Hyperglycemia is a predictor of prognosis in traumatic brain injury: Tertiary intensive care unit study.

BACKGROUND: Hyperglycemia is frequently encountered in critically ill patients and has been shown to contribute to both morbidity and mortality. We aimed to study the predictive role of blood glucose level in clinical outcomes of mechanically ventilated patients with traumatic brain injury during intensive care unit (ICU) stay and to explore its relationship with Glasgow coma scale (GCS) and acute physiology and chronic health examination (APACHE) II scores that are used in the evaluation of ICU patients as predictor. MATERIALS AND METHODS: A total of 185 patients with craniocerebral trauma who were hospitalized in the ICU were included in the study. Comparisons of mean glucose values (MGVs) and APACHE II scores between survivors and nonsurvivors were made with Student's t-test and chi-square test. Survival analysis was performed with log rank (Mantel-Cox) test and Cox regression was used for mortality risk factors analysis. RESULTS: MGVs at the initial, last, and all measurements were significantly higher for nonsurvivors than for survivors. Hazard rate at any given time point for patients with mean glucose value (MGV) between 150 and 179 was found to be 3.691 times that of patients with MGV values between 110 and 149. The hazard rate at any given time point for patients with MGV values ≥180 was found to be 6.571 times that of patients with MGV values between 110 and 149. CONCLUSION: High glucose level is an independent risk factor for mortality in mechanically ventilated ICU patients with traumatic brain injury.

Increased noradrenaline levels in the rostral pons can be reversed by M1 antagonist in a rat model of post-traumatic stress disorder.

The dysregulation of hypothalamic-pituitary-adrenal axis and noradrenergic, serotonergic and glutamatergic systems are thought to be involved in the pathophysiology of post-traumatic stress disorder. The effect of selective M1 muscarinic receptor antagonist, pirenzepine on anxiety indices was investigated by using elevated plus maze, following exposure to trauma reminder. Upon receiving the approval of ethics committee, Sprague-Dawley rats were exposed to dirty cat litter (trauma) for 10 min and 1 week later, the rats confronted to a trauma reminder (clean litter). The rats also received intraperitoneal pirenzepine (1 or 2 mg/kg/day) or saline for 8 days. Noradrenaline (NA) concentration in the rostral pons was analyzed by HPLC with electrochemical detection. The anxiety indices of the rats subjected to the trauma reminder were increased when compared to control rats (p < 0.05). Pirenzepine treatment in traumatized rats displayed similar anxiety indices of non-traumatized rats treated with physiological saline. Although freezing time was prolonged with pirenzepine in traumatized groups the change was not found statistically significant. The NA level was 1.5 ± 0.1 pg/mg in non-traumatized rats and increased to 2.4 ± 0.2 pg/mg in traumatized rats. Bonferroni post hoc test revealed that the NA content of the rostral pons of the traumatized rats treated with physiological saline was significantly higher than the content of other groups (p < 0.01). We conclude that NA content in the rostral pons increases in respect to confrontation to a trauma reminder which can be reversed by M1 antagonist pirenzepine indicating the roles of M1 receptors.

Effects of agmatine on the survival rate in rats bled to hemorrhage.

Agmatine (CAS 2482-00-0), an amine formed by decarboxylation of L-arginine, interacts with several targets like alpha2-adrenergic, imidazoline and N-methyl-D-aspartic acid (NMDA) receptors and besides it is involved in the nitric oxide mediated effects. It has also been proposed that it possesses vasodilator effects and increases glomerular filtration rate in rats. The aim of this study was to supply evidence for the effects of agmatine in a rat model of hemorrhagic shock and explain the possible mechanisms of action. The iliac arteries and veins of Sprague-Dawley rats were catheterized under urethane anesthesia and around 2 ml/100 g blood was withdrawn within 20 min until the mean arterial blood pressure was stabilized around 25 mmHg. The rats were either pretreated with physiological saline, yohimbine (an alpha2-adrenergic receptor antagonist) or L-arginine (a nitric oxide donor) intravenously before administration of agmatine (300 microg/kg). Agmatine restored blood pressure in rats pretreated with physiological saline where all rats survived. Pretreatment with L-arginine abolished the increase in blood pressure produced by agmatine and the 1 h survival rate decreased to 67% (p < 0.01). Yohimbine pretreatment also suppressed agmatine induced restoration of blood pressure; however, the survival rate was found to be 17% for 3 min. No statistically significant effect was observed in the heart rate responses. These results may suggest that agmatine may increase survival through alpha2-adrenergic receptors and restores blood pressure through nitric oxide and adrenergic mechanisms in rats bled to hemorrhage.

