Usefulness of MEG magnetometer for spike detection in patients with mesial temporal epileptic focus

The present study investigated the sensitivity of magnetoencephalography (MEG) for spikes depending on sensor type in patients with mesial temporal epileptic focus. We recorded MEG in 6 patients with mesial temporal epileptic focus using two sensor types (magnetometer and gradiometer) simultaneously. The number of spikes detected and the corresponding equivalent current dipole (ECD) parameters (distance from the coordinated head center (radius), and dipole moment) were evaluated with respect to sensor type. Among 426 MEG 'consensus spikes' determined by 3 reviewers, 378 spikes satisfied the predetermined criteria for source localization. Comparing ECD parameters, spikes detected by magnetometer alone displayed a smaller radius and larger dipole moment than those detected by gradiometer alone. Spikes estimated in the mesial temporal area were more frequently detected by magnetometer alone (38.5%) than by gradiometer alone (11.5%), whereas spikes in the lateral temporal area were detected less by magnetometer alone (3.7%) than by gradiometer alone (53.9%). The present results suggest that a magnetometer is advantageous for spike detection in patients with mesial temporal epileptic focus. This also implies the higher sensitivity of magnetometer for deep sources.     

Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility

Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at G?-G? phase, which resulted from dysregulation of cAMP/protein kinase A (PKA)-activated and mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G?/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor (MPF)), a key regulator of G?/M transition.     

In silico and in vitro immunomodulatory studies on compounds of Lindelofia stylosa

Lindolefia stylosa (Kar. and Kir.) is an important medicinal plant in Central and West Asia. Compounds 1 (ethyl lithospermate), 2 (methyl lithospermate), 3 (lithospermate B), 4 (rosmarinic acid), 5 (methyl rosmarinate), 6 (ethyl rosmarinate), 7 (3-O-feruloyl-6'-O-coumaroyl sucrose), 8 (3-O-feruloyl-6'-O-caffeoyl sucrose), 9 (3,6'-O-diferuloyl sucrose), 10 (3,6'-O-diferuloyl-1-kestose), 11 (3-O-feruloyl-6'-O-coumaroyl-1-kestose), 12 (3,6'-O-diferuloyl nystose), 13 (3-O-Feruloyl-6'-O-coumaroyl nystose), 14 (p-coumaric acid), 15 (ferulic acid), 16 (naphthalene glycoside (8-O-β-D-glucopyranoside)), and 17 (4'-hydroxy-5-methoxy-6,7-methylenedioxyisoflavone), isolated from this plant, were evaluated for their ability to modulate the immune response. Studies included monitoring the effect on reactive oxygen species (ROS) production, T-lymphocyte proliferation, and inhibition of four cytokines (IL-2, TNFα, IL-1β, and IL-4). These cytokines play a major role in immune response modulation. Molecular docking studies on selected compounds were also conducted, which predict a potent activity of compounds 5 and 6 and moderate activity of compounds 1 and 2 as inhibitors of IL-2. Correlation between the predicted binding scores and the experimental results was found to be valid. Compound 5 was identified as the most potent IL-2 inhibitor in the series.     

No impairment of monocyte-derived Langerhans cell phenotype or function in early-onset psoriasis

Background. Migration of epidermal Langerhans cells (LCs) in response to the cytokines interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α is impaired in uninvolved skin of patients with early‐onset psoriasis. Aim. To investigate whether this impairment is a reflection of a systemic defect in dendritic cells (DCs), using an established model of monocyte‐derived LC‐like cells (mLCs). Methods. CD14+ monocytes isolated from both patients with psoriasis and healthy control volunteers were cultured in a cytokine cocktail for 5 days to promote their differentiation into mLCs, then stimulated for 24 h with TNF‐α, IL‐1β (both 100 ng/mL) or medium alone. Cellular surface protein expression was quantified by flow cytometry, and the ability of cells to migrate to media supplemented with C‐C motif ligand (CCL)19 was assessed using a Transwell migration assay. The cytokine and chemokine content of supernatants was analysed by cytokine array. Results. CD14+ cells acquired an LC‐like phenotype with high expression of CD1a and major histocompatibility complex (MHC) class II. There were no differences in the expression of activation markers or in the secretion of cytokines by mLCs isolated from patients with psoriasis and those isolated from healthy controls. Moreover, mLCs isolated from both groups displayed comparable ability to migrate in vitro. Conclusions. These data suggest that the failure of LCs to migrate in response to stimulation in patients with psoriasis is not attributable to a systemic defect in DC function, but is rather a reflection of local changes in the epidermal microenvironment.     

Viewpoint: do we have enough data to estimate the current burden of tuberculosis? The example of Bangladesh

Objective National tuberculosis (TB) programmes need accurate estimates of the burden of TB in order to assess case detection, and progress towards the millennium development goals (MDGs). We reviewed nationwide epidemiological data on TB burden in Bangladesh to decide whether additional information is needed, in order to assess the current burden of TB. Method We collected all nationwide epidemiological information: notification data for the period 1995–2004; reports of TB prevalence surveys in 1964–1966 and 1987–1988 and a tuberculin survey in 1964–1966. Data were evaluated for usefulness to provide information about the current burden of TB. Results The TB prevalence surveys from 1964 to 1966 and 1987 to 1988 provide very different results, respectively, 127/100 000 and 471/100 000 smear positives. In 1964–1966, the annual risk of infection was 0.6% in the 5‐ to 9‐year age group and 1.2% in those aged between 10 and 14 years. The notification data show an increase from 18/100 000 in 1995 to 46/100 000 smear positives in 2004. Conclusion Interpretation and extrapolation of the existing epidemiological data of Bangladesh to estimate the current burden of TB is difficult. Many of the 22 high‐burden countries have as few or even less survey data than Bangladesh. To enable the evaluation of progress towards the MDGs and to be able to assess the global burden of TB, epidemiological surveys are needed.     

Insulin secretory actions of extracts of Asparagus racemosus root in perfused pancreas, isolated islets and clonal pancreatic beta-cells

Asparagus racemosus root has previously been reported to reduce blood glucose in rats and rabbits. In the present study, the effects of the ethanol extract and five partition fractions of the root of A. racemosus were evaluated on insulin secretion together with exploration of their mechanisms of action. The ethanol extract and each of the hexane, chloroform and ethyl acetate partition fractions concentration-dependently stimulated insulin secretion in isolated perfused rat pancreas, isolated rat islet cells and clonal beta-cells. The stimulatory effects of the ethanol extract, hexane, chloroform and ethyl acetate partition fractions were potentiated by glucose, 3-isobutyl-1-methyl xanthine IBMX, tolbutamide and depolarizing concentration of KCl. Inhibition of A. racemosus-induced insulin release was observed with diazoxide and verapamil. Ethanol extract and five fractions increased intracellular Ca(2+), consistent with the observed abolition of insulin secretory effects under Ca(2+) -free conditions. These findings reveal that constituents of A. racemosus root extracts have wide-ranging stimulatory effects on physiological insulinotropic pathways. Future work assessing the use of this plant as a source of active components may provide new opportunities for diabetes therapy.     

Drug resistance of Mycobacterium tuberculosis in the Sunamganj District of Bangladesh

Spread of drug-resistant tuberculosis (TB) threatens TB-control programmes, and all countries need to monitor the patterns and trends of anti-TB drug resistance. Such data assess the quality of control programmes and help forecast future trends of drug resistance. It will also help to establish guidelines for TB therapy. The aim of the current study was to describe the rate of drug-resistant Mycobacterium tuberculosis in the Sunamganj District of Bangladesh. Bacterial isolates were collected from sputum smear positive (ss+) patients who attended the National TB Programme from November 2003 to December 2004. A total of 95 isolates was tested for susceptibility to streptomycin (SM), isoniazid (INH), rifampicin (RMP) and ethambutol (EMB) at the National Reference Laboratory for Mycobacteria at the Norwegian Institute of Public Health (NIPH), Oslo. The total resistance among new cases to any drug was 31%. For SM it was 18%, INH 23%, RMP 2%, EMB 10% and 2% were multidrug-resistant (MDR). The National Tuberculosis Programme (NTP) in Sunamganj is still effective, although the high resistance to INH is alarming. An increased risk of treatment failure has been demonstrated in areas with high levels of INH resistance, and a high proportion of INH resistant cases may develop resistance to RMP during treatment.     

Probing the pharmacophore of ginkgolides as glycine receptor antagonists

Ginkgolides are antagonists of the inhibitory ligand-gated ion channels for the neurotransmitters glycine and gamma-aminobutyric acid (GABA). In this study the ginkgolide structure was modified in order to investigate the minimum structural requirements for glycine receptor antagonism. The five native ginkgolides and a series of 29 ginkgolide derivatives were characterized at the three glycine receptor subtypes alpha1, alpha1beta, and alpha2, which revealed that only minor changes in the ginkgolide skeleton were allowed for maintaining glycine receptor antagonism. A pharmacophore model was generated and applied in a virtual screening of a compound database (300000 compounds), resulting in the identification of 31 hits. Twenty-seven of these hits were screened for biological activity, but none displayed antagonist activity at the glycine receptors. This strongly suggests the importance of other pharmacophore components in the binding of ginkgolides to glycine receptors, and we propose that the structural rigidity of the ginkgolide molecule may be crucial for its glycine receptor activity.