Dexrazoxane Treatments Limits Subclinical Cardiac Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors Exposed to Doxorubicin Treatments.

INTRODUCTION: Doxorubicin leads to dose dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. We investigated survivors' heart health using echocardiography and evaluated doxorubicin and dexrazoxane treatments on cardiac function. METHODS: A total of 196 childhood ALL survivors were stratified (standard risk [SR], high risk with and without dexrazoxane (HR+DEX and HR). We performed a complete transthoracic echocardiographic assessment with M-mode echocardiography, Doppler, and Tissue Doppler. We used 2-dimensional and 3-dimensional echocardiography to measure the left ventricular ejection fraction, whereas myocardial strain imaging was used to obtain global strain indices. RESULTS: Although most cardiac and arterial dimension parameters were not different between groups, a difference was observed in posterior intima of the right carotid ( P =0.017). Diastolic functions analyses reported that LV shortening fraction and left and right ventricular lateral S' wave amplitudes were lower in HR than in SR and HR+DEX groups ( P =0.028, P =0.048, and P =0.005, respectively). The LV lateral E' in diastolic function was lower in the HR than in SR and HR+DEX groups ( P =0.036). The LV end-systolic wall stress was higher in HR than in SR and HR+DEX groups ( P =0.009). A decrease contractility was observed, while the effect was not group specific. Strain rate was not different between groups, as opposed to tissue Doppler measurements. CONCLUSIONS: This study showed that dexrazoxane treatments could limit subclinical cardiac dysfunction in childhood ALL survivors, whereas survivors in HR group who did not receive dexrazoxane had potential subclinical cardiac damage observable in heart failure patients. Echocardiographic screening for survivors must be part of the follow-up routine in cardio-oncology.

Temporal Changes in Gene Expression Profile during Mature Adipocyte Dedifferentiation.

Objective. To characterize changes in gene expression profile during human mature adipocyte dedifferentiation in ceiling culture. Methods. Subcutaneous (SC) and omental (OM) adipose tissue samples were obtained from 4 participants paired for age and BMI. Isolated adipocytes were dedifferentiated in ceiling culture. Gene expression analysis at days 0, 4, 7, and 12 of the cultures was performed using Affymetrix Human Gene 2.0 STvi arrays. Hierarchical clustering according to similarity of expression changes was used to identify overrepresented functions. Results. Four clusters gathered genes with similar expression between day 4 to day 7 but decreasing expression from day 7 to day 12. Most of these genes coded for proteins involved in adipocyte functions (LIPE, PLIN1, DGAT2, PNPLA2, ADIPOQ, CEBPA, LPL, FABP4, SCD, INSR, and LEP). Expression of several genes coding for proteins implicated in cellular proliferation and growth or cell cycle increased significantly from day 7 to day 12 (WNT5A, KITLG, and FGF5). Genes coding for extracellular matrix proteins were differentially expressed between days 0, 4, 7, and 12 (COL1A1, COL1A2, and COL6A3, MMP1, and TGFB1). Conclusion. Dedifferentiation is associated with downregulation of transcripts encoding proteins involved in mature adipocyte functions and upregulation of genes involved in matrix remodeling, cellular development, and cell cycle.

Forest Connectivity Regions of Canada Using Circuit Theory and Image Analysis.

Ecological processes are increasingly well understood over smaller areas, yet information regarding interconnections and the hierarchical nature of ecosystems remains less studied and understood. Information on connectivity over large areas with high resolution source information provides for both local detail and regional context. The emerging capacity to apply circuit theory to create maps of omnidirectional connectivity provides an opportunity for improved and quantitative depictions of forest connectivity, supporting the formation and testing of hypotheses about the density of animal movement, ecosystem structure, and related links to natural and anthropogenic forces. In this research, our goal was to delineate regions where connectivity regimes are similar across the boreal region of Canada using new quantitative analyses for characterizing connectivity over large areas (e.g., millions of hectares). Utilizing the Earth Observation for Sustainable Development of forests (EOSD) circa 2000 Landsat-derived land-cover map, we created and analyzed a national-scale map of omnidirectional forest connectivity at 25m resolution over 10000 tiles of 625 km2 each, spanning the forested regions of Canada. Using image recognition software to detect corridors, pinch points, and barriers to movements at multiple spatial scales in each tile, we developed a simple measure of the structural complexity of connectivity patterns in omnidirectional connectivity maps. We then mapped the Circuitscape resistance distance measure and used it in conjunction with the complexity data to study connectivity characteristics in each forested ecozone. Ecozone boundaries masked substantial systematic patterns in connectivity characteristics that are uncovered using a new classification of connectivity patterns that revealed six clear groups of forest connectivity patterns found in Canada. The resulting maps allow exploration of omnidirectional forest connectivity patterns at full resolution while permitting quantitative analyses of connectivity over broad areas, informing modeling, planning and monitoring efforts.

Biliopancreatic diversion with duodenal switch modifies plasma chemerin in early and late post-operative periods.

OBJECTIVE: Bariatric surgery remains the most effective treatment for obesity and metabolic syndrome. Surgical benefit arises from early-phase resolution of hyperglycemia and late-phase weight loss. The adipokine chemerin is of interest given its roles in immunity, adipogenesis, and metabolism. The study objective was to examine the effects of biliopancreatic diversion with duodenal switch (BPD-DS) on plasma chemerin in the early and late post-operative stages. METHODS: 83 adults with obesity undergoing BPD-DS, 45 obese non-surgical controls, and 9 lean surgical controls were enrolled. Plasma parameters and anthropometric measures were obtained at baseline and at, early (24 h, 5 D) and late (6 months and 12 months) post-operative stages. RESULTS: Plasma chemerin dropped from 176±49 ng/mL at baseline to 132±52 ng/mL 24 h after BPD-DS, rebounded to 200±66 ng/mL after 5 D, and declined to 124±51 and 110±34 ng/mL after 6 and 12 months. Plasma chemerin correlated negatively with measures of inflammation and hepatic injury and positively with measures of obesity, metabolic syndrome, and inflammation in the early and late post-operative periods, respectively. CONCLUSIONS: Chemerin has a novel role in surgical injury but not hyperglycemia resolution early after BPD-DS. Over the long term, plasma chemerin declines to a new set point that is partially determined by body fat reductions.

Ethnic differences in acylation stimulating protein (ASP) in Xinjiang Uygur autonomous region, China.

BACKGROUND: Acylation Stimulating Protein (ASP) stimulates adipocyte triglyceride synthesis and glucose transport. The aim was to examine ethnic difference in ASP and the relation to lipid profile and other parameters among Han, Uygur, and Kazak healthy populations matched for BMI, age and gender distribution. METHODS: 331 healthy persons were recruited in total (age 30-60 yr): 137 Han, 114 Uygur, and 80 Kazak. Anthropometric measurements including height, weight, waist circumference, hip circumference, blood pressure, ankle brachial index (ABI), and pulse wave velocity (PWV) were measured in all participants. Fasting concentrations of fasting glucose, uric acid, and lipids, including triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), ASP, complement C3, insulin, non-esterified fatty acid (NEFA) and C-reactive protein (CRP) were measured. RESULTS: ASP in Uygurs was significantly lower than Han subjects (P=0.0003). The Uygurs demonstrated the highest C3 (P<0.001), CRP (P=0.001), and NEFA concentrations (P=0.008), the lowest %ASP/C3 (P<0.001) and TC levels (P=0.0008) vs those in Han and Kazak populations. In the Han group, glucose, the average ABI (an index of peripheral response) and diastolic blood pressure were significantly different from both Uygur and Kazak group (P=0.0007, P=0.0003, P=0.0001) while Kazaks show the lowest waist/hip circumference (WHR) (P=0.0003). CONCLUSION: There are ethnic differences in ASP, C3, CRP and lipid profiles in healthy Han, Uygur, and Kazak populations. Overall, the Uygur populations presents with a disadvantageous metabolic profile as compared to Han and Kazak groups.

Generation of human adipose stem cells through dedifferentiation of mature adipocytes in ceiling cultures.

Mature adipocytes have been shown to reverse their phenotype into fibroblast-like cells in vitro through a technique called ceiling culture. Mature adipocytes can also be isolated from fresh adipose tissue for depot-specific characterization of their function and metabolic properties. Here, we describe a well-established protocol to isolate mature adipocytes from adipose tissues using collagenase digestion, and subsequent steps to perform ceiling cultures. Briefly, adipose tissues are incubated in a Krebs-Ringer-Henseleit buffer containing collagenase to disrupt tissue matrix. Floating mature adipocytes are collected on the top surface of the buffer. Mature cells are plated in a T25-flask completely filled with media and incubated upside down for a week. An alternative 6-well plate culture approach allows the characterization of adipocytes undergoing dedifferentiation. Adipocyte morphology drastically changes over time of culture. Immunofluorescence can be easily performed on slides cultivated in 6-well plates as demonstrated by FABP4 immunofluorescence staining. FABP4 protein is present in mature adipocytes but down-regulated through dedifferentiation of fat cells. Mature adipocyte dedifferentiation may represent a new avenue for cell therapy and tissue engineering.

C3 Polymorphism Influences Circulating Levels of C3, ASP and Lipids in Schizophrenic Patients.

Excessive activation of complement is associated with many diseases including schizophrenia. Investigation of C3 polymorphisms, circulating C3, cleavage product ASP/C3adesArg, and lipid metabolism. Cross-sectional analysis. C3 genotyping (CC vs GG for R102L) was performed on 434 Tunisian people consisting of 272 schizophrenic (SZ) patients and 162 control subjects. In a age- and gender-matched subgroups of the three genotypes (131 SZ and 112 NOR), plasma triglycerides, total cholesterol (C), LDL-C, HDL-C, ASP, and complement C3 were measured. C3 gene polymorphism influences BMI and plasma C3, ASP, triglyceride, total cholesterol, LDL-C and HDL-C among SZ patients (p < 0.05-0.0001), with increasing values demonstrated from CC (common form) to CG (heterozygote form) to GG (rare homozygote) forms. Significant correlations between plasma C3 and BMI, triglyceride, HDL-C and ASP (p < 0.05-0.0001) were observed, while ASP correlated with BMI and LDL-C (p = 0.005, p = 0.001, respectively) in SZ patients. Further, proportional conversion of C3 to ASP (%ASP/C3) also increased (p < 0.0001, GG>CG>CC). C3 polymorphisms and plasma C3, ASP and %ASP/C3 correlated with lipid parameters in this SZ population, suggesting that factors predisposing patients to schizophrenia are permissive for complement pathway activation and dyslipidemic influences.

Increased vaspin levels are associated with beneficial metabolic outcome pre- and post-bariatric surgery.

PURPOSE: Vaspin (visceral-adipose-tissue-derived-serine-protease-inhibitor) is a recently identified adipokine with putative insulin-sensitizing properties. Plasma vaspin responses to surgery-induced weight loss are sparse and contradictory. DESIGN AND PARTICIPANTS: We evaluated changes in vaspin levels and relationship to post-operative outcomes in men (n = 22) and women (n = 55) undergoing biliopancreatic-diversion/duodenal-switch bariatric surgery. Body composition and plasma parameters were measured at baseline, acutely (1 and 5 days) and medium-term (6 and 12 months) post-surgery. RESULTS: Fasting preoperative vaspin concentrations were comparable in men vs women. The distribution was biphasic (both men and women) with a nadir of 2.5 ng/ml. Subjects were divided into high (≥2.5 ng/mL, HI-group) and low (<2.5 ng/mL, LO-group) vaspin level. Both groups had comparable sex distribution, age and BMI, but the HI-vaspin group had lower insulin, HOMA, and triglyceride and higher HDL-cholesterol, acylation stimulating protein (ASP) and IL-6 levels (all p<0.05). Post-operatively, both groups decreased BMI comparably over 12 months; the HI-vaspin group maintained high vaspin levels, while the LO-vaspin group gradually increased their levels with weight loss over 12 months. The HI-vaspin group maintained a better glucose, insulin, HOMA, fructosamine, HDL-cholesterol, and triglyceride profile throughout. The HI-vaspin group also had higher gamma-glutamyltransferase and ASP profiles. Finally, baseline vaspin level inversely correlated significantly with baseline and 12-month insulin, HOMA, triglyceride and positively correlated with HDL and ASP. Twelve-month vaspin also correlated similarly, including an inverse correlation with BMI. CONCLUSION: Globally, this study supports the concept of vaspin as a beneficial adipokine in obesity, which may potentially lead to possible therapeutic targets.

Acylation stimulating protein, complement C3 and lipid metabolism in ketosis-prone diabetic subjects.

