049). LIMITATION Participants were not blinded to treatment allocation. CONCLUSION This long-term RCT suggests that initiating moderate wine intake, especially red wine, among well-controlled diabetics as part of a healthy diet is apparently safe and modestly decreases cardiometabolic risk. The genetic interactions suggest that ethanol plays an important role in glucose metabolism, and red wine's effects also involve nonalcoholic constituents. PRIMARY FUNDING SOURCE European Foundation for the Study of Diabetes.

Summary Background & aims We aimed to assess the association between the distinct abdominal sub-depots and resting energy expenditure (REE). Methods We performed magnetic resonance imaging (MRI) to quantify abdominal visceral-adipose-tissue (VAT), deep-subcutaneous-adipose-tissue (deep-SAT), and superficial-subcutaneous-adipose-tissue (superficial-SAT). We measured REE by indirect-calorimetry. Non-exercise activity thermogenesis (NEAT) [1–3 metabolic equivalents (METs)] and exercise thermogenesis (activities of 4+MET S ) were estimated based on 6-days of accelerometry to assess total physical activity energy expenditure (PAEE). Results We studied 282 participants: 249 men [mean age = 47.4 years, body-mass-index (BMI) = 31 kg/m 2 , mean VAT proportion from total abdominal fat = 34.5%, mean superficial-SAT proportion from total abdominal fat = 24.3%] and 33 women (mean age = 51.2 years, BMI = 30.1 kg/m 2 , mean VAT proportion from total abdominal fat = 22.8%, mean superficial-SAT proportion from total abdominal fat = 37.8%). As expected, women had lower REE [by 32.4% (1488 ± 234 kcal/day vs. 1971 ± 257 kcal/day; p Conclusions Abdominal fat distribution patterns are associated with varying levels of resting energy expenditure, potentially reflecting different metabolic rates of adipose sub-depots and providing an anatomic/anthropometric link to physiological obese sub-phenotypes.

Aims Observational studies report inconsistent associations between moderate alcohol intake and blood pressure (BP). In a sub-study of a larger randomized controlled trial, we assessed the effect of initiating moderate red wine consumption on 24-h BP recordings and the effect of a common genetic variant of alcohol dehydrogenases (ADH) among patients with type 2 diabetes. Methods Fifty-four type 2 diabetes, alcohol abstainers were randomized to consume 150 ml/dinner dry red wine or mineral water. Both groups were guided to adhere to a Mediterranean diet, without caloric restriction. We measured 24-h ambulatory BP monitoring (ABPM) at baseline and after 6 months. Results Participants (age = 57 years; 85% men; mean 24-h BP = 129/77 mm Hg) had 92% 6-month retention. After 6 months of intervention, the average 24-h BP did not differ between the wine and water groups. A transient decrease in BP was observed in the red wine group at midnight (3-4 hours after wine intake: systolic BP: red wine = -10.6mm Hg vs. mineral water = +2.3 mm Hg; P = 0.031) and the following morning at 7-9 am (red wine: -6.2mm Hg vs. mineral water: +5.6mm Hg; P = 0.014). In a second post hoc sub-analysis among the red wine consumers, individuals who were homozygous for the gene encoding ADH1B*2 variant (Arg48His; rs1229984, TT, fast ethanol metabolizers), exhibited a reduction in mean 24-h systolic BP (-8.0mm Hg vs. +3.7 mm Hg; P = 0.002) and pulse pressure (-3.8 mm Hg vs. +1.2 mm Hg; P = 0.032) compared to heterozygotes and those homozygous for the ADH1B*1 variant (CC, slow metabolizers). Conclusions Initiating moderate red wine consumption at dinner among type 2 diabetes patients does not have a discernable effect on mean 24-h BP. Yet, a modest temporal BP reduction could be documented, and a more pronounced BP-lowering effect is suggested among fast ethanol metabolizers. Clinical trials registration ClinicalTrials.gov Identifier: NCT00784433.

Using genetic algorithms (GA) for solving NP-hard problems is becoming more and more frequent. This paper presents a use of GA with a new selection approach called the queen GA. The main idea is not to select both parents from the entire population, but to create a subgroup of better solutions (the queen cohort), and to use at least one of its members in each performed crossover. We demonstrate the use of the queen GA for the problem of repositioning observers across a polygonal area with obstacles in order to maximize the visual area coverage for a given time horizon. The queen GA gives superior results over a GA with different selection methods (i.e. proportion, ranking and tournament) at the 0.01 significance level. These comparative results were duplicated when elitism was included.

A dysfunctional BBB is a common feature in a variety of brain disorders, a fact stressing the need for diagnostic tools designed to assess brain vessels' permeability in space and time. Biological research has benefited over the years various means to analyze BBB integrity. The use of biomarkers for improper BBB functionality is abundant. Systemic administration of BBB impermeable tracers can both visualize brain regions characterized by BBB impairment, as well as lead to its quantification. Additionally, locating molecular, physiological content in regions from which it is restricted under normal BBB functionality undoubtedly indicates brain pathology-related BBB disruption. However, in-depth research into the BBB's phenotype demands higher analytical complexity than functional vs. pathological BBB; criteria which biomarker based BBB permeability analyses do not meet. The involvement of accurate and engineering sciences in recent brain research, has led to improvements in the field, in the form of more accurate, sensitive imaging-based methods. Improvements in the spatiotemporal resolution of many imaging modalities and in image processing techniques, make up for the inadequacies of biomarker based analyses. In pre-clinical research, imaging approaches involving invasive procedures, enable microscopic evaluation of BBB integrity, and benefit high levels of sensitivity and accuracy. However, invasive techniques may alter normal physiological function, thus generating a modality-based impact on vessel's permeability, which needs to be corrected for. Non-invasive approaches do not affect proper functionality of the inspected system, but lack in spatiotemporal resolution. Nevertheless, the benefit of medical imaging, even in pre-clinical phases, outweighs its disadvantages. The innovations in pre-clinical imaging and the development of novel processing techniques, have led to their implementation in clinical use as well. Specialized analyses of vessels' permeability add valuable information to standard anatomical inspections which do not take the latter into consideration.

The blood-brain barrier (BBB) is a highly complex structure, which separates the extracellular fluid of the central nervous system (CNS) from the blood of CNS vessels. A wide range of neurologic conditions, including stroke, epilepsy, Alzheimer's disease, and brain tumors, are associated with perturbations of the BBB that contribute to their pathology. The common consequence of a BBB dysfunction is increased permeability, leading to extravasation of plasma constituents and vasogenic brain edema. The BBB impairment can persist for long periods, being involved in secondary inflammation and neuronal dysfunction, thus contributing to disease pathogenesis. Therefore, reliable imaging of the BBB impairment is of major importance in both clinical management of brain diseases and in experimental research. From landmark studies by Ehrlich and Goldman, the use of dyes (probes) has played a critical role in understanding BBB functions. In recent years methodologic advances in morphologic and functional brain imaging have provided insight into cellular and molecular interactions underlying BBB dysfunction in animal disease models. These imaging techniques, which range from in situ staining to noninvasive in vivo imaging, have different spatial resolution, sensitivity, and capacity for quantitative and kinetic measures of the BBB impairment. Despite significant advances, the translation of these techniques into clinical applications remains slow. This review outlines key recent advances in imaging techniques that have contributed to the understanding of BBB dysfunction in disease and discusses major obstacles and opportunities to advance these techniques into the clinical realm.

Spreading depolarization describes a sustained neuronal and astroglial depolarization with abrupt ion translocation between intraneuronal and extracellular space leading to a cytotoxic edema and silencing of spontaneous activity. Spreading depolarizations occur abundantly in acutely injured human brain and are assumed to facilitate neuronal death through toxic effects, increased metabolic demand, and inverse neurovascular coupling. Inverse coupling describes severe hypoperfusion in response to spreading depolarization. Ictal epileptic events are less frequent than spreading depolarizations in acutely injured human brain but may also contribute to lesion progression through increased metabolic demand. Whether abnormal neurovascular coupling can occur with ictal epileptic events is unknown. Herein we describe a patient with aneurysmal subarachnoid hemorrhage in whom spreading depolarizations and ictal epileptic events were measured using subdural opto-electrodes for direct current electrocorticography and regional cerebral blood flow recordings with laser-Doppler flowmetry. Simultaneously, changes in tissue partial pressure of oxygen were recorded with an intraparenchymal oxygen sensor. Isolated spreading depolarizations and clusters of recurrent spreading depolarizations with persistent depression of spontaneous activity were recorded over several days followed by a status epilepticus. Both spreading depolarizations and ictal epileptic events where accompanied by hyperemic blood flow responses at one optode but mildly hypoemic blood flow responses at another. Of note, quantitative analysis of Gadolinium-diethylene-triamine-pentaacetic acid (DTPA)–enhanced magnetic resonance imaging detected impaired blood–brain barrier integrity in the region where the optode had recorded the mildly hypoemic flow responses. The data suggest that abnormal flow responses to spreading depolarizations and ictal epileptic events, respectively, may be associated with blood–brain barrier dysfunction.

