Impact of intermittent voluntary ethanol consumption during adolescence on the expression of endocannabinoid system and neuroinflammatory mediators.

The adolescent brain displays high vulnerability to the deleterious effects of ethanol, including greater risk of developing alcohol use disorder later in life. Here, we characterized the gene expression of the endocannabinoid system (ECS) and relevant signaling systems associated with neuroinflammation and emotional behaviors in the brain of young adult control and ethanol-exposed (EtOH) rats. We measured mRNA levels of candidate genes using quantitative real time PCR in the medial prefrontal cortex (mPFC), amygdala and hippocampus. EtOH rats were generated by maintenance on an intermittent and voluntary ethanol consumption during adolescence using the two-bottle choice paradigm (4 days/week for 4 weeks) followed by 2 week-withdrawal, a time-point of withdrawal with no physical symptoms. Mean differences and effect sizes were calculated using t-test and Cohen's d values. In the mPFC and hippocampus, EtOH rats had significantly higher mRNA expression of endocannabinoid-signaling (mPFC: Ppara, Dagla, Daglb and Napepld; and hippocampus: Cnr2, Dagla and Mgll) and neuroinflammation-associated genes (mPFC: Gfap; and hippocampus: Aif1) than in controls. Moreover, EtOH rats had significantly higher mRNA expression of neuropeptide Y receptor genes (Npy1r, Npy2r and Npy5r) in the hippocampus. Finally, EtOH rats also displayed higher plasma endocannabinoid levels than controls. In conclusion, these results suggest that adolescent ethanol exposure can lead to long-term alterations in the gene expression of the ECS and other signaling systems involved in neuroinflammation and regulation of emotional behaviors in key brain areas for the development of addiction.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Cooperative role of the glucagon-like peptide-1 receptor and ß3-adrenergic-mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats.

AIM: To explore the cooperation of GLP-1 receptor and ß3-adrenergic receptor (ß3-AR)-mediated signalling in the control of fat mass/feeding behaviour by studying the effects of a combined therapy composed of the GLP-1R agonist liraglutide and the ß3-AR agonist CL316243. METHODS: The study included the analysis of key mechanisms regulating lipid/cholesterol metabolism, and thermogenesis in brown (BAT) and epididymal white (eWAT) adipose tissues, abdominal muscle and liver of male rats. RESULTS: CL316243 (1 mg kg-1 ) and liraglutide (100 µg kg-1 ) co-administration over 6 days potentiated an overall negative energy balance (reduction in food intake, body weight gain, fat/non-fat mass ratio, liver fat content, and circulating levels of non-essential fatty acids, triglycerides, very low-density lipoprotein-cholesterol and leptin). These effects were accompanied by increased plasma levels of insulin and IL6. We also observed increased gene expression of uncoupling proteins regulating thermogenesis in BAT/eWAT (Ucp1) and muscle (Ucp2/3). Expression of transcription factor and enzymes involved either in de novo lipogenesis (Chrebp, Acaca, Fasn, Scd1, Insig1, Srebp1) or in fatty acid ß-oxidation (Cpt1b) was enhanced in eWAT and/or muscle but decreased in BAT. Pparα and Pparγ, essentials in lipid flux/storage, were decreased in BAT/eWAT but increased in the muscle and liver. Cholesterol synthesis regulators (Insig2, Srebp2, Hmgcr) were particularly over-expressed in muscle. These GLP-1R/ß3-AR-induced metabolic effects were associated with the downregulation of cAMP-dependent signalling pathways (PKA/AKT/AMPK). CONCLUSION: Combined activation of GLP-1 and ß3-ARs potentiate changes in peripheral pathways regulating lipid/cholesterol metabolism in a tissue-specific manner that favours a switch in energy availability/expenditure and may be useful for obesity treatment.

Single administration of recombinant IL-6 restores the gene expression of lipogenic enzymes in liver of fasting IL-6-deficient mice.