BACKGROUND: Ketosis-prone diabetes (KPDM) is new-onset diabetic ketoacidosis without precipitating factors in non-type 1 diabetic patients; after management, some are withdrawn from exogenous insulin, although determining factors remain unclear. METHODS: Twenty KPDM patients and twelve type 1 diabetic patients (T1DM), evaluated at baseline, 12 and 24 months with/without insulin maintenance underwent a standardized mixed-meal tolerance test (MMTT) for 2 h. RESULTS: At baseline, triglyceride and C3 were higher during MMTT in KPDM vs. T1DM (p<0.0001) with no differences in non-esterified fatty acids (NEFA) while Acylation Stimulating Protein (ASP) tended to be higher. Within 12 months, 11 KPDM were withdrawn from insulin treatment (KPDM-ins), while 9 were maintained (KPDM+ins). NEFA was lower in KPDM-ins vs. KPDM+ins at baseline (p = 0.0006), 12 months (p<0.0001) and 24 months (p<0.0001) during MMTT. NEFA in KPDM-ins decreased over 30-120 minutes (p<0.05), but not in KPDM+ins. Overall, C3 was higher in KPDM-ins vs KPDM+ins at 12 months (p = 0.0081) and 24 months (p = 0.0019), while ASP was lower at baseline (p = 0.0024) and 12 months (p = 0.0281), with a decrease in ASP/C3 ratio. CONCLUSIONS: Notwithstanding greater adiposity in KPDM-ins, greater NEFA decreases and lower ASP levels during MMTT suggest better insulin and ASP sensitivity in these patients.

Omentin changes following bariatric surgery and predictive links with biomarkers for risk of cardiovascular disease.

BACKGROUND: Although no receptor has yet been identified, changes in circulating levels of the adipokine designated as Omentin have been demonstrated in obesity and related comorbidities such as cardiovascular disease, insulin resistance, metabolic syndrome and chronic inflammation. METHODS: Changes in Omentin levels at 1 and 5 days and 6 and 12 months in response to biliopancreatic diversion with duodenal switch bariatric surgery were evaluated, specifically to investigate if changes preceded gain of insulin sensitivity. RESULTS: Pre-operative plasma Omentin was not different between men (n = 18) vs women (n = 48), or diabetic status but correlated with body mass index (BMI). Altogether, Omentin increased as early as 24-h post-surgery, with changes maintained up to 1-year. Fifty-nine percent of subjects increased Omentin >10% by 24-H following surgery (OmentinINC p < 0.0001), while 18% of subjects decreased (OmentinDEC p < 0.0001), with changes maintained throughout one-year. These two groups had comparable age, sex distribution, diabetes, BMI, waist circumference and fat mass, however OmentinDEC had elevated levels of cardiovascular risk markers; homocysteine (p = 0.019), NT-proBNP (p = 0.006) and total bilirubin (p = 0.0001) while red blood cell (RBC) count was lower (p = 0.0005) over the one-year period. Omentin levels at 1-DAY also correlated with immune parameters (white blood cell count, % neutrophil, % monocytes, % lymphocytes). CONCLUSION: OmentinDEC at 1 day following surgery may be a marker of cardiovascular "at-risk" group before weight loss or insulin sensitivity restoration.

Complement receptors C5aR and C5L2 are associated with metabolic profile, sex hormones, and liver enzymes in obese women pre- and postbariatric surgery.

OBJECTIVE: Obesity is associated with metabolic dysfunction with sex differences and chronic, low-grade inflammation.We proposed that hepatic expression of immune complement C3 related receptors (C3aR, C5aR, and C5L2) would be associated with pre- or postmenopausal status and metabolic profile in severely obese women. We hypothesized that C5L2/C5aR ratio, potentially influencing the ASP/C5L2 metabolic versus C5a/C5aR immune response, would predict metabolic profiles after weight loss surgery. MATERIALS AND METHODS: Fasting plasma (hormone, lipid, and enzyme analysis) and liver biopsies (RT-PCR gene expression) were obtained from 91 women during surgery. RESULTS: Hepatic C5L2 mRNA expression was elevated in pre- versus postmenopausal women (P < 0.01) and correlated positively with circulating estradiol, estrone, ApoB, ApoA1, ApoA1/B, waist circumference, age, and LDL-C (all P < 0.05).While plasma ASP was lower in pre- versus postmenopausal women (P < 0.01), the hepatic C5L2/C5aR mRNA ratio was increased (P < 0.001) and correlated positively with estrone (P < 0.01) and estradiol (P < 0.001) and negatively with circulating ApoB and liver enzymes ALT, AST, and GGT (all P < 0.05). Over 12 months postoperatively, liver enzymes in low C5L2/C5aR mRNA ratio group remained higher (ALP and ALT, P < 0.05, AST and GGT, P < 0.001 2-way-ANOVA). CONCLUSION: C5L2-C5aR association with other mediators including estrogens may contribute to hepatic metabolic and inflammatory function.