Escitalopram increases cortical nitric oxide synthase (NOS) in rat brain during ethanol withdrawal.

The effect of escitalopram on ethanol withdrawal syndrome (EWS) and involvement of nitric oxide system in rats was investigated. Male Wistar rats divided into five experimental groups of eight animals each: (a) control group; (b) EWS (saline) group; (c) escitalopram 2.5 mg group; (d) escitalopram 5mg group and (e) escitalopram 10 mg group. Ethanol dependence was induced in rats by ethanol-containing liquid diet and ethanol withdrawal was precipitated by replacing ethanol free diet. Ethanol receiving rats in individual groups were decapitated on 21st day of ethanol ingestion and at sixth hour of ethanol withdrawal. Brains were removed and dissected. Five regions of the brain were dissected: the frontal cortex, cerebellum, striatum, hippocampus and hypothalamus. Immunohistochemical NOS staining was performed. The NOS staining intensity in cortex and hypothalamus regions were significantly lower in EWS group than control group. During EWS period, in rats given 2.5 and 10 mg/kg escitalopram, the staining intensity in cortex, striatum and hippocampus were found to be 11.492, 8.519 and 11.234, respectively, and was statistically different than the control group. The hippocampal NOS staining intensity was found to be significantly decreased with 2.5 mg/kg escitalopram, whereas the cortex, striatum and hippocampal staining intensity were increased significantly with 5 mg/kg. In 10 mg/kg escitalopram group, staining properties were not different than those of the control group. Our results suggest that NOS decreases during ethanol withdrawal in cortex and hypothalamus of rat brain and treatment with escitalopram reverses the enzyme density in cortex but not hypothalamus.

Extracellular hypothalamic gamma-aminobutyric acid (GABA) and L-glutamic acid concentrations in response to bicuculline in a genetic absence epilepsy rat model.

The posterior part of the hypothalamus plays a vital role in the homeostatic processes of the internal environment, including blood pressure and heart rate regulation, by means of gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission. In this study we measured the extracellular levels of GABA and L-glutamic acid in the dorsomedial hypothalamic nucleus (DMH) and posterior hypothalamus (PH), following intracerebroventricular (i.c.v.) administration of bicuculline, a GABA(A)-receptor antagonist, in genetic absence epileptic rats from Strasbourg (GAERS), where heart rate, blood pressure, and EEG recordings were also collected simultaneously. The i.c.v. injection of bicuculline (0.3 nmol) produced no response in non-epileptic Wistar rats but caused an increase in mean arterial pressure in GAERS (P<0.01). Microdialysis experiments showed that L-glutamic acid increased in the DMH in GAERS after bicuculline administration (P<0.01). Additionally, extracellular GABA concentration decreased in the PH (P<0.05). Bicuculline suppressed the spike-and-wave discharges, the characteristic sign of absence seizures. All these results suggest that the bicuculline-induced blood pressure response is accompanied by changes in L-glutamic acid levels in the DMH and GABA levels in the PH, indicating a bicuculline hypersensitivity in the DMH and PH of GAERS that may make the GAERS display an altered mode of central cardiovascular regulation. These results suggest that the circuits affected in GAERS are not only restricted to the regions responsible for seizure generation but also present in the hypothalamus.

Fluoxetine partly exerts its actions through GABA: a neurochemical evidence.

