Outcome of Microsurgical Revascularization in Patients with Moyamoya Disease: First Report from the Iranian Population.

AIM: To report the outcome of microsurgical revascularization in patients with Moyamoya Disease (MMD) in Southern Iran. MATERIAL AND METHODS: This cross-sectional study was conducted in Southern Iran during a 7-year period from 2009 to 2016. All the patients with Moyamoya Disease (confirmed with digital substraction angiography) who underwent microsurgical revascularization (extracranial-intracranial bypass or synangiosis) were included. All the patients were followed for at least 1 year and the outcome was measured using the Glasgow outcome scale (GOS) and modified Rankin scale (MRS). RESULTS: Overall we included 13 patients with 14 involved hemispheres undergoing direct and indirect revascularization. The mean age of the patients was 20.6±17.5 (ranging from 0.5 to 55) years and there were 5 (38.4%) males and 8 (61.6%) females. We did not have any unfavorable outcome defined as mortality and persistent vegetative state. We performed 12 (85.7%) superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and 2 (14.3%) encephalo-myo-synangiosis (EMS) procedures. The symptoms improved in 7 (53.8%) patients and remained as the preoperative course in 5 (38.5%) patients. Only 1 (7.7%) patient developed immediate postoperative vasospasm and brain swelling, and was managed successfully with decompressive craniectomy and subsequent cranioplasty (GOS=5, MRS=0). CONCLUSION: This is the first study to report the safety, efficacy and outcome of the direct (STA-MCA bypass) and indirect (EMS) revascularization in patients with MMD in the Iranian population. As the prevalence of MMD is low in Iranian population, the experience and technique remains in its infancy and further advancements in the field is required.

Effects of Human Erythropoietin on Functional Outcome of Patients with Traumatic Cervical Cord Injury; A Pilot Randomized Clinical Trial.

OBJECTIVE: To determine the effects of recombinant human erythropoietin (rhEPO) on functional outcome and disability of patients with traumatic cervical spinal cord injury (SCI). METHODS: This was a randomized, double blind, placebo controlled clinical trial being performed in Nemazee and Shahid Rajaei hospitals of Shiraz during a 3-year period from 2011 to 2014. A total number of 20 patients with acute traumatic cervical SCI less than 8 hours after injury were included. We excluded those with anatomic cord dissection, penetrating cord injury and significant concomitant injury. Patients were randomly assigned to receive rhEPO in 500IU/mL dosage immediately and 24-hour later (n=11) or placebo (n=9). All the patient received standard regimen of methylprednisolone. Neurological function was assessed on admission, 1, 6 and 12 months after the injury according to the American Spinal Cord Injury Association (ASIA). RESULTS: Overall we include a total number of 20 patients. The mean age of the patients was found to be 40.1±9.5 (ranging from 19 to 59) years. There were 18 (90.0%) men and 2 (10.0%) women among the patients. There was no significant difference between two study groups regarding the baseline characteristics. The baseline ASIA score was comparable between two study groups. The motor and sensory ASIA scores were comparable between two study groups after 1, 6 and 12 months follow-ups. We also found that there was no significant difference between two study groups regarding the motor and sensory outcome in complete cord injury and incomplete cord injury subgroups. CONCLUSION: Administration of rhEPO does not improve the functional outcome of patients with traumatic cervical SCI.

A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity.

BACKGROUND: Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight. METHODS AND RESULTS: C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46±2% and 60±2% greater body weight relative to regular chow diet-fed mice at 16 and 32 weeks, respectively (both P<0.0001), manifesting impaired glucose tolerance, insulin resistance, and cardiac ceramide accumulation by 16 weeks. One-week treatment with liraglutide (30 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase-dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-α-activated human endothelial cells in vitro. CONCLUSIONS: Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity.

GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.

