Endoscopic injection of botulinum toxin in the gastric antrum for the treatment of obesity. Results of a pilot study

OBJECTIVES: The aim of this study was to observe the effects of endoscopic injections of botulinum toxin (BT) in the gastric antrum on body weight and gastric emptying in obese patients. PATIENTS AND METHODS: Obese patients were selected for the study. By endoscopy, 100 U of BT type A was injected into the prepyloric antral gastric wall. Before and after treatment body weight and solid gastric emptying were evaluated. RESULTS: Twelve patients were included into this study. Four and twelve weeks after the treatment median values of body weight and gastric emptying did not show significant changes compared to baseline values: body weight: (- 0.5 kg and - 1.0 kg respectively, P > 0.05) and gastric retention for solids at 90 min (+ 4.5% and +10.5% respectively, P > 0.05). Abnormal gastric emptying (solid gastric retention at 90 min > 50%) was observed in 22% of patients after 4 weeks and in 25% after 12 weeks. CONCLUSIONS: BT injected into the gastric antrum does not seem to significantly reduce body weight or delay gastric emptying in obese patients.     

Melatonin restores endothelium-dependent relaxation in aortic rings of pancreatectomized rats

In rats turned hyperglycemic by a subtotal pancreatectomy, a decreased relaxation response of aortic rings to acetylcholine (ACh) was found; this effect was amplified by preincubation in a high glucose medium (44 mmol/L). The relaxation response to ACh did not occur in endothelium-denuded rings or after the aortic rings were exposed to l-nitro-arginine methyl ester [L-NAME, a nitric oxide (NO) synthase inhibitor]. Incubation with the NO donor sodium nitroprusside (SNP) restored the impaired relaxation response seen in endothelium-denuded or L-NAME-treated aortic rings. Pancreatectomy decreased the vasorelaxation of aortic rings caused by SNP. Only in pancreatectomized rats, incubation in a high glucose medium impaired the relaxation effect of SNP. To assess whether melatonin preincubation reversed the impaired relaxation response to ACh (intact endothelium aortic rings) or to SNP (endothelium-denuded or L-NAME-treated rings) in hyperglycemic rats, cumulative dose-response curves were performed in the presence of 10(-5) mol/L melatonin. Melatonin preincubation did not modify ACh-induced relaxation of aortic rings in a normal glucose concentration but was highly effective in preventing the impairment of relaxation caused by a high glucose solution. Melatonin was also effective in restoring the impaired SNP-induced vasorelaxation seen in endothelium-denuded or L-NAME-treated aortic rings from hyperglycemic rats. The results further support the improvement by melatonin of the endothelial-mediated relaxation in blood vessels of diabetic rats.     

Cortitrol supplementation reduces serum cortisol responses to physical stress

The supplement Cortitrol was formulated to mitigate the cortisol response to physiological and psychological stress. Therefore, the purpose of this study was to examine the effects of Cortitrol on serum cortisol concentrations before, during, and after a high-intensity resistance exercise protocol (EX) and a resting control day (REST). We used a matched, balanced, randomized, double-blind, placebo-controlled, cross-over design. Blood samples were obtained at matching time points during EX and REST. Cortitrol significantly ( P < .05) reduced cortisol area under the curve concentrations during REST. During EX, Cortitrol reduced cortisol concentrations at 20, 10, and 0 minutes pre-exercise, at mid-exercise, immediately post-exercise, and at 5 minutes post-exercise. In addition, serum cortisol and plasma adrenocorticotropin hormone area under the curve concentrations during EX were significantly lower after Cortitrol than placebo. Furthermore, Cortitrol significantly reduced free radical production. This was indicated by significantly lower plasma malondialdehyde concentrations at the 65-minute post-exercise time point during REST, and at pre-exercise, immediate post-exercise, and 65 minutes post-exercise during EX. Serum total testosterone, free testosterone, dehydroepiandrosterone, and growth hormone showed exercise-induced increases but no treatment effects. These data demonstrate that Cortitrol was effective in modulating the physiological stress responses of exercise from the anticipatory rises before physical stress and into early recovery by reducing cortisol and associated free radical production.     

Posaconazole treatment of refractory eumycetoma and chromoblastomycosis

Eumycetoma and chromoblastomycosis are chronic, disfiguring fungal infections of the subcutaneous tissue that rarely resolve spontaneously. Most patients do not achieve sustained long-term benefits from available treatments; therefore, new therapeutic options are needed. We evaluated the efficacy of posaconazole, a new extended-spectrum triazole antifungal agent, in 12 patients with eumycetoma or chromoblastomycosis refractory to existing antifungal therapies. Posaconazole 800 mg/d was given in divided doses for a maximum of 34 months. Complete or partial clinical response was considered a success; stable disease or failure was considered a nonsuccess. All 12 patients had proven infections refractory to standard therapy. Clinical success was reported for five of six patients with eumycetoma and five of six patients with chromoblastomycosis. Two patients were reported to have stable disease. As part of a treatment-use extension protocol, two patients with eumycetoma who initially had successful outcome were successfully retreated with posaconazole after a treatment hiatus of > 10 months. Posaconazole was well tolerated during long-term administration (up to 1015 d). Posaconazole therapy resulted in successful outcome in most patients with eumycetoma or chromoblastomycosis refractory to standard therapies, suggesting that posaconazole may be an important treatment option for these diseases.     

The kappa-opioid receptor is involved in the stimulating effect of nicotine on adrenocortical activity but not in nicotine induced anxiety

The kappa (kappa) opioid system appears to interact with nicotine in the modulation of locomotion and addiction related processes. In this study we have investigated the possible implication of the kappa-opioid system in the effects of nicotine on anxiety and adrenocortical activity. In two different experiments, we analysed the possible interaction between nicotine (0.5 mg/kg i.p.) and either the kappa-opioid receptor antagonist nor-binaltorphimine (5 mg/kg i.p.) or the kappa-opioid receptor agonist U50,488H (1 mg/kg s.c.). Behavioural and endocrine experiments were performed in different groups of animals. Animals were exposed to the holeboard immediately followed by the plus-maze. Serum corticosterone levels were determined by radioimmunoassay. Nicotine induced an anxiogenic-like effect in the plus-maze and a significant decrease of holeboard activity. The anxiogenic-like effect in the plus-maze was not modified by any of the kappa-opioid receptor ligands. Nicotine also induced a significant increase in the corticosterone levels, and the kappa antagonist, which did not exert any effect per se, antagonised this effect. The kappa-agonist U50,488H induced a significant increase in corticosterone concentration when administered alone. We provide the first evidence for the involvement of the kappa-opioid receptor in the stimulatory effect of nicotine on adrenocortical activity.     

Sleep homeostasis in rats assessed by a long-term intermittent paradoxical sleep deprivation protocol

Numerous studies have evaluated the sleep homeostasis of rats after short- or long-periods of sleep deprivation, but none has assessed the effects of prolonged sleep restriction on the rat's sleep pattern. The purpose of the present study, therefore, was to evaluate the sleep homeostasis of rats under a protocol of chronic sleep restriction. Male Wistar rats were implanted with electrodes for EEG and EMG recordings. Using the single platform method, the animals were submitted to 18 h of sleep restriction, beginning at 16:00 h (lights on at 07:00 h), followed by a 6 h sleep window (from 10:00 h to 16:00 h) for 21 days. Immediately after this period, rats were allowed to sleep freely for 4 days (recovery period). The sleep–wake cycle was recorded throughout the entire experiment and the results showed that during the 6 h sleep window there was an increase on the percentage of sleep time, reflected by augmented time in high amplitude slow wave sleep and in paradoxical sleep, when compared to baseline sleep, whereas bouts of awakening longer than 1.5 min were greatly reduced, with the animals exhibiting a monophasic-type sleep pattern. During the deprivation period, paradoxical sleep was abolished. High amplitude slow wave sleep was also greatly affected by the protocol. Nonetheless, one day of recovery was sufficient to restore the normal sleep pattern. These findings indicate that this protocol was capable to induce many changes in the rat's sleep patterns, suggesting that during the 6 h sleep window there is a sleep adaptive homeostatic process.     