BACKGROUND AND PURPOSE: Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic lipogenic enzymes. EXPERIMENTAL APPROACH: Gene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6(-/-) ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. KEY RESULTS: During feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6(-/-) mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL-6(-/-) mice. Protein levels of hepatic lipogenic enzymes were lower in IL-6(-/-) than in WT mice at the end of the fasting period. In WT, circulating IL-6 levels paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed that IL-6-mediated signalling was associated with the up-regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL-6 mediated up-regulation of lipogenic gene transcription levels. CONCLUSIONS AND IMPLICATIONS: IL-6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3-associated signalling cytokines, particularly against steatosis, should be undertaken with caution.

The use of small personal ultrasound devices by internists without formal training in echocardiography.

AIMS: Hand-held ultrasound devices will probably be used for bedside cardiac diagnoses by internists without formal training in echocardiography. We compared the accuracy of hand-held ultrasound devices studies performed by expert echocardiographers vs internal medicine residents with brief training in echocardiography. METHODS AND RESULTS: Three internal medicine residents participated in an organized training program in echocardiographic principles, image acquisition, and interpretation. Subsequently, these residents and three echocardiographers imaged 300 patients with a hand-held ultrasound device. Sensitivity, specificity, positive and negative predictive values for internist- and echocardiographer-performed studies for the detection of cardiac abnormalities were compared using a full-featured exam as the gold standard. Resident- and echocardiographer-performed scans had similar overall sensitivity and specificity. There was a higher positive predictive value for the echocardiographer-performed scans. For clinically important findings (likely to affect patient care), sensitivity was slightly but significantly higher for the echocardiographer-performed scans. Clinically important findings most often missed by residents included regional wall motion abnormalities, intra-cardiac thrombus, right ventricular dysfunction and non-trivial pericardial effusions. CONCLUSION: Hand-held ultrasound devices provide useful screening tools for cardiac disease but should not replace a standard platform study. Training guidelines and competency evaluation are needed if these devices are to be used by non-echocardiographers for clinical decision-making.

Thrombolytic therapy of a left-sided prosthetic valve thrombosis without hemodynamic obstruction: a case report.

We report a case of a 38-year-old woman with a prosthetic mitral valve who presented with multiple embolic events. Transesophageal echocardiography was used to diagnose nonobstructive thrombi on the prosthetic valve. She underwent successful thrombolytic therapy. The patient was discovered to be in a hypercoagulable state, which probably was caused by the concomitant use of phenytoin. We review the literature for diagnosis and treatment of nonobstructive prosthetic valve thrombosis.

Dofetilide: a new pure class III antiarrhythmic agent.

BACKGROUND: Although there are a variety of antiarrhythmic agents used for the treatment of atrial fibrillation of flutter, each drug has drawbacks, and room exists for new pharmacologic agents. Dofetilide, a pure class III agent, has recently been approved by the Food and Drug Administration for therapy of these arrhythmias and is reviewed. METHODS: Data for dofetilide, published in full or in abstract form, were reviewed, concentrating on the properties related to its efficacy for the therapy of supraventricular arrhythmias. RESULTS: Results from animal and human studies indicate that dofetilide, a renally excreted drug, has pure class III properties related to blockade of the delayed rectifier potassium current. It is effective for the therapy of atrial arrhythmias, particularly atrial fibrillation and flutter, and has no demonstrable negative inotropic effect. Despite an incidence of torsades de pointes of approximately 2% in patients with impaired ventricular function, dofetilide exhibited no association with an increased mortality rate when studied in a large series of patients with a reduced ejection fraction. CONCLUSIONS: Dofetilide's electrophysiologic and clinical profiles suggest that it will be safe and clinically useful for the termination and prevention of atrial fibrillation or flutter, even in patients with impaired ventricular function.

Positive atrial inotropic effect of dofetilide after cardioversion of atrial fibrillation or flutter.

The pure class III agent dofetilide was evaluated to determine its effect on atrial function after cardioversion of atrial fibrillation or flutter. Compared with placebo, dofetilide-treated patients had evidence of better atrial function after cardioversion, indicating that this agent has a positive atrial inotropic effect during the period of postcardioversion atrial stunning.