Fluoxetine, as a serotonin re-uptake inhibitor augments serotonin concentration within the synapse by inhibiting the serotonin transporter. The contribution of amino acids has also been shown in depression. We hypothesized that fluoxetine exerts its actions at least in part by intervening brain signaling operated by amino acid transmitters. Therefore the aim of this study is to supply neurochemical evidence that fluoxetine produces changes in amino acids in cerebrospinal fluid of rats. Sprague-Dawley rats were anesthetized and concentric microdialysis probes were implanted stereotaxically into the right lateral ventricle. Intraperitoneal fluoxetine (2.5 or 5 mg/kg) or physiological saline was administered and the probes were perfused with artificial cerebrospinal fluid at a rate of 1 mul/min. In the chronic fluoxetine group, the rats were treated daily with oral fluoxetine solution or inert syrup for 3 weeks. The microdialysis probes were placed on the 21st day and perfused the next day. Fluoxetine was ineffective in changing the cerebrospinal fluid GABA levels at the dose of 2.5 mg/kg but produced a significant increase in the perfusates following injection of 5 mg/kg of fluoxetine (P < 0.05). Oral fluoxetine administration (5 mg/kg) for 21 days also elevated the CSF GABA levels by approximately 2-fold (P < 0.05). L: -glutamic acid levels were not affected in all groups. These neurochemical findings show that fluoxetine, a selective serotonin re-uptake inhibitor affects brain GABA levels indirectly, and our results suggest that acute or chronic effects may be involved in beneficial and/or adverse effects of the drug.

The in vivo metabolism of 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine in rats.

The purpose of the study was to investigate the in vivo metabolic pathway of 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine (substrate) in rats. Firstly its potential metabolites, i.e. N-dealkylation, ring scission of pyridazine and aromatic hydroxylation products, were synthesized and then the substrate was given orally (100 mg/kg) to male or female Wistar rats at a dose of 100 mg/kg to body weight. Blood samples were collected at 0, 1, 2, 4, 6 and 8 hours after administration of substrate and blood was centrifuged to obtain serum. The substrate and its potential metabolites were separated using a gradient HPLC method on a reverse phase system. This study revealed that 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine was not metabolized to the proposed metabolites and was present unchanged in the serum.

The effects of ethosuximide on amino acids in genetic absence epilepsy rat model.

Genetic absence epilepsy rats from Strasbourg (GAERS), a selectively inbred strain of Wistar rats, has been validated as an experimental model for human absence epilepsy. In this model, systemic administration of ethosuximide (ETX) was shown to reduce the spike and wave discharges (SWD). In this study, gamma-aminobutyric acid (GABA) and L-glutamic acid levels in response to ETX injections (i.p., 100 mg/kg) were measured in the microdialysis samples collected from the ventrolateral thalamus (VLT) and the primary motor cortex (M1) area of Wistar rats and GAERS by using HPLC with fluorescent detection. Throughout the microdialysis procedure, continuous EEG recording was performed where ETX was shown to suppress the SWD activity. We demonstrated increased basal GABA levels in the M1 and VLT of GAERS, and ETX treatment did not produce any effect on higher GABA levels in the VLT, but suppressed the increased GABA levels significantly in the M1 of GAERS. All these findings denote the importance of corticothalamic circuitry and the role of increased GABA tonus in primary motor cortex and thalamus of GAERS. The primary motor cortex also seems to be involved in the SWD activity and ETX exerts, at least partially, its neurotransmitter effects through it.

5-hydroxytryptamine release in the anterior hypothalamic and the hippocampal areas of cholestatic rats.

Cholestasis contributes to the genesis of fatigue through several mechanisms. Among these mechanisms, affected serotonergic neurotransmission is important in the pathogenesis of central fatigue. Previously, elevated levels of 5-hydroxyindole acetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT) and increased 5-HT(2) receptor density were demonstrated in the anterior hypothalamus and in the hippocampus of bile duct resected rats (BDR), respectively. The aim of this paper is to demonstrate evoked 5-HT release in selected brain regions like anterior hypothalamus and hippocampal CA1 regions of cholestatic rats using BDR rats as an experimental model for cholestasis. In this study, we analyzed the K+ evoked 5-HT and its metabolite 5-HIAA levels by using HPLC with electrochemical detection in the microdialysis samples collected from anterior hypothalamic and hippocampal CA1 regions of sham-operated and BDR rats (n = 6). The ratios of [5-HIAA] to [5-HT] following perfusion with 100 mM K+ artificial cerebrospinal fluid was used for the comparison of the evoked release of 5-HT. Locomotor activity was used to assess the signs of cholestasis associated fatigue in the BDR rats. The vertical and horizontal activity counts within 15 min were found to be decreased in the BDR rats compared to sham-operated rats (p < 0.05). Besides, the number of fecal boli (an index of emotionality) was also significantly fewer in the cholestatic rats (p < 0.05). No significant difference between the sham-operated and the BDR rats was detected in the basal 5-HT and 5-HIAA levels of anterior hypothalamus. K+ stimulation yielded a more profound increase in the [5-HIAA]/[5-HT] in the BDR rats (p < 0.05). The basal levels of 5-HT in CA1 region of the BDR rats was found to be lower than that of sham-operated group (p < 0.05), but no significant difference was observed in terms of evoked 5-HT release in both sham-operated and BDR rats. These findings imply the presence of affected serotonergic system in cholestasis.

Prescription audit adjunct to rational pharmacotherapy education improves prescribing skills of medical students.

OBJECTIVE: To assess the impact of a rational pharmacotherapy (RP) teaching program during clinical pharmacology clerkship by analyzing the results of prescription audits (PAs) of the medical students. Collectively, we intended to observe the possible improvement of the students in their prescribing, problem solving and self-directed learning skills. DESIGN: At the beginning and end of the clerkship, the students were presented with cases of uncomplicated osteoarthritis to assess their prescribing skills; format and rationality were scored. SETTING: A medical school in Turkey that teaches RP to the fourth-year students in clinical pharmacology clerkship. PARTICIPANTS: There were 94 students of the 2002-2003 academic year in three groups and a single group of students belonging to the previous academic year tested. Of those students from the previous academic year, 26 were also analyzed a year later to demonstrate the long-term impact of the training. MAIN OUTCOME MEASURES: Prescribing skills of medical students and their opinions about PA. RESULTS: Direct assessment via PA demonstrated that the scores for post-clerkship prescriptions were far better than those for pre-clerkship prescriptions in terms of format and rationality. Long-term assessment showed that the scores declined within a year following clerkship, but they were still higher than those of their pre-clerkship scripts. Analysis of the questionnaires revealed that the students were satisfied with PA. The majority of the students stated they had learned the general principles of RP and gained better prescribing skills, and they intended to apply most of the principles learned to their future professional lives. The script format scores of a retrospectively created PA-exempted group were significantly lower than those of the students to whom an established PA education was given. CONCLUSION: PA sessions were shown to be an easy and a useful method of both evaluating and reinforcing prescribing skills gained though problem-based RP education.

Fatigue of cholestasis and the serotoninergic neurotransmitter system in the rat.

Fatigue associated with cholestasis may impair health-related quality of life. The pathogenesis of this symptom is largely unknown, but it has been suggested that central serotoninergic neurotransmission may be implicated and that serotonin 1A receptor agonists may yield improvement. The aim of this study was to study the central serotoninergic system, specifically the serotonin (5-HT)(1A) receptor-mediated pathway of serotoninergic neurotransmission, in a bile duct resection rat model of cholestasis. Fatigue was assessed in the forced swim test in sham and bile duct-resected rats. The serotonin behavioral syndrome, which includes hyperlocomotion, was assessed in both groups of rats after escalating doses of the 5-HT(1A) receptor agonist 8-hydroxy(di-n-propylamine)tetralin (8-OH DPAT). 5-HT(1A) and 5-HT(2) receptor densities were explored in four brain regions using a receptor-binding assay. Extracellular 5-HT and 5-hydroxyindoleacetic acid were measured via in vivo brain dialysis. Bile duct-resected rats spent more time floating in the forced swim test, and 8-OH DPAT decreased floating time in cholestatic rats (P < .01). Dose-response curves created with 8-OH DPAT for the serotonin behavioral syndrome were similar in bile duct-resected and sham-operated rats. 5-HT(1A) and 5-HT(2) receptor densities in most brain regions and extracellular serotonin levels were similar in both groups of rats. In conclusion, 5-HT(1A) receptor agonist-induced amelioration of fatigue in cholestatic rats may be nonspecific and not linked to reversal of the pathophysiology of fatigue associated with cholestasis; however, these data do not exclude a potential role of the central serotoninergic system in the evolution of fatigue.