Downregulation of complement C3 and C3aR expression in subcutaneous adipose tissue in obese women.

BACKGROUND: The central component of the complement system, C3, is associated with obesity, metabolic syndrome and cardiovascular disease however the underlying reasons are unknown. In the present study we evaluated gene expression of C3, the cleavage product C3a/C3adesArg and its cognate receptor C3aR in subcutaneous and omental adipose tissue in women. METHODS: Women (n = 140, 21-69 years, BMI 19.5-79 kg/m2) were evaluated for anthropometric and blood parameters, and adipose tissue gene expression. RESULTS: Subjects were separated into groups (n = 34-36) according to obesity: normal/overweight (≤30 kg/m2), obese I (≤45 kg/m2), obese II (≤51 kg/m2), and obese III (≤80 kg/m2). Overall, while omental expression remained unchanged, subcutaneous C3 and C3aR gene expression decreased with increasing adiposity (2-way ANOVA, p<0.01), with a concomitant decrease in SC/OM ratio (p<0.001). In subcutaneous adipose, both C3 and C3aR expression correlated with apoB, and apoA1 and inversely with waist circumference and blood pressure, while C3aR also correlated with glucose (p<0.05-0.0001). While omental C3aR expression did not correlate with any factor, omental C3 correlated with waist circumference, glucose and apoB (all p<0.05). Further, while plasma C3a/C3adesArg increased and adiponectin decreased with increasing BMI, both correlated (C3a negatively and adiponectin positively) with subcutaneous C3 and C3aR expression (p<0.05-0.001) or less). CONCLUSIONS: The obesity-induced down-regulation of complement C3 and C3aR which is specific to subcutaneous adipose tissue, coupled to the strong correlations with multiple anthropometric, plasma and adipokine variables support a potential role for complement in immunometabolism.

Association of immune and metabolic receptors C5aR and C5L2 with adiposity in women.

Adipose tissue receptors C5aR and C5L2 and their heterodimerization/functionality and interaction with ligands C5a and acylation stimulating protein (ASP) have been evaluated in cell and rodent studies. Their contribution to obesity factors in humans remains unclear. We hypothesized that C5a receptors, classically required for host defense, are also associated with adiposity. Anthropometry and fasting blood parameters were measured in 136 women divided by body mass index (BMI): normal/overweight (≤30 kg/m(2); n = 34), obese I (≤45 kg/m(2); n = 33), obese II (≤51 kg/m(2); n = 33), and obese III (≤80 kg/m(2); n = 36). Subcutaneous and omental adipose tissue C5aR and C5L2 expression were analysed. C5L2 expression was comparable between subcutaneous and omental across all BMI groups. Plasma ASP and ASP/omental C5L2 expression increased with BMI (P < 0.001 and P < 0.01, resp.). While plasma C5a was unchanged, C5aR expression decreased with increasing BMI in subcutaneous and omental tissues (P < 0.01 and P < 0.05, resp.), with subcutaneous omental depots. Omental C5L2/C5aR ratio increased with BMI (P < 0.01) with correlations between C5L2/C5aR and waist circumference, HDL-C, and adiponectin. Tissue and BMI differences in receptors and ligands, particularly in omental, suggest relationship to metabolic disturbances and highlight adipose-immune interactions.

Acute post-bariatric surgery increase in orexin levels associates with preferential lipid profile improvement.

