Subtype specificity of γ-aminobutyric acid type A receptor antagonism by clozapine

Clozapine, an atypical neuroleptic, functionally antagonizes the -aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, -aminobutyric acid type A (GABA_A) receptor, in brain vesicles. GABA_A antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [³⁵S]t-butylbicyclophosphorothionate ([³⁵S]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABA_A antagonist 2-(3-carboxy-2,3-propyl)-3-amino-6-p-methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [³⁵S]TBPS binding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [³H]muscimol and [³H]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [³⁵S]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [35S]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas where its antagonism was greater than average. Recombinant 622 receptors, the predominant 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism by clozapine up to 100 M. In contrast, recombinant 122 receptors, forming the predominant receptor subtype in the brain, were clozapine sensitive. Recombinant 622 and 632 receptors resulted in clozapine-insensitive receptors, whereas 612 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in 1x2 receptors decreased in the order of 112>122>132. The results indicate that clozapine antagonizes the function of most GABA_A receptor subtypes, and that the interaction is determined by the interaction of the and subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment.     

Medical and dental implications of cocaine abuse

With the ever-increasing supply of cocaine and use of "crack," the potent and smokeable form of cocaine, the dangers of cocaine abuse, with its high morbidity and mortality, have become recognized. Oral and maxillofacial surgeons may frequently and unknowingly be treating patients who use cocaine, and, therefore, they must be educated about cocaine-related problems and be prepared to deal with the complications. This article discusses the nature of cocaine, its pharmacology, systemic affects, the oral manifestations of cocaine abuse, and recommended clinical management of the patient.     

Interaction of topiramate with glycine receptor channels

Glycine receptor channels are pentameric ligand-gated ion channels that respond to the application of inhibitory neurotransmitters by opening of a chloride-selective central pore. Topiramate (TPM) is a broad-spectrum antiepileptic drug used as add-on or monotherapy for focal seizures. In the present study the interaction of TPM with glycine receptor channels was studied on outside-out patches from HEK293 cells expressing alpha1beta glycine receptor channels. The patch clamp techniques combined with ultra fast solution exchange enabled us to investigate the kinetics of receptor channels in presence of TPM. Our study showed no agonistic or potentiating effect for TPM on glycine receptor channels. However, in presence of 1 mM glycine + 1 mM TPM, the desensitization got faster and the peak current amplitude decreased. After the end of glycine + TPM pulses, off-currents occurred, suggestive for a specific channel block mechanism.     

Molecular survey of ITS1 spacer and Rickettsia infection in human flea,Pulex irritans

Parasitology Research - The human flea is an important ectoparasite causing serious public health problems worldwide. Planning and monitoring the control programs against this vector require the...     

Relationship between Field Strength and Abnormal Development in Chick Embryos Exposed to 50 Hz Magnetic Fields

Summary

Chick embryos were exposed to sinusoidally oscillating 50 Hz magnetic fields during their first 2 days of development. In the first series of experiments magnetic field strengths of 0·1, 0·3, 1 and 10 A/m were used. The percentage of abnormal embryos (%AE) was 16 per cent in the sham-exposed control group. %AE was increased at 1 A/m (29 per cent) and 10 A/m (32 per cent), but not at 0·1 A/m (16 per cent) or 0·3 A/m (14 per cent). In the second series of experiments field strengths of 0·4, 0·6, 0·9 and 1·35 A/m were used. %AE was 17 per cent in the control group, 10 per cent at 0·4 A/m, 19 per cent at 0·6 A/m, 17 per cent at 0·9 A/m and 36 per cent at 1·35 A/m. Only the 1·35 A/m group was significantly different from the controls. The results of this study suggest that exposure of chick embryos to a 50 Hz magnetic field causes abnormal development, and that no abnormalities are induced below a threshold between 0·9 and 1 A/m.     

Synthetic quantitative MRI through relaxometry modelling

Quantitative MRI (qMRI) provides standardized measures of specific physical parameters that are sensitive to the underlying tissue microstructure and are a first step towards achieving maps of biologically relevant metrics through in vivo histology using MRI. Recently proposed models have described the interdependence of qMRI parameters. Combining such models with the concept of image synthesis points towards a novel approach to synthetic qMRI, in which maps of fundamentally different physical properties are constructed through the use of biophysical models. In this study, the utility of synthetic qMRI is investigated within the context of a recently proposed linear relaxometry model. Two neuroimaging applications are considered. In the first, artefact‐free quantitative maps are synthesized from motion‐corrupted data by exploiting the over‐determined nature of the relaxometry model and the fact that the artefact is inconsistent across the data. In the second application, a map of magnetization transfer (MT) saturation is synthesized without the need to acquire an MT‐weighted volume, which directly leads to a reduction in the specific absorption rate of the acquisition. This feature would be particularly important for ultra‐high field applications. The synthetic MT map is shown to provide improved segmentation of deep grey matter structures, relative to segmentation using T₁‐weighted images or R₁ maps. The proposed approach of synthetic qMRI shows promise for maximizing the extraction of high quality information related to tissue microstructure from qMRI protocols and furthering our understanding of the interrelation of these qMRI parameters.     

Nonexpanded Adipose Stromal Vascular Fraction Local Therapy on Peripheral Nerve Regeneration Using Allografts

Aim of the study: Adipose tissue possesses a population of multi-potent stem cells which can be differentiated to a Schwann cell phenotype and may be of benefit for treatment of peripheral nerve injuries. Effects of local therapy of nonexpanded adipose stromal vascular fraction (SVF) on peripheral nerve regeneration was studied using allografts in a rat sciatic nerve model. Materials and Methods: Thirty male white Wistar rats were divided into three experimental groups (n = 10), randomly: Sham-operated group (SHAM), allograft group (ALLO), SVF-treated group (ALLO/SVF). In SHAM group left sciatic nerve was exposed through a gluteal muscle incision and after homeostasis muscle was sutured. In the ALLO group the left sciatic nerve was exposed through a gluteal muscle incision and transected proximal to the tibio-peroneal bifurcation where a 10 mm segment was excised. The same procedure was performed in the ALLO/SVF group. The harvested nerves of the rats of ALLO group were served as allograft for ALLO/SVF group and vice versa. The SHAM and ALLO groups received 100 μL phosphate buffered saline and the ALLO/SVF group received 100 μL SVF (2.25 ± 0.45 × 10⁷ cells) locally where the grafting was performed. Results: Behavioral, functional, biomechanical, and gastrocnemius muscle mass showed earlier regeneration of axons in ALLO/SVF than in ALLO group (p < .05). Histomorphometic and immunohistochemical studies also showed earlier regeneration of axons in ALLO/SVF than in ALLO group (p < .05). Conclusions: Administration of nonexpanded SVF could accelerate functional recovery after nerve allografting in sciatic nerve. It may have clinical implications for the surgical management of patients after nerve transection.     

State-of-the-Art in Biosafety and Biosecurity in European Countries

The terms biosafety and biosecurity are widely used in different concepts and refer not only to protection of human beings and their surrounding environment against hazardous biological agent, but also to global disarmament of weapons of mass destruction. As a result, the biosafety and biosecurity issues should be considered interdisciplinary based on multilateral agreements against proliferation of biological weapons, public health and environmental protection. This publication presents information on both, international and national biosafety and biosecurity legislation. Status of national implementation of the Biological and Toxin Weapons Convention, penalization issues and measures to account for and secure production, use, storage of particularly dangerous pathogens or activities involving humans, plants and animals where infection may pose a risk have been analyzed. Safety and security measures in laboratories have been studied. Moreover, dual-use technology and measures of secure transport of biohazard materials have been also taken into account. In addition, genetic engineering regulations, biosecurity activities in laboratories and code of conducts have been investigated, as well.     

The relationship between occupational exposure to organic solvents and metabolic syndrome in petroleum refinery workers in Tehran,Iran

AimsThe rising prevalence of metabolic syndrome has made it a major health concern. Chronic occupational exposure to organic solvents affects different systems of the body. This study aimed to investigate the association between exposure to organic solvents and the prevalence of metabolic syndrome in petroleum refinery workers.MethodThis study was conducted in 2019–2020 on workers employed in an Iranian petroleum refinery. The demographic and occupational information on the participants was obtained using the interview method. Their height, weight, and blood pressure were measured by the occupational health team, and fasting blood samples were taken from them to measure the paraclinical parameters.ResultsIn this study, 1009 petroleum refinery workers were analyzed. The prevalence of metabolic syndrome in workers was 20.1% and it was about two times higher in exposed workers (CI 95%: 1.61–3.35) compared to non-exposed ones. Factors associated with the prevalence of metabolic syndrome include age, higher BMI, exercise, and longer exposure to organic solvents.ConclusionFindings of this study suggested that exposure to organic solvents is associated with increased prevalence of metabolic syndrome (the highest association was observed with elevated serum triglycerides). Besides, longer exposure to organic solvents increased the risk of developing metabolic syndrome.