Cardiac effects of MDMA on the metabolic profile determined with 1H-magnetic resonance spectroscopy in the rat

Despite the potential for deleterious (even fatal) effects on cardiac physiology, 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) abuse abounds driven mainly by its euphoric effects. Acute exposure to MDMA has profound cardiovascular effects on blood pressure and heart rate in humans and animals. To determine the effects of MDMA on cardiac metabolites in rats, MDMA (0, 5, or 10 mg/kg) was injected every 2 h for a total of four injections; animals were sacrificed 2 h after the last injection (8 h drug exposure), and their hearts removed and tissue samples from left ventricular wall dissected. High resolution magic angle spinning proton magnetic resonance spectroscopy ((1)H-MRS) at 11.7 T, a specialized version of MRS aptly suited for analysis of semi-solid materials such as intact tissue samples, was used to measure the cardiac metabolomic profile, including alanine, lactate, succinate, creatine, and carnitine, in heart tissue from rats treated with MDMA. MDMA effects on MR-visible choline, glutamate, glutamine, and taurine were also determined. Body temperature was measured following each MDMA administration and serotonin and norepinephrine (NE) levels were measured by high pressure liquid chromatography (HPLC) in heart tissue from treated animals. MDMA significantly and dose-dependently increased body temperature, a hallmark of amphetamines. Serotonin, but not NE, levels were significantly and dose-dependently decreased by MDMA in the heart wall. MDMA significantly altered the MR-visible profile with an increase in carnitine and no change in other key compounds involved in cardiomyocyte energy metabolomics. Finally, choline levels were significantly decreased by MDMA in heart. The results are consistent with the notion that MDMA has significant effects on cardiovascular serotonergic tone and disrupts the metabolic homeostasis of energy regulation in cardiac tissue, potentially increasing utilization of fatty acid metabolism. The contributions of serotonergic signaling on MDMA-induced changes in cardiac metabolism remain to be determined.     

Epileptogenic brain malformations: radiological and clinical presentation and indications for genetic testing

Malformations of cortical development (MCD) represent a major cause of developmental disabilities and severe epilepsy. Advances in imaging and genetics have improved the diagnosis and classification of these conditions. Up to now, eight genes have been involved in different types of MCD. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Additional forms are X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia associated with mutations of the ARX gene. Lissencephaly with cerebellar hypoplasia (LCH) encompass heterogeneous disorders named LCH type a to d. LCHa are related with mutation in LIS1 or DCX, LCHb with mutation of RELN gene, and LCHd could be related with TUBA1A gene. Polymicrogyria encompass a wide range of clinical, aetiological and histological findings. Among several syndromes, recessive bilateral fronto-parietal polymicrogyria has been associated with mutations of the GPR56 gene. Bilateral perisylvian polymicrogyria showed a linkage to chromosome Xq28 in some pedigrees, and mutations in SRPX2 gene in others conditions. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of BPNH with focal epilepsy in females and prenatal lethality in males. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. It is possible to infer the most likely causative gene by brain imaging studies and other clinical findings. Based on this experience, a detailed phenotype analysis is needed to develop the most efficient research on MCD in the future.     

Recent progress in the diagnosis, prognostic evaluation and treatment of pheochromocytomas

INTRODUCTION: Pheochromocytoma is a catecholamine-secreting neoplasm of chromaffin tissue. It is a rare disease. Biochemical tests should be performed only in patients at high risk of pheochromocytoma, and an imaging procedure only in those with positive biochemical tests. CURRENT KNOWLEDGE AND KEY POINTS: The most specific and sensitive diagnostic test for the disease is the determination of plasma or urinary metanephrines. The tumor can be located by computerized tomography, magnetic resonance imaging, and specific scintigraphy. Ten to 20% of pheochromocytomas result from hereditary diseases, including multiple endocrine neoplasia type 2, von Hippel Lindau disease, and neurofibromatosis 1. Familial cases are diagnosed earlier, and are more frequently bilateral and recurring than sporadic cases. About 10% of the cases are malignant either at first operation or during follow-up, malignancy being diagnosed by the presence of lymph node, visceral or bone metastases. The probability of a recurrence is positively correlated with the urinary excretion of metanephrines and tumor size. Recurrences are more frequent in cases with ectopic tumors and in those with a low plasma epinephrine to total catecholamine ratio. Patients, especially those with familial tumors or low epinephrine secretion, should be followed-up indefinitely. FUTURE PROSPECTS AND PROJECTS: Treatment for malignant recurrences includes surgery, therapeutic embolization, chemotherapy, and the application of therapeutic doses of metaiodobenzylguanidine. Metyrosine, phenoxybenzamine, or somatostatin analogs may help to control blood pressure and to alleviate symptoms in patients with malignant pheochromocytoma; however such a treatment has no antiproliferative effect.     

