Evaluation of interactions between cannabinoid compounds and diazepam in electroshock-induced seizure model in mice

Several studies have shown that cannabinoids have anticonvulsant properties that are mediated through activation of the cannabinoid CB1 receptors. In addition, endogenous cannabinoid compounds (endocannabinoids) regulate synaptic transmission and dampen seizure activity via activation of the same receptors. The aim of this study was to evaluate the possible interactions between antiepileptic effects of cannabinoid compounds and diazepam using electroshock-induced model of seizure in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, fixed current intensity 35 mA, stimulus duration 0.2 s) and tonic hindlimb extension was taken as the endpoint. All experiments were performed on groups of ten mice and the number of animals who did not display seizure reported as percent protection. Intraperitoneal (i.p.) administration of diazepam (0.25-2 mg/kg) and CB1 receptor agonist WIN55212-2 (0.5-4 mg/kg) dose dependently produced an antiepileptic effect evaluated in terms of increased percentage of protection against electroshock-induced seizure. Logistic regression analysis indicated synergistic interactions in anticonvulsant action after co-administration of diazepam and WIN55212-2 in fixed-ratio combination of 3:1 (diazepam:WIN55212-2), while an additive effect was resulted after co-administration of 1:1 and 1:3 fixed-ratio combinations. Administration of various doses of the endocannabinoid reuptake inhibitor, AM404, did not produce any effect on electroshock-induced seizure. Moreover, co-administration of AM404 and diazepam did not produce significant interaction in antiepileptic properties of these compounds. Administration of the fatty acid amide hydrolase inhibitor, URB597, produced significant antiepileptic effect. Co-administration of URB597 and diazepam led to an antagonistic interaction in protection against shock-induced seizure. Co-administration of different doses of the cannabinoid CB1 receptor antagonist, AM251 did not alter the antiepileptic effect of diazepam in the electroshock-induced seizure test. These results demonstrate that endocannabinoid system participates in the modulation of seizure and combination of small doses of exogenous CB1 receptor agonists with diazepam may have effective consequences in seizure control. Furthermore, inhibiting the endocannabinoid degradation could be more efficacious in modulating seizure than preventing their uptake. This study also suggests that the effects of cannabinoids on epilepsy depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission. While, the antiepileptic effects of cannabinoid compounds are likely by affecting excitatory glutamate neurotransmission, the antagonistic interaction between cannabinoid compounds and diazepam to protect seizure is due to the cannabinoid action on inhibitory GABAergic system.     

The response of fibrinogen,platelets, endothelial and smooth muscle cells to an electrochemically modified SS316LS surface: Towards the enhanced biocompatibility of coronary stents

Modification of a biomedical-grade stainless steel 316LS surface by electrochemical cyclic potentiodynamic passivation (CPP) and the response of fibrinogen (Fg), platelets, endothelial cells (ECs) and smooth muscles cells (SMCs) to this surface was investigated. Polarization modulation infrared reflection absorption spectroscopy revealed a significant difference between the secondary structure of Fg adsorbed on the unmodified and CPP surface, the latter being closer to that of native Fg. This was postulated as the origin of the significantly lower surface density of attached platelets on the CPP surface. The competitive interaction of ECs and SMCs with the surface showed that the ECs/SMCs surface density ratio is significantly higher on the CPP surface over the first 2 h of attachment, suggesting faster initial attachment kinetics of ECs on the CPP surface. The presented results thus clearly demonstrate an increase in biocompatibility of the CPP 316LS surface.     

Distribution of Helicobacter pylori cagA, cagE, oipA and vacA in different major ethnic groups in Tehran, Iran

Background and Aim:  There are geographical variations in Helicobacter pylori virulence genes; cagA , cagE , vacA and oipA . The present study compared the distribution of these genotypes in major ethnic groups residing in Tehran, Iran and their association with clinical outcomes.
Methods:  A total of 124 H. pylori -positive patients living in Tehran were enrolled in this study. The ethnic distribution was 74 Persians, 33 Turks and 17 other ethnics including Kurds, Lurs, Afghanis and Arabs. The presence of the cagA , cagE and oipA genes and vacA alleles (signal [s] and middle [m] region) were determined by polymerase chain reaction (PCR) from H. pylori DNA.
Results:  The cagA -positive status was predominant in all three ethnic groups (e.g. 65% in Persians and 73% in Turks). In contrast, the cagE -positive status was less than half in Persians (47%) and Turks (30%), whereas it was 77% in other ethnicities ( P  = 0.008). The predominant vacA genotypes were s1 and m1 in all three ethnic groups (e.g. 68% in Persians and 70% in Turks were s1). There was no significant association between cagA and cagE status or vacA genotypes and clinical outcomes. The oipA -positive strains were more common in non-ulcer dyspepsia (NUD) (63%) than in peptic ulcer patients (15%) ( P  = 0.001) in Persians, but the association was not observed in other ethnic groups.
Conclusion:  There are some differences in the H. pylori genotypes among the ethnic groups in Iran. However, none of these markers seemed to be clinically helpful in predicting the clinical presentation of a H. pylori infection in Iran.     

Boundary Conditions in Simulation of Stenosed Coronary Arteries

A powerful alternative means to studying hemodynamics in diseased or healthy coronary arteries can be achieved by providing a numerical model in which blood flow can be virtually simulated, for instance, using the computational fluid dynamics (CFD) method. In fact, it is well documented that CFD allows reliable physiological blood flow simulation and measurements of flow parameters. A requisite for obtaining reliable results from coronary CFD is to use exact anatomical models and realistic boundary conditions. To date, in almost all of the modeling studies on hemodynamics of stenosed coronary arteries, a velocity based boundary conditions has been assigned. The objective of this study is to show that inlet velocity actually depends on the degree of stenosis and thus for severe constriction in coronary artery, a velocity based boundary conditions cannot be realistic. We then prove that regardless of severity of stenosis in coronary arteries, the upstream pressure, systemic pressure, is always constant, thus, should be used as boundary conditions instead. The two sets of boundary conditions are implemented to demonstrate the robustness of each in modeling of stenosed coronary artery in a CFD study. These boundary conditions are applied in a stenosed cylindrical pipe including three categories of symmetrical stenosis (mild, moderate and severe stenosis starting from 15 to 95% diameter reduction) for steady state and pulsatile flow. Results strongly indicate that inlet velocity boundary conditions are no longer valid when effective diameter in stenosis goes below ~2.8 mm (a healthy diameter is considered 3.2 mm) which corresponds to 10–15% diameter reduction. Further work will determine the effect of flow reduction on the oxygen tension in blood to better define conditions for clinical symptoms such as angina.     

Clinical and immunological features of 65 Iranian patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and recurrent bacterial infections. The records of 65 patients with CVID (37 males and 28 females) in the age range of 24 to 537 months were reviewed. By the year 2003, 11 patients had died and seven patients could not be located. The total follow-up period was 221 patient-years. The median diagnostic delay (time between onset and diagnosis) in our patient group was 60 months. At the time of diagnosis, the baseline serum immunoglobulin G (IgG), IgM, and IgA levels were below the level normal for the patients' age; the medians for this group were 120, 10, and 0 mg/dl, respectively. All of the patients presented with infectious diseases at the time of onset, the most common of which were otitis media, diarrhea, pneumonia, and sinusitis. Acute and recurrent infections were also found in almost all of the patients, particularly involving respiratory and gastrointestinal systems. The most common infections, before diagnosis and during follow-up, were pneumonia, acute diarrhea, acute sinusitis, and otitis media. CVID should be considered in any patient with a history of recurrent infections and decreased levels of all serum immunoglobulin isotypes.     

Development of bactericidal spinel ferrite nanoparticles with effective biocompatibility for potential wound healing applications

The current study was devised to explore the antibacterial activity and underlying mechanism of spinel ferrite nanoparticles (NPs) along with their biocompatibility and wound healing potentials. In this regard, nickel ferrite and zinc/nickel ferrite NPs were synthesized via a modified co-precipitation method and were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy Energy-dispersive X-ray spectroscopy (EDX). The biocompatibility of the synthesized NPs with human dermal fibroblast (HDF) and red blood cells (RBCs) was assessed. The biocompatible concentrations of the NPs were used to investigate the antimicrobial activity against various pathogenic Gram-negative and Gram-positive bacteria. The mode of bactericidal action was also explored. In vitro scratch assay was performed to evaluate the wound healing potential of NPs. The SEM-EDX analysis showed that the average particles size of nickel ferrite and zinc/nickel ferrite were 49 and 46 nm, respectively, with appropriate elemental composition and homogenous distribution. The XRD pattern showed all the characteristic diffraction peaks of spinel ferrite NPs, which confirmed the synthesis of the pure phase cubic spinel structure. The biocompatible concentration of nickel ferrite and zinc/nickel ferrite NPs was found to be 250 and 125 μg ml⁻¹, respectively. Both the NPs showed inhibition against all the selected strains in the concentration range of 50 to 1000 μg ml⁻¹. Studies on the underlying antimicrobial mechanism revealed damage to the cell membrane, protein leakage, and intracellular reactive oxygen species production. The in vitro scratch assay confirmed the migration and proliferation of fibroblast with artificial wound shrinkage. This study shows that nickel ferrite and zinc/nickel ferrite NPs could be a strong candidate for antibacterial and wound healing nano-drugs.

The current study was devised to explore the antibacterial activity and underlying mechanism of spinel ferrite nanoparticles (NPs) along with their biocompatibility and wound healing potentials.     

Expression Analysis of Fyn and Bat3 Signal Transduction Molecules in Patients with Chronic Lymphocytic Leukemia

Background: Chronic lymphocytic leukemia (CLL) is correlated with defects in T-cell function resulting imparity in antitumor immune responses. Tim-3 is a co-inhibitory immune checkpoint receptor expressed on exhausted T-cells during tumor progression. Fyn and Bat3 are two important adaptor molecules involved in inhibition and activation of Tim-3 downstream signaling, respectively. In this study, the expression of Tim-3, Fyn, and Bat3 mRNA was evaluated in CLL patients. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 54 patients with CLL and 34 healthy controls. Total RNA was extracted from all samples and applied for cDNA synthesis. The relative expression of Tim-3, Fyn, and Bat3 mRNA was determined by TaqMan Real-Time PCR using GAPDH as an internal control. Results: Tim-3 mRNA expression was not significantly different between CLL patients and healthy controls. Fyn mRNA expression was significantly lower in CLL patients and conversely, Bat3 mRNA expression was higher in CLL patients compared to healthy controls. Interestingly, the mRNA expression of Fyn inhibitory adaptor molecule was remarkably associated with expression of Tim-3 in CLL patients. Conclusion: We have highlighted for the first time the expression of Fyn and Bat3 adaptor molecules in CLL patients. Our data demonstrated the strong correlation between the expression of Tim-3 and Fyn inhibitory molecules in CLL implying an important role for Tim-3-Fyn cooperation in induction of T-cell exhaustion.     

Preliminary results of Phase I/II study of high-dose-rate intraoperative radiation therapy for pediatric tumors

Ten children with locally advanced or recurrent tumors were treated on a Phase I/II study to assess the feasibility and toxicity of intraoperative radiotherapy (IORT) for primary and recurrent pediatric solid malignancies at high risk for local recurrence. Eligible patients include all primary and recurrent pediatric solid tumors that are amenable to resection and have residual microscopic or gross disease after surgery. In all cases, after a gross tumor resection was performed, a flexible, transparent, multichannel applicator was placed and secured within the tumor bed. Once the position of the applicator was optimized, the applicator catheters were attached to the cables of a high-dose-rate remote afterloader, and 1,200 cGy prescribed to 0.5–1.0 cm from the applicator was delivered to the tumor bed via the remote afterloader. One patient with a malignant teratoma developed a peri-rectal abscess 1 month after treatment; no other complications were noted. The 2-year actuarial local recurrence-free and distant metastases-free survival were 80% and 59%, respectively, with a median follow-up of 12 months (range: 3–18 months). The preliminary results suggest that high-dose-rate IORT is a safe and feasible modality for pediatric tumors at high risk for local recurrence. Longer follow-up will be needed to assess fully the toxicity and efficacy of this approach. © 1996 Wiley-Liss, Inc.