Ischemic preconditioning ameliorates excitotoxicity by shifting glutamate/gamma-aminobutyric acid release and biosynthesis

Excitotoxicity is recognized to play a major role in cerebral ischemia-induced cell death. The main goal of the present study was to define whether our model of ischemic preconditioning (IPC) promotes a shift from excitatory to inhibitory neurotransmission during the test ischemia to diminish metabolic demand during the reperfusion phase. We also determined whether gamma-aminobutyric acid (GABA) played a role in IPC-induced neuroprotection. Ten minutes of cerebral ischemia was produced by tightening the carotid ligatures bilaterally following hypotension. Samples of microdialysis perfusate, representing extracellular fluid, were analyzed for amino acid content by HPLC. IPC promoted a robust release of GABA after lethal ischemia compared with control rats. We also observed that the activity of glutamate decarboxylase (the predominant pathway of GABA synthesis in the brain) was higher in the IPC group compared with control and ischemic groups. Because GABAA receptor up-regulation has been shown to occur following IPC, and GABAA receptor activation has been implicated in neuroprotection against ischemic insults, we tested the hypothesis that GABAA or GABAB receptor activation was neuroprotective during ischemia or early reperfusion by using an in vitro model (organotypic hippocampal slice culture). Administration of the GABAB agonist baclofen during test ischemia and for 1 hr of reperfusion provided significant neuroprotection. We concluded that increased GABA release in preconditioned animals after ischemia might be one of the factors responsible for IPC neuroprotection. Specific activation of GABAB receptor contributes significantly to neuroprotection against ischemia in organotypic hippocampal slices.     

Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31

OBJECTIVE: Autism is a neurodevelopmental disorder with childhood onset and a known major genetic component. A recent study identified a highly significant association between autism and a two-single-nucleotide-polymorphism haplotype in the SLC25A12 gene, with a homozygote genotype relative risk between 2.4 and 4.8. The authors' goal was to investigate this association with autism in Irish affected child-parent trios because replication in an independent sample is essential in the validation of such potentially important findings. METHOD: Markers rs2056202 and rs2292813 were genotyped in a total of 158 trios (442 individuals). The Transmission Disequilibrium Test was used to examine these markers for association with autism. RESULTS: In agreement with the recent study, the authors found significant association between autism and the C alleles of both rs2056202 and rs2292813 as well as the two-marker haplotype. CONCLUSIONS: These findings provide replication of the association between autism and SLC25A12.     

Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death?

Among the causes for sudden death in epilepsy, cardiac dysfunction has been an area of interest. Based on this, the aim of our study was to evaluate the heart rate (in vivo and in vitro) and ventricular pressure in vitro of rats with epilepsy induced by pilocarpine. Adult male Wistar rats (n=6) were given pilocarpine hydrochloride to induce status epilepticus. Control rats (n=6) received saline solution instead pilocarpine. Our results showed significant differences in the mean of heart rate in vivo between the groups. In contrast, we did not find differences during in vitro experiments. Our results suggest a central nervous system modulation on the heart, which could explain the sudden unexpected death in epilepsy.     

Antiepileptic effect of acylpolyaminetoxin JSTX-3 on rat hippocampal CA1 neurons in vitro

The Joro spider toxin (JSTX-3), derived from Nephila clavata, has been found to block glutamate excitatory activity. Epilepsy has been studied in vitro, mostly on rat hippocampus, through brain slices techniques. The aim of this study is to verify the effect of the JSTX-3 on the epileptiform activity induced by magnesium-free medium in rat CA1 hippocampal neurons. Experiments were performed on hippocampus slices of control and pilocarpine-treated Wistar rats, prepared and maintained in vitro. Epileptiform activity was induced through omission of magnesium from the artificial cerebrospinal fluid (0-Mg2+ ACSF) superfusate and iontophoretic application of N-methyl-D-aspartate (NMDA). Intracellular recordings were obtained from CA1 pyramidal neurons both of control and epileptic rats. Passive membrane properties were analyzed before and after perfusion with the 0-Mg2+ ACSF and the application of toxin JSTX-3. During the ictal-like activity, the toxin JSTX-3 was applied by pressure ejection, abolishing this activity. This effect was completely reversed during the washout period when the slices were formerly perfused with artificial cerebrospinal fluid (ACSF) and again with 0-Mg2+ ACSF. Our results suggest that the toxin JSTX-3 is a potent blocker of induced epileptiform activity.