Self-administration of cannabinoids by experimental animals and human marijuana smokers

Drug self-administration behavior has been one of the most direct and productive approaches for studying the reinforcing effects of psychoactive drugs, which are critical in determining their abuse potential. Cannabinoids, which are usually abused by humans in the form of marijuana, have become the most frequently abused illicit class of drugs in the United States. The early elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC) in 1964, which is now recognized as the principal psychoactive ingredient in marijuana, activated cannabinoid research worldwide. This review examines advances in research on cannabinoid self-administration behavior by humans and laboratory animals. There have been numerous laboratory demonstrations of the reinforcing effects of cannabinoids in human subjects, but reliable self-administration of cannabinoids by laboratory animals has only recently been demonstrated. It has now been shown that strong and persistent self-administration behavior can be maintained in experimentally and drug-na?ve squirrel monkeys by doses of THC comparable to those in marijuana smoke inhaled by humans. Furthermore, reinforcing effects of some synthetic CB1 cannabinoid agonists have been recently reported using intravenous and intracerebroventricular self-administration procedures in rats and mice. These findings support previous conclusions that THC has a pronounced abuse liability comparable to other drugs of abuse under certain experimental conditions. Self-administration of THC by squirrel monkeys provides the most reliable animal model for human marijuana abuse available to date. This animal model now makes it possible to study the relative abuse liability of other natural and synthetic cannabinoids and to preclinically assess new therapeutic strategies for the treatment or prevention of marijuana abuse in humans.     

The reduced tolerance of rat fatty liver to ischemia reperfusion is associated with mitochondrial oxidative injury

BACKGROUND: Oxidative stress contributes to the pathogenesis of hepatic ischemia-reperfusion injury. This study aimed to determine whether fatty degeneration affects the oxidative damage during warm ischemia reperfusion and whether mitochondria, the major intracellular site of energy synthesis, represent a preferential target of this injury. MATERIALS AND METHODS: Fed rats with control or fatty liver induced by choline deficiency underwent 60' lobar ischemia and reperfusion. Oxidative damage was assessed by measuring in whole liver tissue and in isolated mitochondria the thiobarbituric acid-reactive substances (TBARs), protein carbonyls (PC), and total and oxidized glutathione (GSH and GSSG) concentrations. The mitochondrial F0-F1-ATPase content and the oxidative phosphorylation activity were also determined. Rat survival and ALT release were assessed as parameters of liver injury. RESULTS: In the whole liver tissue, with the exception of TBARs, no differences were observed for GSH, GSSG, and PC between the two groups throughout all of the experiment. In contrast, in isolated mitochondria, fatty infiltration was associated with a mild oxidative imbalance already under basal conditions. The preischemic differences in the mitochondrial TBARs, PC, and GSSG levels were significantly amplified by reperfusion in the presence of steatosis. The enhanced oxidative damage was associated to a reduced F0-F1-ATPase content and oxidative phosphorylation activity in fatty liver mitochondria. Finally, serum ALT levels were significantly greater and survival significantly lower in rats with steatotic liver. CONCLUSIONS: Fatty infiltration exacerbates mitochondrial oxidative injury during warm ischemia reperfusion. The increased oxidative stress can alter mitochondrial functions, including key processes for ATP synthesis, thus, contributing to the reduced tolerance to reperfusion injury.     

Surgical treatment of lone atrial fibrillation in an awake patient

Surgical treatment of atrial fibrillation recently gained new popularity since the introduction of different energy sources and the development of minimally invasive techniques as an alternative to the original "cut-and-sew" technique. However, closed-chest ablation procedures are not feasible in presence of pericardial or pleural adhesions. To our knowledge, this is the first report of surgical treatment of atrial fibrillation in a conscious patient by means of a high epidural anesthesia. Since evidence of fibrothorax was found, a conscious patient suffering from lone atrial fibrillation underwent a beating-heart pulmonary veins isolation with a microwave device through a standard sternotomic approach. At 6 months follow-up, the patient is in stable sinus rhythm, without any palpitation nor electrocardiographic evidence (Holter monitoring) of recurrent atrial fibrillation.     

The need of a hybrid approach for the treatment of atrial fibrillation

Atrial fibrillation represents nowadays one of the most important burdens in the field of arrhythmia. Albeit often inadequate, medical treatment is still considered the "first-step" approach. Non-pharmacological strategies, either surgical or interventional, recently gained an increasing interest among both cardiac surgeons and electrophysiologists. From the surgical standpoint, the introduction of different energy sources and the development of minimally invasive techniques as an alternative to the original "cut-and-sew" technique allowed a new dawn in the surgical treatment of atrial fibrillation. In the meanwhile, electrophysiologists developed more complex ablation systems that allowed the creation of linear lesions, similar to the surgical ones, while mapping the atria with three-dimensional (3D) navigation systems. Nevertheless, the success rate in terms of sinus rhythm restoration was around 80%-85% in both fields. We foresee that the combination of the two approaches (i.e., surgical and percutaneous approach), in common hybrid approach, will allow a substantial reform for the definitive cure of atrial fibrillation, either paroxysmal or permanent, providing the highest success rates along with the best care for patients' health.     

