Ligand based pharmacophore model development for the identification of novel antiepileptic compound

Epilepsy is a common neurological disorder throughout the world which is characterized by recurrent unprovoked epileptic seizures. A need exists for the development of new antiseizure drugs with improved efficacy and tolerability, as several of the currently available antiepileptic drugs (AEDs) have been associated with severe side effects. A ligand based pharmacophore approach has been generated for 44 new antiepileptic compounds with emphasis on the development of new drugs by using LigandScout software and distance estimation using Jmol. The pharmacophore of the compounds contained three features hydrophobic unit, hydrogen bonding domain and electron donor. The pharmacophore models derived were then filtered using the Lipinski's rule of five criteria and orally bio-available compounds were obtained. Thus, this approach was able to reclaim few leads which had projected inhibitory activity alike to most active compounds with suitable calculated drug-like properties and therefore they could be recommended for further studies.     

Mitochondrial oxidative stress-induced brain and hippocampus apoptosis decrease through modulation of caspase activity,Ca2+ influx and inflammatory cytokine molecular pathways in the docetaxel-treated mice by melatonin and selenium treatments

Docetaxel (DOCE) is widely used to treat several types of glioblastoma. Adverse effects DOCE seriously limit its clinical use in several tissues. Its side effects on brain cortex and hippocampus have not been clarified yet. Limited data indicated a protective effect of melatonin (MLT) and selenium (SELEN) on DOCE-induced apoptosis, Ca²⁺ influx and mitochondrial reactive oxygen species (ROS) in several tissues except brain and hippocampus. The purpose of this study is to discover the protective effect of MLT and SELEN on DOCE-induced brain and hippocampus oxidative toxicity in mice. MLT and SELEN pretreatments significantly ameliorated acute DOCE-induced mitochondrial ROS production in the hippocampus and brain tissues by reducing levels of lipid peroxidation, intracellular ROS production and mitochondrial membrane depolarization, while increasing levels of total antioxidant status, glutathione, glutathione peroxidase, MLT, α-tocopherol, γ-tocopherol, vitamin A, vitamin C and β-carotene in the tissues. Furthermore, MLT and SELEN pretreatments increased cell viability and TRPM2 channel activation in the hippocampus and brain followed by decreased activations of TNF-α, IL-1β, IL-6, and caspase ?3 and???9, suggesting a suppression of calcium ion influx, apoptosis and inflammation responses. However, modulator role of SELEN on the values in the tissues is more significant than in the MLT treatment. MLT and SELEN prevent DOCE-induced hippocampus and brain injury by inhibiting mitochondrial ROS and cellular apoptosis through regulating caspase ?3 and???9 activation signaling pathways. MLT and SELEN may serve as potential therapeutic targets against DOCE-induced toxicity in the hippocampus and brain.

     

Patterns of recognition of Arabic consonants by non-native children with cochlear implants and normal hearing

Objective: This study examined the patterns of recognition of Arabic consonants, via information transmission analysis for phonological features, in a group of Malay children with normal hearing (NH) and cochlear implants (CI).

Method: A total of 336 and 616 acoustic tokens were collected from six CI and 11 NH Malay children, respectively. The groups were matched for hearing age and duration of exposure to Arabic sounds. All the 28 Arabic consonants in the form of consonant–vowel /a/ were presented randomly twice via a loudspeaker at approximately 65?dB SPL. The participants were asked to repeat verbally the stimulus heard in each presentation.

Results: Within the native Malay perceptual space, the two groups responded differently to the Arabic consonants. The dispersed uncategorized assimilation in the CI group was distinct in the confusion matrix (CM), as compared to the NH children. Consonants /?/, /t?/, /s?/ and /?/ were difficult for the CI children, while the most accurate item was /k/ (84%). The CI group transmitted significantly reduced information, especially for place feature transmission, then the NH group (p?Conclusion: CI and NH Malay children may be using different acoustic cues to recognize Arabic sounds, which contribute to the different assimilation categories’ patterns within the Malay perceptual space.     

Kras-mutation influences outcomes for palliative primary tumor resection in advanced colorectal cancer-a Turkish Oncology Group study

Purpose

We aimed to investigate the prognostic effect of primary tumor resection (PTR) prior to bevacizumab-based treatments in unresectable metastatic colorectal cancer (mCRC).

