Antidepressants activate CaMKII in neuron cell body by Thr286 phosphorylation

CaM kinase II, a regulator of synaptic plasticity, is implicated in pathophysiology and pharmacology of psychiatric disorders. Chronic treatment with antidepressants desipramine and reboxetine up-regulated CaM kinase II in neuronal cell bodies of hippocampus. mRNA/protein expression for alphaCaM kinase II was unchanged, whereas Thr phosphorylation was increased in pyramidal/granular cell bodies, suggesting that increased phosphorylation is responsible for kinase activation. Short-term treatment of neuronal cultures with reboxetine reduced kinase activation in a concentration-dependent manner. The short-term inhibitory effect of reboxetine suggests that kinase up-regulation during antidepressant drug treatment is an adaptive response compensating for initial functional down-regulation.     

Primary prevention of epilepsy in patients with different epileptogenic conditions

Epileptic seizures are a common complication of several clinical conditions affecting the CNS. In these cases, the occurrence of seizures and epilepsy may increase the functional damage provoked by the underlying epileptogenic condition and affect the patient's quality of life to a significant extent. Therefore, the search of effective means for primary prevention of seizures and epilepsy is necessary in these cases. However, the use of antiepileptic drugs for the primary prevention of seizures and epilepsy can be considered only if the ratio between efficacy, safety and tolerability of treatment is favorable, in that the advantages, in terms of seizure prevention, outweigh the disadvantages in terms of adverse effects and overall costs of treatment. In this article, the efficacy, safety and tolerability of antiepileptic drugs for the primary prevention of seizures and epilepsy are reviewed. The areas covered include: the definition of early (provoked) and late (unprovoked) seizures; knowledge of the overall risk of seizures and epilepsy in CNS disorders for which primary prevention of seizures can be attempted; rationale for the use of antiepileptic drugs for the primary prevention of epilepsy; experimental data on the antiepileptogenic properties of antiepileptic drugs; available literature findings on the prevention of early and late seizures, with specific emphasis on randomized clinical trials; and the main problems with experimental trials for the primary prevention of epileptic seizures. On this basis, practice recommendations for the primary prevention of epilepsy will be offered where indicated. Suggestions for future research are also made as concluding remarks, by indicating the areas of investigation and the design of future studies.     

Morbidity in patients with epilepsy: type and complications: a European cohort study

PURPOSE: To investigate the risk of illnesses in a cohort of patients with epilepsy and in matched nonepilepsy controls, by type and complications. METHODS: A total of 951 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 904 matched controls seen in secondary and tertiary centers in eight European countries (England, Estonia, Germany, Italy, the Netherlands, Portugal, Russia, Slovenia) were followed prospectively for 17,484 and 17,206 person-months and asked to report any spontaneous complaint requiring medical attention (illness), its type and complications (hospitalization, absence from work or school, medical action). Risk assessment was done by actuarial methods, relative risks (RR), and 95% confidence intervals (CIs). RESULTS: During the study period 644 patients (68%) and 504 controls (56%) reported an illness (p < 0.0001); 30% were seizure related. The cumulative probability of illness at 12 and 24 months was 49 and 86% in the cases and 39 and 75% in the controls (p < 0.0001). The largest differences regarded disorders affecting the nervous system (NS) (RR, 3.3; 95% CI, 2.3-4.2) and ear, nose, and throat (ENT) (RR, 1.3; 95% CI, 1.0-1.6). In patients with epilepsy, an NS illness was more likely to be followed by hospital admission, work absence, or medical intervention. All risks were significantly reduced after excluding seizure-related events. CONCLUSIONS: Patients with epilepsy are at higher risk of NS and ENT illnesses and complications than the general population. However, the risk of illness is significantly reduced when seizure-related events are excluded.     

Localization of language function in children: results of electrical stimulation mapping

OBJECT: The authors examined the localization of language sites and the frequency of naming errors at these sites in a population of children undergoing electrical stimulation mapping during surgeries in which epileptic foci and dominant hemisphere neoplasms were resected. The frequency with which essential language sites were found (that is, "the frequency of language sites") in children was compared with that of a population of adults who had undergone this procedure, to assess the relationship of age to the distribution of essential areas for language. METHODS: The results of electrical stimulation mapping to determine sites of naming and speech arrest in 26 children ranging in ages from 4 to 16 years are presented in this report. Mapping was performed in the intraoperative setting in eight patients and in the extraoperative setting, by stimulation across a subdural grid, in 18 patients. The frequency and distribution of essential language areas were analyzed in populations of different ages and according to the method used to obtain the map. Considerable variability was found in the localization of language sites. When the language site distribution in pediatric patients was compared with the language site distribution found previously in a population of patients older than 16 years of age, a relative paucity of language sites was found in all perisylvian cortices in the younger age group. This relationship was also found within the group of patients 16 years of age and younger, when segregated into two groups: those patients 8 years of age or younger, and those patients between 9 and 16 years of age. These findings are relevant to theories of the intrahemispheric organization of the cortex devoted to language function. CONCLUSIONS: The differences found between groups of younger and older patients in the frequencies of sites where stimulation produces naming errors was identified suggests the possibility that, with advancing age, maturational processes contribute new foci of cortex essential for language.     

Surgical treatment of complicated sigmoid diverticulitis: our experience

Traditionally, surgical sigmoid diverticular emergencies used to be treated in stages, but more recently there has been a trend towards definitive surgery with immediate resection plus anastomosis under certain conditions. The aim of this study was to define the morbidity and mortality of resection plus anastomosis with on-table antegrade irrigation and of the Hartmann procedure for complicated sigmoid diverticulitis in relation to the type of peritonitis and to the American Society of Anesthesiologists (ASA) grade of the patients. From April 1999 to April 2002, 38 emergency operations for complicated sigmoid diverticulitis were performed at the San Sebastiano Hospital in Caserta. Six patients underwent operations for obstructions and 32 for perforation (19 Hinchley stage III and 13 Hinchley stage IV). Surgical therapy for obstruction consisted in 4 resections plus anastomosis, 1 subtotal colectomy and 1 Hartmann procedure. Surgical therapy for perforation consisted in 14 resections plus anastomosis and 18 Hartmann procedures. There was 1 case (5%) of anastomotic dehiscence out of 19 primary anastomoses versus 2/19 surgical complications (10%) after the Hartmann procedure. The mortality amounted to 1 death out of 38 (2.6%) in a patient treated with the Hartmann procedure. Left-sided colonic obstruction should be treated by resection plus anastomosis or by subtotal colectomy for ASA II-III patients and by Hartmann's procedure for ASA IV-V patients. ASA II-III patients with localised or generalised non-faecal peritonitis should be treated by resection plus anastomosis, while a Hartmann procedure should be the reasonable option for generalised faecal peritonitis and for ASA IV-V patients with localised or generalised non-faecal peritonitis.     

Downregulation of bcl-2 expression in lymphoma cells by bcl-2 ARE-targeted modified,synthetic ribozyme

Synthetic ribozymes are catalytic RNA molecules designed to inhibit gene expression by cleaving specific mRNA sequences. We investigated the potential of synthetic ribozymes to inhibit bcl-2 expression in apoptosis defective bcl-2 overexpressing tumors. A chemically stabilized hammerhead ribozyme has been targeted to the A+U-rich regulative element of bcl-2 mRNA that is involved in bcl-2 gene switch-off during apoptosis. The design of the ribozyme was based on the results of probing accessibility of the RNA target in cellular extracts with antisense DNA. The ribozyme was lipotransfected to a bcl-2 overexpressing human lymphoma cell line (Raji). The cellular uptake of this ribozyme resulted in a marked reduction of both bcl-2 mRNA and BCL-2 protein levels and dramatically increased cellular death by apoptosis. Our results suggest a potential therapeutic application of such ribozyme for the treatment of bcl-2 overexpressing tumors.     

Does pizza protect against cancer?

We analyzed the potential role of pizza on cancer risk, using data from an integrated network of case-control studies conducted in Italy between 1991 and 2000. Cancer sites were: oral cavity and pharynx (598 cases), esophagus (304 cases), larynx (460 cases), colon (1,225 cases) and rectum (728 cases). Controls were 4,999 patients admitted for acute, non-neoplastic conditions to the same hospital network as cases. Odds ratios for regular pizza consumers were 0.66 (95% confidence interval, CI = 0.47-0.93) for oral and pharyngeal cancer, 0.41 (95% CI = 0.25-0.69) for oesophageal, 0.82 (95% CI = 0.56-1.19) for laryngeal, 0.74 (95% CI = 0.61-0.89) for colon and 0.93 (95% CI = 0.75-1.17) for rectal cancer. Pizza appears therefore to be a favorable indicator of risk for digestive tract neoplasms in this population.     

Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors

In rats subjected to myocardial ischemia/reperfusion, melanocortin peptides, including gamma(1)-melanocyte-stimulating hormone (gamma(1)-MSH), are able to exert a protective effect by stimulating brain melanocortin MC(3) receptors. A non-melanocortin receptor belonging to a group of receptors for Phe-Met-Arg-Phe-NH(2) (FMRFamide)-like peptides may be involved in some of the cardiovascular effects of the gamma-MSHs. FMRFamide-like peptides and gamma(1)-/gamma(2)-MSH share, among other things, the C-terminal Arg-Phe sequence, which seems to be essential for cardiovascular effects in normal animals. So we aimed to further investigate which receptor and which structure are involved in the protective effects of melanocortins in anesthetized rats subjected to myocardial ischemia by ligature of the left anterior descending coronary artery (5 min), followed by reperfusion. In saline-treated rats, reperfusion induced, within a few seconds, a high incidence of ventricular tachycardia and ventricular fibrillation, and a high percentage of death within the 5 min of observation period. Reperfusion was associated with a massive increase in free radical blood levels and with an abrupt and marked fall in systemic arterial pressure. The i.v. treatment (162 nmol/kg) during the ischemic period with the adrenocorticotropin fragment 1-24 [ACTH-(1-24): the reference protective melanocortin which binds all melanocortin receptors], as well as with both the melanocortin MC(3) receptor agonists gamma(2)-MSH and [D-Trp(8)]gamma(2)-MSH, reduced the incidence of ventricular tachycardia, ventricular fibrillation and death, the increase in free radical blood levels and the fall in arterial pressure. On the contrary, gamma(2)-MSH-(6-12) (a fragment unable to bind melanocortin receptors) was ineffective. Such protective effect was prevented by the melanocortin MC(3)/MC(4) receptor antagonist SHU 9119. In normal (i.e., not subjected to myocardial ischemia/reperfusion) rats, the same i.v. dose (162 nmol/kg) of gamma(2)-MSH, [D-Trp(8)]gamma(2)-MSH and gamma(2)-MSH-(6-12) provoked a prompt and transient increase in arterial pressure; on the other hand, ACTH-(1-24), which lacks the C-terminal Arg-Phe sequence, decreased arterial pressure, but only at higher doses. Heart rate of normal rats was not affected by any of the assayed peptides. The present data confirm and extend our previous findings that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC(3) receptors. Moreover, they further support the notion that, in normal rats, cardiovascular effects of gamma-MSHs are mediated by receptors for FMRFamide-like peptides, for whose activation, but not for that of melanocortin MC(3) receptors, the C-terminal Arg-Phe structure being relevant.