OBJECTIVE: Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat type 2 diabetes, and transient GLP-1 administration improved cardiac function in humans after acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R activation before ischemic myocardial injury remain unclear. RESEARCH DESIGN AND METHODS: We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the GLP-1R agonist liraglutide. RESULTS: Male C57BL/6 mice were treated twice daily for 7 days with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. Liraglutide reduced cardiac rupture (12 of 60 versus 46 of 60; P = 0.0001) and infarct size (21 +/- 2% versus 29 +/- 3%, P = 0.02) and improved cardiac output (12.4 +/- 0.6 versus 9.7 +/- 0.6 ml/min; P = 0.002). Liraglutide also modulated the expression and activity of cardioprotective genes in the mouse heart, including Akt, GSK3beta, PPARbeta-delta, Nrf-2, and HO-1. The effects of liraglutide on survival were independent of weight loss. Moreover, liraglutide conferred cardioprotection and survival advantages over metformin, despite equivalent glycemic control, in diabetic mice with experimental MI. The cardioprotective effects of liraglutide remained detectable 4 days after cessation of therapy and may be partly direct, because liraglutide increased cyclic AMP formation and reduced the extent of caspase-3 activation in cardiomyocytes in a GLP-1R-dependent manner in vitro. CONCLUSIONS: These findings demonstrate that GLP-1R activation engages prosurvival pathways in the normal and diabetic mouse heart, leading to improved outcomes and enhanced survival after MI in vivo.

Phase 2 protein inducers in the diet promote healthier aging.

Oxidative stress drives many aging-associated problems. Because oxidative stress can be decreased by induction of phase 2 proteins, we hypothesized that incorporating the phase 2 protein inducer 2(3)-tert-butyl-4-hydroxyanisole (tBHA) into the diet would result in healthier aging. C57BL/6 mice were placed either on control mouse chow diet or on chow containing tBHA and were examined at 6, 12, and 18 months. Dietary tBHA resulted in the antioxidant response activation, decreased both oxidative stress and pro-inflammatory gene expression in tissues examined, counteracted the decrease in the transcription factors peroxisome proliferator-activated receptor-gamma and increase in CCAAT/enhancer binding protein-alpha levels seen in liver with aging, and was associated with mice having less weight gain, despite having no differences in food consumption, and better locomotor function. We conclude that simple changes in the diet such as incorporation of phase 2 protein inducers can have a profound influence on health and, thereby, the aging process.

Dietary approaches to positively influence fetal determinants of adult health.

An imbalance between production and scavenging of oxidants is a commonality found in factors that result in fetal determinants that negatively affect adult health. We reasoned that a dietary intervention that promotes oxidant scavenging through phase 2 protein induction would have positive effects on fetal programming of adult health. Previously, we demonstrated that a diet containing broccoli sprouts high in glucoraphanin (Grn), precursor of the phase 2 protein inducer sulforaphane, decreased oxidative stress and associated problems in male spontaneously hypertensive stroke-prone rats (SHRsp). We hypothesized that placing females on a Grn-containing (Grn+) diet would have similar positive effects and that the adult offspring of such females would have lower blood pressures and less tissue inflammation than offspring from mothers on control diet. We demonstrate that female SHRsp on a Grn+ diet had decreased oxidative stress and associated problems such as hypertension than females on control diet. The offspring of females on Grn+ diet also had lower blood pressures and less tissue inflammation in adulthood regardless of diet, with offspring placed on a Grn+ diet having the best health outcomes. We conclude that reducing oxidative stress in pregnant females has profound outcomes in the health of their adult offspring.

Constitutive nuclear localization of activated caspase 3 in subpopulations of the astroglial family of cells.

In a study examining for apoptosis in spontaneously hypertensive rats (SHR), we observed the constitutive presence of activated caspase 3 in Bergmann glia. We then examined stroke-prone SHR as well as the normotensive strains Wistar, Wistar Kyoto, and Sprague-Dawley. In all these strains, we found that Bergmann glia expressed activated caspase 3 in nuclei. Furthermore, subpopulations of astrocytes in the granular layer of the cerebellar cortex, in the hippocampus, and spinal cord gray matter, particularly in the dorsal part of the dorsal horns, expressed nuclear activated caspase 3. This distribution corresponds to the distribution of astrocytes that express the glutamate transporter GLAST. We conclude that Bergmann glia and a subpopulation of astrocytes throughout the CNS express activated caspase 3 in nuclei to fulfill a yet-to-be defined non-apoptotic function. GLIA.