CONTEXT: Orexin is a recently identified neuropeptide hormone. OBJECTIVES: Acute and long-term post-bariatric changes in Orexin and relationship to post-operative metabolic outcomes. DESIGN AND PARTICIPANTS: Men and women undergoing biliopancreatic diversion with duodenal switch bariatric surgery (n = 76, BMI≥35 kg/m(2)) were evaluated for body composition and plasma parameters at baseline, acutely (1 and 5 days) and long-term (6 and 12 months) post-surgery. SETTING: University Hospital Centre, Canada. INTERVENTIONS AND MAIN OUTCOME MEASURES: Groups were subdivided based on acute (average 1 and 5 day) changes in Orexin prior to weight loss: (i)>10% Orexin decrease (n = 33, OrexinDEC) and (ii)>10% Orexin increase (n = 20, OrexinINC), to evaluate impact on long-term changes. RESULTS: Both groups had comparable preoperative Orexin levels, BMI, age, sex distribution, diabetes and lipid lowering medication, plasma glucose and lipid parameters except for apolipoproteinB (p<0.007). Orexin increase was rapid and maintained throughout one year, while OrexinDEC subjects remained significantly lower throughout. Over 12 months, changes in BMI, fat mass, and %fat mass were comparable. Fasting glucose and insulin increased immediately 1-day post-operatively, decreasing rapidly (5-day) and declining thereafter with the OrexinINC group remaining lower than the OrexinDEC group throughout (p = 0.001). Similarly, plasma cholesterol, triglyceride, LDL-C and HDL-C decreased at 1-day, increased slightly (5-day), except HDL-C, then decreased over 1 year, with greater decreases in OrexinINC group relative to OrexinDEC group. CONCLUSION: Rapid postoperative increases in plasma Orexin are associated with better improvement of glucose and lipid profiles following bariatric surgery.

C5aR and C5L2 act in concert to balance immunometabolism in adipose tissue.

Recent studies suggested that the immunometabolic receptors; C5aR and C5L2, constitutively self-associate into homo-/heterodimers and that acylation stimulating protein (ASP/C3adesArg) or C5a treatment of adipocytes increased their colocalization. The present study evaluates the C5aR contribution in adipocytes to the metabolic and immune responses elicited by ligand stimulation. The effects of C5a, ASP, and insulin on cytokine production, triglyceride synthesis (TGS), and key signaling pathways were evaluated in isolated primary adipocytes and cultured 3T3-L1 differentiated adipocytes. In addition, mRNA expression of IRS1 and PGC1α was compared in adipose tissue samples from WT vs. C5aRKO mice. Both C5a and ASP directly increased MCP-1 (238±4%; P<0.001, and 377±2% vs. basal 100%; P<0.001, respectively) and KC (413±11%; P<0.001, and 529±16%; P<0.001 vs. basal 100%, respectively) secretion, TGS (131±1%; P<0.001, and 152±6%; P<0.001, vs. basal 100% respectively), and Akt/NFκB phosphorylation pathways in adipocytes. However, in C5aRKO adipocytes, C5a effects were disrupted, while stimulatory effects of ASP were mostly maintained. Addition of C5a completely blocked ASP signaling and activity in both C5aRKO and WT adipocytes as well as 3T3-L1 adipocytes. Furthermore, C5aRKO adipocytes revealed impaired insulin stimulation of cytokine production, with partial impairment of signaling and TGS stimulation, consistent with decreased IRS1 and PGC1α mRNA expression in adipose tissue. These observations indicate the importance of C5aR in adipose tissue metabolism and immunity, which may be regulated through heterodimerization with C5L2.

A multicenter, randomized, double-blinded, placebo-controlled phase III study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III).

BACKGROUND: In adults, intraventricular thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) facilitates resolution of intraventricular haemorrhage (IVH), reduces intracranial pressure, decreases duration of cerebrospinal fluid diversion, and may ameliorate direct neural injury. We hypothesize that patients with small parenchymal haematoma volumes (<30 cc) and relatively large IVH causing acute obstructive hydrocephalus would have improved clinical outcomes when given injections of low-dose rtPA to accelerate lysis and evacuation of IVH compared with placebo. METHODS: The Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III trial is an investigator-initiated, phase III, randomized, multicenter, double-blind, placebo-controlled study comparing the use of external ventricular drainage (EVD) combined with intraventricular injection of rtPA to EVD plus intraventricular injection of normal saline (placebo) for the treatment of IVH. Patients with known symptom onset within 24 h of the computed tomography scan confirmed IVH and third or fourth ventricle obstruction, with or without supratentorial intracerebral haemorrhage volume <30 cc, who require EVD are screened with a computed tomography scan at least six hours after EVD placement and, if necessary, at consecutive 12-h intervals until stabilization of any intracranial bleeding has been established. Patients who meet clinical and imaging criteria (no ongoing coagulopathy and no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly) will be randomized to either intraventricular rtPA or placebo. RESULTS: The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 180 days. Clinical secondary outcomes include additional modified Rankin Scale dichotomizations at 180 days (0-4 vs. 5-6), ordinal modified Rankin Scale (0-6), mortality and safety events at 30 days, mortality at 180 days, functional status measures, type and intensity of intensive care unit management, rate and extent of ventricular blood clot removal, and quality of life measures.