OBJECTIVE Unlike visceral adipose tissue (VAT), the association between subcutaneous adipose tissue (SAT) and obesity-related morbidity is controversial. In patients with type 2 diabetes, we assessed whether this variability can be explained by a putative favorable, distinct association between abdominal superficial SAT (SSAT) (absolute amount or its proportion) and cardiometabolic parameters. RESEARCH DESIGN AND METHODS We performed abdominal magnetic resonance imaging (MRI) in 73 patients with diabetes (mean age 58 years, 83% were men) and cross-sectionally analyzed fat distribution at S1-L5, L5-L4, and L3-L2 levels. Patients completed food frequency questionnaires, and subgroups had 24-h ambulatory blood pressure monitoring and 24-h ambulatory electrocardiography. RESULTS Women had higher %SSAT (37 vs. 23% in men; P < 0.001) despite a similar mean waist circumference. Fasting plasma glucose (P = 0.046) and HbA1c (P = 0.006) were both lower with increased tertile of absolute SSAT. In regression models adjusted for age, waist circumference, and classes of medical treatments used in this patient population, increased %SSAT was significantly associated with decreased HbA1c (β = −0.317; P = 0.013), decreased daytime ambulatory blood pressure (β = −0.426; P = 0.008), and increased HDL cholesterol (β = 0.257; P = 0.042). In contrast, increased percent of deep SAT (DSAT) was associated with increased HbA1c (β = 0.266; P = 0.040) and poorer heart rate variability parameters (P = 0.030). Although total fat and energy intake were not correlated with fat tissue distribution, increased intake of trans fat tended to be associated with total SAT (r = 0.228; P = 0.05) and DSAT (r = 0.20; P = 0.093), but not with SSAT. CONCLUSIONS Abdominal SAT is composed of two subdepots that associate differently with cardiometabolic parameters. Higher absolute and relative distribution of fat in abdominal SSAT may signify beneficial cardiometabolic effects in patients with type 2 diabetes.

The blood–brain barrier (BBB) is a functional and structural barrier separating the intravascular and neuropil compartments of the brain. It characterizes the vascular bed and is essential for normal brain functions. Dysfunction in the BBB properties have been described in most common neurological disorders, such as stroke, traumatic injuries, intracerebral hemorrhage, tumors, epilepsy and neurodegenerative disorders. It is now obvious that the BBB plays an important role in normal brain activity, stressing the need for applicable imaging and assessment methods. Recent advancements in imaging techniques now make it possible to establish sensitive and quantitative methods for the assessment of BBB permeability. However, most of the existing techniques require complicated and demanding dynamic scanning protocols that are impractical and cannot be fulfilled in some cases. We review existing methods for the evaluation of BBB permeability, focusing on quantitative magnetic resonance-based approaches and discuss their drawbacks and limitations. In light of those limitations we propose two new approaches for BBB assessment with less demanding imaging sequences: the “post-pre” and the “linear dynamic” methods, both allow semi-quantitative permeability assessment and localization of dysfunctional BBB with simple/partial dynamic imaging protocols and easy-to-apply analysis algorithms. We present preliminary results and show an example which compares these new methods with the existing standard assessment method. We strongly believe that the establishment of such “easy to use” and reliable imaging methods is essential before BBB assessment can become a routine clinical tool. Large clinical trials are awaited to fully understand the significance of BBB permeability as a biomarker and target for treatment in neurological disorders.