The cannabinoid receptor antagonist SR-141716A induces penile erection in male rats: involvement of paraventricular glutamic acid and nitric oxide

The cannabinoid CB1 receptor antagonist SR141716A (0.5, 1 and 2 microg) induces penile erection when injected into the paraventricular nucleus of male rats. The pro-erectile effect of SR 141716A occurs concomitantly with an increase in the concentration of NO2- and NO3- in the paraventricular dialysate obtained by means of intracerebral microdialysis. Both penile erection and NO2- increase induced by SR 141716A were reduced by the prior injection into the PVN of the cannabinoid CB1 agonists WIN 55,212-2 (5 microg) or HU 210 (5 microg), given into the paraventricular nucleus at doses unable to induce penile erection or to modify NO2- concentration. SR 141716A responses were also reduced by nitro-L-arginine methylester (20 microg), a non-selective NO synthase inhibitor, S-methyl-L-thiocitrulline (20 microg), a selective neuronal NO synthase inhibitor, the excitatory amino acid NMDA receptor antagonist dizocilpine ((+)MK 801) (1 microg), or the GABAA receptor agonist muscimol (0.2 microg) injected into the PVN 15 min before SR 141716A. In contrast, the inducible NO synthase inhibitor L-N(6)-(1-iminoethyl)lysine (20 microg), the GABAB receptor agonist baclofen (0.2 microg), the mixed dopamine receptor antagonist cis-flupenthixol (10 microg), and the oxytocin receptor antagonist d(CH2)5Tyr(Me)-Orn8 -vasotocin (1 microg), were ineffective. Despite its inability to reduce penile erection and NO2- increase induced by SR 141716A when injected into the PVN, d(CH2)5Tyr(Me)-Orn8 -vasotocin (1 microg) reduced almost completely penile erection without reducing paraventricular NO2- increase when injected into the lateral ventricles 15 min before SR 141716A. The present results show that SR 141716 induces penile erection by a mechanism (possibly activation of excitatory amino acid neurotransmission), which causes the activation of neuronal NO synthase in paraventricular oxytocinergic neurons mediating penile erection.     

Molecular aspects of insulin therapy in critically ill patients

PURPOSE OF REVIEW: This review provides an overview of molecular mechanisms involved in beneficial effects of insulin in insulin resistant critically ill patients. RECENT FINDINGS: Intense insulin therapy reduced morbidity in critically ill patients. Insulin acts by two major molecular pathways: reduction of the inflammation process induced by free fatty acid excess in tissues and decrease of reactive oxygen species production induced by hyperglycemia. By these actions, insulin preserves mitochondrial function, enhances adiponectin secretion and probably modulates AMP-activated protein kinase activity, which in turn depletes lipid depots in tissues and restores glucose uptake and oxidation. Furthermore, it was recently established that insulin prevents microcirculation alteration and subsequent cellular hypoxia by reducing inducible nitric oxide synthase expression and activity in the endothelium. So, insulin beneficial effects in critically ill patients are dependent on metabolic and non-metabolic molecular pathways. SUMMARY: Critically ill patients requiring intensive care for more than a few days have a high risk of death. A tight control of glucose levels by intense insulin therapy reduced morbidity in critically ill patients. Unraveling the molecular mechanisms of insulin will provide new insights into the pathogenesis of multiple organ failure and will allow novel therapeutic strategies to manage patients needing intensive care.     

Data Analysis of Kinetic Modelling Used in Drug Stability Studies: Isothermal Versus Nonisothermal Assays

Purpose Kinetic modelling was applied to predict the stability of cholecystokinin fragment CCK-4 in aqueous solution, which was analyzed by isothermal and nonisothermal methods using a validated stability indicating HPLC method.Methods The isothermal studies were performed in the temperature range 40 to 80°C at pH 12 and ionic strength 0.01 M as constants, whereas nonisothermal stability studies were performed using a linear increasing temperature program, heating rate 0.25°C/h and a temperature interval 40–82°C. The isothermal studies require two-step linear regression to estimate the parameters, resulting in a well-defined confidence interval. Nonisothermal kinetic studies require nonlinear or linear regression by previous transformation of data to estimate the parameters. In this case, the two most popular approaches, derivative and integral, were used and compared.Results Under isothermal conditions, an apparent first-order degradation process was observed at all temperatures. The linear Arrhenius plot suggested that the CCK-4 degradation mechanism was the same within the studied temperature range, with quite large uncertainties due to the small number of degrees of freedom based only on the scatter in the plot, and giving an estimated shelf life at 25°C of 35.2 days. The derivative approach yields high variability in the Arrhenius parameters, since they are dependent on the number of polynomial terms chosen, so several statistical criteria were applied to select the best model. The integral approach allows activation parameters to be calculated directly from experimental data, and provides results in good agreement with those of the traditional method, but have the advantage that the uncertainty in the final result directly reflects the goodness of fit of the experimental data to the chosen kinetic model. The application of the bootstrap technique to estimating confidence limits for the Arrhenius parameters and shelf life is also illustrated, and shows there is no difference between the asymptotic and bootstrap confidence intervals.Conclusions Nonisothermal studies give us fast and valuable information about drug stability, although their potential for predicting isothermal behaviour is conditioned by the data analysis method applied.     

Impairment of adult male reproductive function in rats exposed to ethanol since puberty

The objective of this work was to evaluate reproductive function in adult male rats exposed to ethanol since puberty. Male Wistar rats, 50 days old, received a liquid diet with 36% of the daily calories derived from ethanol or an isocaloric control diet for 55 days. The ethanol treatment impaired sexual behavior and only 22% of these rats reached ejaculation. The fertility of ethanol-treated animals was significantly reduced, mainly after natural mating. Serum testosterone levels, daily sperm production and sperm count in the epididymis were also significantly diminished after ethanol treatment, associated with an acceleration of the sperm transit time in the cauda epididymidis, decrease in sperm motility and increased percentage of abnormal shaped sperm cells. The results showed that chronic consumption of ethanol beginning at puberty impairs the reproductive function of adult male rats.     

Gastro-intestinal problems and concomitant medication in NSAID users: additional findings from a questionnaire-based survey in Italy

Background In a previous questionnaire-based survey, we found extensive use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects with risk factors for serious gastrointestinal complications. Aim This study focused on the use of NSAIDs in subjects who reported either (a) pre-existing disorders which would have required caution in using NSAIDs (e.g. dyspepsia/heartburn or peptic ulcer) or (b) co-medication with drugs having a high risk of interacting with NSAIDs. Methods Between March and September 2002, 65 general practitioners (GPs) submitted a validated self-administered questionnaire on health status and drug use to 3,250 subjects (age ≥18 years, stratified by sex and age). The questionnaire was divided into three parts: (1) sociodemographic information, (2) symptoms/illnesses (in the previous 6 months) and (3) drugs taken during the previous week. Results Of the 2,738 subjects who filled in the questionnaire (84% of responders), 633 (23%) used NSAIDs and, among them, 114 (18%) were chronic users. Among the subjects reporting dyspepsia/heartburn or ulcer (n=909 of 2,738), 24% were occasional NSAID users and 6% chronic users. Of the chronic NSAID users reporting gastrointestinal symptoms, 35% also used a drug for acid-related disorders, but only 14% used daily a proton pump inhibitor (PPI). One hundred six subjects used concomitantly more than one NSAID. Eighteen percent of the subjects using corticosteroids also reported NSAID use; similar proportions were seen in subjects using selective serotonin reuptake inhibitor (SSRI) antidepressants or calcium channel blockers, whereas 6% of the subjects with oral anticoagulants used NSAIDs. Conclusions Our study shows that NSAIDs are frequently used in patients with upper gastrointestinal complaints or in combination with potentially interacting medications. Adverse effects and untoward drug interactions should be monitored in patients treated with NSAIDs in order to minimise their occurrence.     

Observations during clinical 2:1 and 3:1 A-V block below the A-V node. Evidence of partial penetration of atrial impulses into the His bundle

A clinical His bundle recording during 2:1 A-V block below the A-V node displayed RBBB, a prolonged H-V interval, and alternating amplitude and duration of the His potentials. The reduced amplitude of the non-conducted His potential suggests a lesser depth of penetration into the His tissue with subsequent block. The reduced His potential amplitude may be due to decremental conduction within the His bundle and/or prolonged refractoriness of the His tissue following atrioventricular conduction of the preceding atrial impulse.During 3:1 A-V block progressively deeper penetration of the atrial impulses into the His-Purkinje system occurred. Progressive penetration into the more proximal His-Purkinje system may have permitted recovery of a more distal area of refractoriness with subsequent atrioventricular conduction. This mechanisms appears similar to one of the mechanisms of 3:1 A-V block demonstrated experimentally, except that in this clinical record the major site of impaired conduction and progressive penetration is within the His-Purkinje system rather than within the A-V node.     