Clevidipine rapidly and safely reduces blood pressure in acute intracerebral hemorrhage: the ACCELERATE trial.

BACKGROUND: Intracerebral hemorrhage (ICH) causes 10-15% of primary strokes, with mortality related to hematoma volume. Blood pressure (BP) reduction may attenuate hematoma expansion. ACCELERATE (the Evaluation of Patients with Acute Hypertension and Intracerebral Hemorrhage with Intravenous Clevidipine Treatment) is a pilot study representing the first evaluation of safety and efficacy of intravenous clevidipine for the rapid treatment of hypertension in ICH patients. METHODS: ICH patients with a systolic BP (SBP) >160 mm Hg who present within 6 h (n = 27) or 12 h (n = 10) of symptoms were prospectively enrolled, treated with open-label clevidipine until SBP ≤160 mm Hg was achieved and then titrated to keep target SBP between 140-160 mm Hg. RESULTS: A total of 35 patients with baseline median Glasgow Coma Scale score of 12, median NIH Stroke Scale score of 14, mean SBP of 186 mm Hg and a mean time from onset of symptoms of 5.5 h received clevidipine. Median time to achieve SBP target range was 5.5 min. All patients achieved target SBP within 30 min; 96.9% achieved target SBP with clevidipine monotherapy. CT scans showed minimal hematoma volume change for the overall population (median change 0.01 ml, -2.9%). Mild/moderate hypotension was reported in 3 patients and resolved with dose reduction or drug discontinuation. CONCLUSION: Clevidipine monotherapy was effective and safe for rapid BP reduction in this cohort of critically ill ICH patients. Overall, patients showed minimal hematoma expansion with BP reduction, suggesting that rapid BP control with clevidipine may have a beneficial impact on hematoma expansion and warrants further investigation.

Obesity-inducing diet promotes acylation stimulating protein resistance.

Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system that is involved in energy homeostasis and inflammation. ASP acts on and correlates positively with postprandial fat clearance in healthy subjects. However, in obesity, ASP levels are elevated and correlate inversely with fat clearance, indicative of a potential resistance to ASP. Using a mouse model, we hypothesized that, over time, diet-induced obesity (DIO) would result in development of ASP insensitivity, as compared to chow-fed animals as controls. Injection of recombinant ASP in DIO mice failed to accelerate fat clearance to the same extent as in chow-fed mice. DIO mice exhibited higher basal levels of plasma ASP and, after 30weeks of diet, showed lower ASP receptor (C5L2) expression in adipose tissue compared to chow-fed mice. Additionally, ex vivo ASP stimulation failed to induce normal Ser(473)AKT phosphorylation in adipose tissue from DIO mice VS chow-fed controls. These results demonstrate for the first time a state of diet-induced ASP resistance. Changes in the ASP-C5L2 pathway dynamics in obesity could alter the development of obesity and co-morbidities such as atherosclerosis and type 2 diabetes.

Paradoxical glucose-sensitizing yet proinflammatory effects of acute ASP administration in mice.

Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which stimulates fat storage and is typically increased in obesity, type 2 diabetes, and cardiovascular disease. Using a diet-induced obesity (DIO) mouse model, the acute effects of ASP on energy metabolism and inflammatory processes in vivo were evaluated. We hypothesized that ASP would specifically exert proinflammatory effects. C57Bl/6 wild-type mice were put on a high-fat-high-sucrose diet for 12 weeks. Mice were then subjected to both glucose and insulin tolerance tests, each manipulation being preceded by recombinant ASP or vehicle (control) bolus injection. ASP supplementation increased whole-body glucose excursion, and this was accomplished with reduced concomitant insulin levels. However, ASP did not directly alter insulin sensitivity. ASP supplementation induced a proinflammatory phenotype, with higher levels of cytokines including IL-6 and TNF-α in plasma and in adipose tissue, liver, and skeletal muscle mRNA. Additionally, ASP increased M1 macrophage content of these tissues. ASP exerted a direct concentration-dependent role in the migration and M1 activation of cultured macrophages. Altogether, the in vivo and in vitro experiments demonstrate that ASP plays a role in both energy metabolism and inflammation, with paradoxical whole-body glucose-sensitizing yet proinflammatory effects.