Ten years of laparoscopic adrenalectomy: lesson learned from 104 procedures

The purpose of this study was to evaluate the short- and long-term results of 104 consecutive laparoscopic adrenalectomies performed during a period of 10 years in two specialist centers. One hundred four patients underwent laparoscopic adrenalectomy in two specialist centers in Italy between 1994 and 2003. Indications to laparoscopic adrenalectomy were aldosterone-secreting adenoma (20%), pheochromocytoma (24%), cortisol-secreting adenoma (11.5%), incidentaloma (26.9%), multiple endocrine neoplasia (MEN) type 2A (2.8%), adrenal metastases from lung cancer (3.8%), adrenal cyst (6.7%), and angiomyolipoma (3.8%). Transperitoneal anterior and lateral approaches were adopted in 17 and 84 patients, respectively. Retroperitoneal approach was adopted in three patients. Mean operative time was 108 +/- 39.1 minutes (range, 40-300 minutes). There was no correlation between adrenal tumor diameter and operative time. Mean intraoperative blood loss was 106 mL (range, 40-600 mL). Intraoperative complication rate and conversion rate were 4.8 per cent (5 cases). Laparoscopic adrenalectomy is a safe procedure. After a relatively short learning curve, it can be performed successfully by any surgeon with low operative morbidity and mortality. The size of the adrenal tumor should not be considered a contraindication to this procedure.     

Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases

Bloodstream infection (BSI) due to Proteus mirabilis strains is a relatively uncommon clinical entity, and its significance has received little attention. This study was initiated to evaluate risk factors and treatment outcome of BSI episodes due to P. mirabilis producing extended-spectrum beta-lactamases (ESBLs). Twenty-five BSI episodes caused by P. mirabilis occurred at our hospital (Ospedale di Circolo e Fondazione Macchi, Varese, Italy) over a 7.5-year period. Phenotypic and molecular methods were used to assess ESBL production. Clinical records of BSI patients were examined retrospectively. Demographic data, underlying diseases (according to McCabe and Jackson classification and Charlson weighted index), risk factors, and treatment outcome were investigated by comparing cases due to ESBL-positive strains to cases due to ESBL-negative strains. Eleven isolates were found to express ESBLs (TEM-52 or TEM-92). The remaining 14 isolates were ESBL negative and were uniformly susceptible to extended-spectrum cephalosporins and monobactams. Comparison of the two groups showed that previous hospitalization in a nursing home (P = 0.04) and use of bladder catheter (P = 0.01) were significant risk factors for infections due to ESBL-positive strains. In addition, cases due to ESBL-positive strains showed a significantly higher mortality attributable to BSI (P = 0.04). BSI cases due to ESBL-negative isolates uniformly responded to therapy, whereas 5/11 cases due to ESBL-positive isolates failed to respond (P < 0.01). Use of carbapenems was associated with complete response independently of ESBL production. Therapeutic failure and mortality may occur in BSI episodes caused by ESBL-positive P. mirabilis isolates. Thus, recognition of ESBL-positive strains appears to be critical for the clinical management of patients with systemic P. mirabilis infections.     

Congestive heart failure secondary to right ventricular metastasis of colon cancer. A case report and review of the literature.

Although metastatic tumors of the heart occur more frequently than primary ones, infiltration of the right heart by a metastatic colon cancer has rarely been reported. We report the case of a woman previously operated on for colon cancer, presenting with symptoms of congestive heart failure due to metastatic invasion of the right ventricular cavity. Both transthoracic and transesophageal echocardiography were useful in detecting the mass, but not in defining its nature. The patient underwent a palliative surgical resection of the neoplastic mass but died soon after the intervention.     

Rat nicastrin gene: cDNA isolation, mRNA variants and expression pattern analysis

Nicastrin is a type 1 transmembrane glycoprotein that interacts with presenilin, Aph-1, and Pen-2 proteins to form a high molecular complex with gamma secretase activity. Then, nicastrin has a central role in presenilin-mediated processing of beta-amyloid precursor protein and in some aspects of Notch/glp-1 signaling in vivo. Here, we isolated a rat nicastrin cDNA and investigated gene expression in embryonic and adult rat tissues. The predicted amino acid sequence is comprised of 708 residues and showed a high degree of identity with other vertebrate orthologs. Besides full-length nicastrin mRNA, we identified an alternative spliced variant lacking the whole exon 3 and predicted to encode a 62-residue-long truncated protein. Full-length nicastrin mRNA was observed to be ubiquitously expressed, while the spliced variant was preferentially transcribed in the nervous system, whether in embryonic or adult neural tissues. Studies performed on primary cell cultures demonstrated that the short isoform was expressed in neurons, but not in astrocyte and microglial cells. Further experiments performed to verify the presence of the variant in neuroblastoma culture failed to show any truncated protein. Treatments by cyclohexamide showed the involvement of a quality control-based surveillance mechanism, which selectively degrades the exon 3-skipped isoform. In summary, this is the first report describing a novel skipped isoform of nicastrin which may suggest a new possible control mechanism based on the alternative splicing and nonsense-mediated mRNA decay to regulate brain protein expression and provide newer insights into potential implication in Alzheimer's disease.