How immigrant workers experience workplace problems: a qualitative study

In this qualitative study, the authors describe work organization factors, problems workers encounter on the job, consequences of these problems, and actions taken to deal with them. Study participants were immigrant workers seeking assistance at the Chicago Interfaith Workers' Rights Center. Using a grounded theory approach, the investigators coded narratives from 455 records describing workers' problems. Emerged sequences of events were then integrated into a model. Data show that workers' rights are systematically violated and problems are rooted in how jobs are designed and managed. Work organization factors are associated with occupational injury/illness, job loss, and worker actions. Employer responses included indifference and various forms of retaliation. This model provides insight into the work-related troubles immigrants face and informs hypothesis generation and action initiatives.     

Bimoclomol ameliorates mercuric chloride nephrotoxicity through recruitment of stress proteins

Bimoclomol (BIM), is a stress proteins coinducer, that acts synergistically with a mild stressor to activate cytoprotective stress proteins. BIM has been successfully utilized in animal models for the treatment of various nervous, cardiac and cerebrovascular diseases. Mercuric chloride (HgCl(2)) induces acute renal failure in rats by a single dosage. The present in vivo study was conducted to assess the efficacy of BIM against acute HgCl(2) nephrotoxicity. At different times after BIM and/or HgCl(2) exposure we evaluated renal morphology and the localization/abundance of three stress proteins (HSP72, GRP75, HSP60) by electron microscopy, immunohistochemistry and Western blot analysis. BIM delivery to rats 6h before mercury, ameliorated damage to renal ultrastructure, with recovery of tubular and mitochondrial membranes 24h after mercury treatment. In rats pretreated with BIM prior to HgCl(2) exposure, HSP72 was significantly overexpressed in proximal tubules in a time-dependent manner. In contrast, the amounts of GRP75 and HSP60 after BIM pretreatment were comparable to the group treated with mercury alone, but these stress proteins had translocated to the nuclei at 14 and 24h, respectively. These novel findings suggest that BIM mitigates HgCl(2) nephrotoxicity in rats through the early recruitment of stress proteins in midcortical proximal tubules that are the main renal mercury-targets.     

Role of cytomegalovirus and Epstein-Barr virus in patients with de novo colon cancer after renal transplantation

AIMS: The development of new effective immunosuppressive agents has provided long-term survival for transplant recipients, thereby increasing the risk of de novo malignancy in chronic immunocompromised hosts. Although de novo post-transplant lymphoproliferative diseases and skin cancer have been shown to have an increased incidence in long-term surviving solid organ transplant recipients, the association with colon cancer is controversial. PATIENTS AND METHODS: Over a 12-year period, 20 patients (5%) out of 400 renal transplant recipients (treated at the University Hospitals of Udine and Ancona) developed 24 de novo tumors; 11 skin cancers and 13 non-skin cancers. Three patients developed de novo colon cancer. Immunosuppressive therapy was reduced immediately after diagnosis, and all patients were shifted from cyclosporine to rapamycin within 30 days. The tumor was surgically resected with curative intent in 2 cases, and 1 patient had only palliative surgery due to metastatic disease. The postoperative course was uneventful, and all patients maintained normal graft function. RESULTS: Two of 3 patients died of progression of the neoplasm, within a median time from the diagnosis of 12 months. We analyzed the possible correlations between de novo colon cancer and "serology (hepatitis C virus-hepatitis B virus, HCV-HBV) status" infections, cytomegalovirus and Epstein-Barr virus reactivation, episodes of rejection, and blood transfusions. CONCLUSIONS: Differently from other de novo skin and non-skin tumors, our cases developed cytomegalovirus and Epstein-Barr virus reactivation within 3 months of transplantation. Therefore, we suggest a closer follow-up for de novo colon cancer in renal transplants with early cytomegalovirus and Epstein-Barr virus reactivation in order to avoid a delay in diagnosis.