Isolated systolic hypertension: data on a cohort of young subjects from a French working population (IHPAF)

Elderly patients with isolated systolic hypertension (ISH)--systolic blood pressure (SBP) > or =140 mmHg and diastolic blood pressure (DBP) <90 mmHg--have increased mortality and morbidity. The aim was to study the incidence of ISH in a younger population of between 15 and 60 years of age, and to measure pulse pressure (PP), mean arterial pressure (MAP) and heart rate (HR) in these subjects. The study population consisted of 27 783 subjects, aged 15-60 years, untreated for hypertension (HT) from a cohort of employees formed to study the incidence of HT in the French working population (AIHFP). BP and HR were measured with a validated, automatic device after 5, 6 and 7 min at rest. The prevalence of ISH was 6.9% in men, 2.3% in women. This prevalence was over 5% in young men and increased at 40-44 years; it was negligible in young women, but increased at 50-54 years to about 10% (ie to the same level as in men of the same age): PP in subjects with ISH (46.9 mmHg) was significantly higher than in the normotensive group (NT-40.9 mmHg); it was comparable in both young men (65.5 mmHg) and older men (66 mmHg); it was higher in men (63.1 mmHg) than in women (61.5 mmHg). HR was higher in ISH than in NT and it was higher in women ( approximately 5 bpm) in whom it decreased with age. The prevalence of ISH is not negligible in HT (30% men, 25% women), with a high prevalence in young subjects and elevated PP, MAP and HR values. These data should be taken into account as elevated ISH, PP and HR are considered as cardio-vascular risk factors.     

Exposure of Staphylococcus aureus to Subinhibitory Concentrations of β-Lactam Antibiotics Induces Heterogeneous Vancomycin-Intermediate Staphylococcus aureus

Glycopeptides are known to select for heterogeneous vancomycin-intermediate Staphylococcus aureus (h-VISA) from susceptible strains. In certain clinical situations, h-VISA strains have been isolated from patients without previous exposure to glycopeptides, such as cystic fibrosis patients, who frequently receive repeated treatments with beta-lactam antibiotics. Our objective was to determine whether prolonged exposure to beta-lactam antibiotics can induce h-VISA. We exposed 3 clinical vancomycin-susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains to ceftazidime, ceftriaxone, imipenem, and vancomycin (as a control) at subinhibitory concentrations for 18 days in vitro. Population analyses showed progressive increases in vancomycin resistance; seven of the 12 derived strains obtained after induction were classified as h-VISA according to the following criteria: area under the curve (AUC) on day 18/AUC of Mu3 of ≥90% and/or growth on brain heart infusion (BHI) agar with 4 mg/liter vancomycin. The derived isolates had thickened cell walls proportional to the level of glycopeptide resistance. Genes known to be associated with glycopeptide resistance (vraSR, yvqF, SA1703, graRS, walKR, and rpoB) were PCR sequenced; no de novo mutations were observed upon beta-lactam exposure. To determine whether trfA, a gene encoding a glycopeptide resistance factor, was essential in the selection of h-VISA upon beta-lactam pressure, a trfA-knockout strain was generated by allelic replacement. Indeed, beta-lactam exposure of this mutated strain showed no capacity to induce vancomycin resistance. In conclusion, these results showed that beta-lactam antibiotics at subinhibitory concentrations can induce intermediate vancomycin resistance in vitro. This induction required an intact trfA locus. Our results suggest that prior use of beta-lactam antibiotics can compromise vancomycin efficacy in the treatment of MRSA infections.     

Short, discontinuous exposure to butyrate effectively sensitizes latently EBV-infected lymphoma cells to nucleoside analogue antiviral agents

Antiviral drugs alone have been unsuccessful in the treatment of Epstein-Barr virus (EBV)-associated malignancies because the virus maintains a latent state of replication in these tumors. In recent years, novel therapeutic approaches are being investigated wherein lytic replication of the virus is induced prior to the use of cytotoxic antiviral drugs. The choice of suitable agents to induce lytic replication has been a critical step in this novel approach. We have previously demonstrated that butyrate derivatives induce a lytic pattern of EBV gene expression in patient-derived EBV-positive lymphoblastoid cell lines and, together with nucleoside analogue ganciclovir, effectively reduce or eliminate tumor growth in humans. Butyrate has drawbacks as a therapeutic agent, however, as constant intravenous infusion is required to achieve detectable plasma levels of this drug. In this study, we investigated whether discontinuous exposure to butyrate is capable of initiating lytic phase gene expression and thymidine kinase induction, and sensitizing EBV-positive lymphoma cells to ganciclovir-mediated cell growth arrest and apoptosis. We demonstrate that multiple daily 6-h exposures of the EBV-positive Burkitt's lymphoma cell line P3HR1 to butyrate induced sustained expression of the EBV lytic phase protein BMRF. Viral thymidine kinase was also induced by intermittent exposure, although to a lower level than with continuous exposure treatment. However, discontinuous exposure to butyrate in combination with ganciclovir induced a similar level of tumor cell growth inhibition as did continuous treatment, as measured by serial enumeration of viable cells, MTT cell proliferation assays and measurement of cellular DNA content. We further demonstrated that those cells which survived initial exposure to butyrate plus ganciclovir remained susceptible to further cycles of combination treatment. These findings suggests that continuous infusion of butyrate may not be necessary for maintaining viral thymidine kinase gene expression and sensitization to antiviral agents in EBV-associated tumors, and that therapeutic regimens which employ more convenient, discontinuous exposure to butyrate may also be effective clinically.