Interleukins-6 and −8 Levels in Sera and Cervical Mucus of Fertile,Idiopathic Infertile,and Immunoinfertile Women: Implication in Infertility

PROBLEM: The purpose of this study was to investigate the levels of interleukin-6 and ?8 (IL-6 and IL-8) in sera and cervical mucus of infertile (idiopathic and immunoinfertile) women and to compare the levels with those in age-matched normally cycling fertile women. METHODS: Levels of IL-6 and IL-8 were measured in the sera and cervical mucus of fertile and infertile women by the enzyme-linked immunosorbent assay (ELISA). A non-parametric Mann-Whitney test was used to evaluate significance between the means. Linear regression analysis of IL-6 and IL-8 concentrations in serum versus cervical mucus and with antisperm antibody titers was performed by condition as well as all groups together. P < 0.05 was considered significant. RESULTS: Both IL-6 and IL-8 were detected in sera and cervical mucus of fertile as well as infertile groups. Although serum levels of IL-6 and IL-8 were significantly different between fertile and infertile groups, the differences were more pronounced in the cervical mucus samples. Cervical mucus of idiopathic and immunoinfertile women demonstrated significantly (P = 0.002 to < 0.0001) greater concentrations of IL-6 and IL-8 compared to fertile controls. In general, there was no significant correlation between the serum and cervical mucus IL-6 and IL-8 levels, whether analyzed by condition or all groups together. CONCLUSIONS: Elevated levels of IL-6 and IL-8 in cervical mucus of infertile groups may play a role in etiology of idiopathic and immunologic infertility. These findings suggest that the measurements of cytokines (especially IL-6 and IL-8) in cervical mucus may provide a tool for specific diagnosis and possibly treatment of infertility, especially idiopathic infertility.     

Presence of antibodies to sperm YLP(12) synthetic peptide in sera and seminal plasma of immunoinfertile men

Using an enzyme-linked immunosorbent assay (ELISA), sera (n = 15) and seminal plasma (n = 30) from antisperm antibody-positive immunoinfertile men (n = 45) and from fertile men (n = 45), were tested for the immunoreactivity with the synthetic YLP(12) sperm peptide. Of the 15 immunoinfertile sera tested, 46% were positive for immunoglobulin (Ig)M, 73% for IgG, and 40% for IgA. Of the 30 samples of immunoinfertile seminal plasma tested, 10% were positive for IgM, 20% for IgG, and 43% for IgA. None of the sera or seminal plasma from fertile men showed a positive reaction. There was no significant correlation between the sperm immobilization technique (SIT) or tray agglutination technique (TAT) titres or percentage binding in immunobead binding technique (IBT) and the antibody reactivity for any class in the ELISA. The YLP(12) peptide conjugated to bovine serum albumin-Sepharose 4B beads pulled out IgG antibodies from the serum of the immunoinfertile, but not the fertile, men. The beads pulled out IgA antibodies from the immunoinfertile, but not the fertile, seminal plasma. The immuno-affinity purified antipeptide antibodies reacted with a specific band of 72 +/- 5 kDa in the human testis and with a specific band of approximately 50 +/- 5 kDa in the human sperm extracts. The YLP(12) peptide may have applications in the specific diagnosis and treatment of male infertility and in contraceptive vaccine development.     

The influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis

OBJECTIVE: To investigate the influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis (IP), and to examine predictors of mortality in relation to disease duration. METHODS: From 1990 to 1994, patients with recent-onset IP were registered with the Norfolk Arthritis Register (NOAR) and followed up prospectively. Standardized mortality ratios (SMRs) were calculated for all-cause and cardiovascular disease (CVD) mortality and for those who were younger than age 55 years at disease onset and for the first 5 and 10 years of followup. Cox proportional hazards models were developed to assess predictors of early and later mortality. RESULTS: Of 1,098 patients, 224 (20%) had died by the end of 2004. All-cause and CVD mortality were increased in rheumatoid factor (RF)-positive patients and in this subgroup, CVD mortality was increased at both early and later followup (SMR 5-year followup 1.93 [95% confidence interval 1.08-3.19]; SMR 10-year followup 2.00 [95% confidence interval 1.37-2.80]). CVD mortality was highest in seropositive patients<55 years of age at disease onset (SMR 5.58 [95% confidence interval 2.24-11.50]). In multivariate models, age at onset, male sex, RF positivity, Health Assessment Questionnaire score>or=1.5, and nodules were predictors of early and later mortality. CONCLUSION: Patients with IP had higher rates of CVD mortality throughout the followup period studied, and this was highest in seropositive patients who were <55 years of age at symptom onset. This subgroup deserves particular attention in terms of disease and risk factor modification. Nodules were independent predictors of CVD mortality, suggesting that extraarticular/vascular inflammation identifies patients at particularly high CVD risk.