Spatially clustered neuronal assemblies comprise the microstructure of synchrony in chronically epileptic networks

Epilepsy is characterized by recurrent synchronizations of neuronal activity, which are both a cardinal clinical symptom and a debilitating phenomenon. Although the temporal dynamics of epileptiform synchronizations are well described at the macroscopic level using electrophysiological approaches, less is known about how spatially distributed microcircuits contribute to these events. It is important to understand the relationship between micro and macro network activity because the various mechanisms proposed to underlie the generation of such pathological dynamics are united by the assumption that epileptic activity is recurrent and hypersynchronous across multiple scales. However, quantitative analyses of epileptiform spatial dynamics with cellular resolution have been hampered by the difficulty of simultaneously recording from multiple neurons in lesioned, adult brain tissue. We have overcome this experimental limitation and used two-photon calcium imaging in combination with a functional clustering algorithm to uncover the functional network structure of the chronically epileptic dentate gyrus in the mouse pilocarpine model of temporal lobe epilepsy. We show that, under hyperexcitable conditions, slices from the epileptic dentate gyrus display recurrent interictal-like network events with a high diversity in the activity patterns of individual neurons. Analysis reveals that multiple functional clusters of spatially localized neurons comprise epileptic networks, and that network events are composed of the coactivation of variable subsets of these clusters, which show little repetition between events. Thus, these interictal-like recurrent macroscopic events are not necessarily recurrent when viewed at the microcircuit scale and instead display a patterned but variable structure.     

Death following ingestion of MDMA (ecstasy) and moclobemide

Four deaths following the ingestion of moclobemide and MDMA ('ecstasy') are described. The probable cause of death in each case was serotonin syndrome as a result of an interaction between the two drugs. As none of the victims had been prescribed moclobemide it seems that each had taken the drug to enhance the effects of MDMA, with fatal consequences. Warnings are needed against misinformed attempts to potentiate the pharmacological effects of illicit drugs.     

Is there a role for Chlamydia pneumoniae infection in systemic lupus erythematosus and in the associated atherosclerotic cardiovascular disease?

OBJECTIVE: To search for molecular evidence of Chlamydial infection in systemic lupus erythematosus (SLE) subjects and to assess if there is an association of this infectious agent with coronary artery calcification (CAC), a marker of total atherosclerotic burden. METHODS: 28 SLE subjects had blood samples drawn and DNA extracted from peripheral blood mononuclear cells (PBMC) and an electron beam computed tomography (EBCT) scan. Polymerase chain reaction (PCR) analysis was performed for Chlamydia trachomatis 16srRNA and major outer membrane protein (MOMP) and for C. pneumoniae 16srRNA, MOMP, as well as nested PCR for MOMP. RESULTS: Four of 28 subjects (14.2%) had evidence of C. pneumoniae nucleic acid in PBMC. The 16srRNA primers detected C. pneumoniae in one patient (3.57%) and the nested PCR MOMP primers in 3 subjects (10.71%). None were positive for Chlamydia trachomatis. Two of the 4 subjects with C. pneumoniae DNA had abnormal EBCT scans and 2/11 (18.3%) subjects with abnormal EBCT were positive for C. pneumoniae. There were significant associations of C. pneumoniae DNA with smoking (OR = 3) and corticosteroid use. The odds ratio for subjects with abnormal CAC and detectable C. pneumoniae was 1.67. CONCLUSION: This pilot study demonstrates for the first time that C. pneumoniae DNA can be identified in the PBMC of some SLE subjects and there may be an association with CAC. Smoking may be an additional risk factor for infection in this population. Determination of pathogenicity of this organism in atherosclerotic coronary vascular disease in SLE will require further study.     

Impact of 2-Dimensional echocardiography on the management of distressed newborns in whom cardiac disease is suspected

The course and management of 40 consecutive newborns (aged less than 2 weeks) who presented with signs and symptoms of congenital heart disease were reviewed to determine the impact of 2-dimensional (2-D) echocardiography on their subsequent management. Of the 40 patients with congenital heart disease, 60% did not undergo cardiac catheterization. Forty-two percent of the patients who were treated surgically went directly to operation without preoperative cardiac catheterization. Only 40% of the patients with congenital heart disease required cardiac catheterization in the newborn period, and 43% of these procedures were primarily therapeutic (that is, balloon atrial septostomy). In each patient 2-D echocardiography correctly identified the major cardiac malformation and there was good agreement with angiographic, surgical, and autopsy findings. The most commonly overlooked defect was a patent ductus arteriosus. Thus, 2-D echocardiography not only allows diagnosis of congenital heart disease in the newborn but can expedite clinical management. No longer is cardiac catheterization necessarily the primary means for an anatomic diagnosis of congenital cardiac malformations in the newborn.     

Vitamin d, metabolic dyslipidemia, and metabolic syndrome in rheumatoid arthritis

PurposeVitamin D deficiency is a potential risk factor for cardiometabolic disease. We investigated the associations between vitamin D and dyslipidemia and the metabolic syndrome in patients with rheumatoid arthritis, a group at high risk for cardiovascular disease.MethodsSerum 25(OH)vitamin D and lipoprotein levels were measured at baseline in a random sample of 499 participants, ages 18-85 years, enrolled in a randomized trial of golimumab (GOlimumab Before Employing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset or GO-BEFORE Trial). Participants had rheumatoid arthritis with active disease, and were naïve to methotrexate and biologic therapies. Multivariable linear regression was performed to assess associations between vitamin D levels and lipoprotein fractions. Multivariable logistic regression was performed to determine the odds of hyperlipidemia and the metabolic syndrome in participants with vitamin D deficiency (<20 ng/mL).ResultsIn multivariable linear regression, vitamin D levels (per 10 ng/mL) were associated inversely with low-density lipoprotein (β: ?0.029 [?0.049, ?0.0091], P = .004) and triglyceride (β: ?0.094 [?0.15, ?0.039] P = .001) levels, adjusted for demographic, cardiovascular, and disease-specific variables. Vitamin D and high-density lipoprotein levels were not associated in univariate or multivariate analyses. Vitamin D deficiency was associated independently with an increased odds of hyperlipidemia (odds ratio 1.72; 95% confidence interval, 1.10-2.45; P = .014) and metabolic syndrome (odds ratio 3.45; 95% confidence interval, 1.75-6.80; P <.001) in adjusted models.ConclusionsIn conclusion, vitamin D deficiency was associated with the metabolic syndrome and dyslipidemia in rheumatoid arthritis, suggesting a potential role in cardiovascular disease risk. Large-scale, prospective studies are needed to determine if vitamin D supplementation improves lipoprotein levels and reduces cardiovascular risk in rheumatoid arthritis.     

High prevalence of hepatitis B and syphilis co-infections among HIV patients initiating antiretroviral therapy in the north-west region of Cameroon

Hepatitis B virus (HBV) and syphilis co-infections contribute significantly to HIV-associated morbidity and mortality, but the burden of these diseases is not fully appreciated in sub-Saharan Africa, as prevalence data are scarce. Both infections often remain undiagnosed in resource-limited settings because routine testing is not a part of most of the national guidelines. Epidemiological studies provide important information on prevalence and risk factors for such co-infections and can provide guidance for clinical management and for the development of test strategies. We analysed data on baseline characteristics, CD4 cell counts, HBV and syphilis co-infection rates of 690 patients enrolling for antiretroviral therapy in rural Cameroon. The prevalence of both hepatitis B surface antigen (HBsAg, 12.6%, 95% CI 10.1-15.1) and treponemal antibodies (11.4%, 95% CI 8.9-13.7) was high, with significantly higher prevalences for both infections in men; detection of treponemal antibodies increased with age. Although liver enzyme elevations were common, they were not useful to identify HBsAg-positive patients. In this setting, routine serological screening for HBV and syphilis co-infection should be considered to avoid complications and ongoing transmission.     

Synthesis and in vitro anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates as potential SERMs with computational validation

A series of naphthalimide-chalcone/pyrazoline conjugates was prepared and evaluated for their anti-breast cancer potential against estrogen responsive, i.e. MCF-7 (ER+), and triple-negative, i.e. MDA-MB-231 (ER−), cell lines. The structure-activity-relationship (SAR) was deduced based on the influence of linker length, substituents on the phenyl ring and the generated functionalities, on anti-proliferative activities. Docking simulations further delineate the type of interactions of the designed molecules with the selected targets. This report discloses the scope of triazole tethered naphthalimide-chalcone/pyrazoline conjugates as anti breast cancer agents.

Design, synthesis and anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates.