Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson's disease and depression.

Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson's disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or 'enhancer/suppressor' screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo, we used a mutation in the Drosophila vesicular monoamine transporter (dVMAT) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae ∼ 1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems

PENGARUH FANATISME, RANGSANG SITUASIONAL, DEINDIVIDUASI, DAN FRUSTRASI TERHADAP AGRESI PENONTON SEPAKBOLA : SUATU MODEL KAUSAL

Hasil analisis jalur dengan menggunakan program ISREL menunjukkan hahwa: agresi penonton sepakboia dipengaruhi oleh fanatisme, deindividuasi dan frustrasi. Agresi penon ton tidak dipengaruhi oleh rangsang situasional. Variabel deindividuasi tidak dipengaruhi oleh fanatisme. namun dipengaruhi oleh rangsang situasional,sedangkan frustrasi dipengaruhi oleh rangsang situasional. Masih banyak faktor yang berpengaruh pada agresi penonton sepakbola. Dan masih banyak pula pendekatan yang bisa digunakan untuk memahami perilaku agresi penon ton sepakbola. Gleh karena itu penelitian lanjutan dengan variabel penelitian lain sangat diharapkan

Film blowing of PHBV blends and PHBV-based multilayers for the production of biodegradable packages

Poly(hydroxy butyrate-co-valerate) (PHBV) is a biodegradable polymer that is difficult to melt process into films. Such difficulty is mirrored in the lack of literature on film blowing of PHBV- or PHBV-based materials. To circumvent this problem, 70/30 wt % blends of PHBV with a biodegradable compound (PBSebT), or with poly(butylene adipate-co-terephtalate) (PBAT), were prepared and tested for extrusion film blowing. Both blends showed a similar rheological pattern at 175°C, which is the maximum processing temperature with tolerable thermal degradation. Blending stabilized the film bubbles, thus widening the processing window. However, film properties such as tensile modulus, strain at break and tear resistance remained isotropic and crystallinity characteristics in the machine and transverse directions were generally similar. To bypass the thermal degradation associated with polymer blending, PHBV/PBAT films were coextruded. These showed enhanced functional properties when compared with films blown from blends. The mechanical properties of bilayered films matched those of films blown from commercial PBAT designed for food packaging.The authors acknowledge the European Commission for the financial support of the ECOefficient BIOdegradable Composite Advanced Packaging project (EcoBioCAP) within the Seventh Framework Programme (Contract-No. FP7-265669). This work was also supported by FEDER funds through the program COMPETE (project PTDC/AGR-ALI/122741/2010), by the Portuguese Foundation for Science and Technology (PEst-C/CTM/LA0025/2013 - Projecto Estrategico - LA 25 - 2013-2014 - Strategic Project - LA 25 - 2013-2014) and by Programa Operacional Regional do Norte (ON.2) through project "Matepro - Optimizing Materials and Processes", with reference NORTE-07-0124-FEDER-000037 FEDER COMPETE

Attenuation of acute systemic inflammatory response after valve surgery

Objective: This study highlights the protective effects of montelukast on myocardial ischemic reperfusion injury induced by cardiopulmonarybypass during valve replacement surgery.Methods: A total of 60 patients with valvular disease undergoing elective valve surgery were enrolled in this randomized single-blinded study.Participants were divided into two main groups: Montelukast-treated group consisted of 30 patients who were given 10 mg montelukast sodium(Singulair®, MSD, USA) tablet, once daily at bedtime for 3 days before valve surgery. Control group consisted of 30 patients who underwent valvesurgery without taking montelukast tablets. Blood samples were collected at following times (T0; T1 before aortic cross clamp; T2 after aortic crossclamp; and T3 24 h after the surgery), for measuring several inflammatory markers. Ejection fraction (EF) was measured before surgery and threemonths after surgery. Pulmonary functions were measured before and after the surgery in both study groups.Results: There were significant increase in the levels of TNF-a, IL-6, a2 macroglobulin/creatinine ratio and CTnI, in the control groupcompared to the montelukast-treated group among different study times, (P Conclusion: This study shows the benefits of using pre-surgical montelukast supplement in ameliorating the inflammatory process inpatients undergoing cardiopulmonary bypass during valve replacement surgery

Gravitational collapse with tachyon field and barotropic fluid

A particular class of space-time, with a tachyon field, \phi, and a barotropic fluid constituting the matter content, is considered herein as a model for gravitational collapse. For simplicity, the tachyon potential is assumed to be of inverse square form i.e., V(\phi) \sim \phi^{-2}. Our purpose, by making use of the specific kinematical features of the tachyon, which are rather different from a standard scalar field, is to establish the several types of asymptotic behavior that our matter content induces. Employing a dynamical system analysis, complemented by a thorough numerical study, we find classical solutions corresponding to a naked singularity or a black hole formation. In particular, there is a subset where the fluid and tachyon participate in an interesting tracking behaviour, depending sensitively on the initial conditions for the energy densities of the tachyon field and barotropic fluid. Two other classes of solutions are present, corresponding respectively, to either a tachyon or a barotropic fluid regime. Which of these emerges as dominant, will depend on the choice of the barotropic parameter, \gamma. Furthermore, these collapsing scenarios both have as final state the formation of a black hole.Comment: 18 pages, 7 figures. v3: minor changes. Final version to appear in GR

Educating and Informing Patients Receiving Psychopharmacological Medications: Are Family Physicians in Pakistan up to the Task?

Introduction: Studies have shown a high prevalence of psychiatric illnesses among Patients in primary health care settings. Family physicians have a fundamental role in managing psychiatric illness with psychopharmacological medications. Providing information about the disease, its management and the potential adverse effects of the medications is an important part of the management of mental illnesses. Our objective was to determine if Patients who were prescribed psychopharmacological drugs by family physicians at a community health center in Karachi, Pakistan were provided adequate education about their disease and its management. Methods: A cross-sectional study was conducted at the Community Health Centre (CHC), Aga Khan University Hospital Karachi, Pakistan. Details about the prescriptions and Patient education were acquired from the Patients after their consultations. Results: A total of 354 adult Patients were interviewed during 3 days. Among them, 73 (20.6%) were prescribed psychopharmacological medications. Among Patients receiving psychopharmacological medicines, 37 (50.7%) did not know their diagnosis, 50 (68.5%) were unaware of the disease process, 52 (71.2%) were unaware of alternative treatments, 63 (86.3%) were not cautioned about the potential adverse effects of the drugs, 24 (32.9%) were unaware of the duration of treatment and in 60 (82.2%) of the participants an appropriate referral had not been discussed. For all aspects of education, Patients prescribed psychopharmacological medications knew less as compared to those Patients that were prescribed other medications. Discussion: The practice of imparting information to Patients who receive psychopharmacological medications seems to be inadequate in Pakistan. We have hypothesized about the possible reasons for our findings, and identified a need for further research to determine the cause for such findings and to address them accordingly. At the same time there is a need to educate family physicians in Pakistan about the special importance of providing adequate information to such Patients

Increased Recruitment but Impaired Function of Leukocytes during Inflammation in Mouse Models of Type 1 and Type 2 Diabetes

BACKGROUND: Patients suffering from diabetes show defective bacterial clearance. This study investigates the effects of elevated plasma glucose levels during diabetes on leukocyte recruitment and function in established models of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: Diabetes was induced in C57Bl/6 mice by intravenous alloxan (causing severe hyperglycemia), or by high fat diet (moderate hyperglycemia). Leukocyte recruitment was studied in anaesthetized mice using intravital microscopy of exposed cremaster muscles, where numbers of rolling, adherent and emigrated leukocytes were quantified before and during exposure to the inflammatory chemokine MIP-2 (0.5 nM). During basal conditions, prior to addition of chemokine, the adherent and emigrated leukocytes were increased in both alloxan- (62±18% and 85±21%, respectively) and high fat diet-induced (77±25% and 86±17%, respectively) diabetes compared to control mice. MIP-2 induced leukocyte emigration in all groups, albeit significantly more cells emigrated in alloxan-treated mice (15.3±1.0) compared to control (8.0±1.1) mice. Bacterial clearance was followed for 10 days after subcutaneous injection of bioluminescent S. aureus using non-invasive IVIS imaging, and the inflammatory response was assessed by Myeloperoxidase-ELISA and confocal imaging. The phagocytic ability of leukocytes was assessed using LPS-coated fluorescent beads and flow cytometry. Despite efficient leukocyte recruitment, alloxan-treated mice demonstrated an impaired ability to clear bacterial infection, which we found correlated to a 50% decreased phagocytic ability of leukocytes in diabetic mice. CONCLUSIONS/SIGNIFICANCE: These results indicate that reduced ability to clear bacterial infections observed during experimentally induced diabetes is not due to reduced leukocyte recruitment since sustained hyperglycemia results in increased levels of adherent and emigrated leukocytes in mouse models of type 1 and type 2 diabetes. Instead, decreased phagocytic ability observed for leukocytes isolated from diabetic mice might account for the impaired bacterial clearance

Prevalence and phase variable expression status of two autotransporters, NalP and MspA, in carriage and disease isolates of Neisseria meningitidis.

Neisseria meningitidis is a human nasopharyngeal commensal capable of causing life-threatening septicemia and meningitis. Many meningococcal surface structures, including the autotransporter proteins NalP and MspA, are subject to phase variation (PV) due to the presence of homopolymeric tracts within their coding sequences. The functions of MspA are unknown. NalP proteolytically cleaves several surface-located virulence factors including the 4CMenB antigen NhbA. Therefore, NalP is a phase-variable regulator of the meningococcal outer membrane and secretome whose expression may reduce isolate susceptibility to 4CMenB-induced immune responses. To improve our understanding of the contributions of MspA and NalP to meningococcal-host interactions, their distribution and phase-variable expression status was studied in epidemiologically relevant samples, including 127 carriage and 514 invasive isolates representative of multiple clonal complexes and serogroups. Prevalence estimates of >98% and >88% were obtained for mspA and nalP, respectively, with no significant differences in their frequencies in disease versus carriage isolates. 16% of serogroup B (MenB) invasive isolates, predominately from clonal complexes ST-269 and ST-461, lacked nalP. Deletion of nalP often resulted from recombination events between flanking repetitive elements. PolyC tract lengths ranged from 6-15 bp in nalP and 6-14 bp in mspA. In an examination of PV status, 58.8% of carriage, and 40.1% of invasive nalP-positive MenB isolates were nalP phase ON. The frequency of this phenotype was not significantly different in serogroup Y (MenY) carriage strains, but was significantly higher in invasive MenY strains (86.3%; p<0.0001). Approximately 90% of MenB carriage and invasive isolates were mspA phase ON; significantly more than MenY carriage (32.7%) or invasive (13.7%) isolates. This differential expression resulted from different mode mspA tract lengths between the serogroups. Our data indicates a differential requirement for NalP and MspA expression in MenB and MenY strains and is a step towards understanding the contributions of phase-variable loci to meningococcal biology

Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro