Search

Abstract: Chronic idiopathic singultus (hiccup) is a debilitating condition affecting mostly elderly males. While in the past, pharmacologic singultus treatment was mostly “trial and error,” more recently, treatment has become both more evidence based and pathophysiology guided. A combination of an acidity-reducing drug (H2-receptor blocker or proton pump inhibitor) with baclofen (gamma-amino-butyric-acid receptor type B agonist) has become the most widely used regimen. Some clinicians replace or supplement baclofen with gabapentin. We present three cases of chronic idiopathic hiccup managed with gabapentin or another alpha-2-delta ligand, pregabalin. This is the first reported use of pregabalin for this indication. [Copyright &y& Elsevier]

Post-mortem studies in schizophrenic patients revealed alterations in glutamate transporter gene expression. The question concerning a possible influence of chronic antipsychotic treatment on these gene expressions, however, remained open. In this study, 11 rats per group were treated with either haloperidol (1.5 mg/kg per day) or clozapine (45 mg/kg per day) over a period of 6 months in doses comparable to clinic application. Gene expression of glial glutamate transporter EAAT2 and the predominantly neuronal glutamate transporter EAAT3 were examined by in situ hybridization. Clozapine significantly downregulated EAAT2 in hippocampal CA1 and parietal cortex and EAAT3 in the cingulate cortex compared to the expression upon haloperidol treatment and controls. Additionally, clozapine decreased EAAT2 in temporal, cingulate and frontal cortex and downregulated EAAT3 in cingulate and infralimbic cortex, striatum and hippocampal CA1 and CA2 compared to controls. Haloperidol downregulated EAAT2 in cingulate and frontal cortex and reduced EAAT3 in nucleus accumbens, infralimbic cortex and hippocampal CA2. We hypothesize that glutamate transporter downregulation by neuroleptics increases glutamatergic action at the postsynaptic neuron and thereby may be related to beneficial antipsychotic effects and side effects. [Copyright &y& Elsevier]

Artificial neural networks (ANNs) have a huge potential in toxicology research. They may be used to predict toxicity of various chemical compounds or classify the compounds based on their toxic effects. Today, numerous ANN models have been developed, some of which may be used to detect and possibly explain complex chemico-biological interactions. Fully connected multilayer perceptrons may in some circumstances have high classification accuracy and discriminatory power in separating damaged from intact cells after exposure to a toxic substance. Regularized and not fully connected convolutional neural networks can detect and identify discrete changes in patterns of two-dimensional data associated with toxicity. Bayesian neural networks with weight marginalization sometimes may have better prediction performance when compared to traditional approaches. With the further development of artificial intelligence, it is expected that ANNs will in the future become important parts of various accurate and affordable biosensors for detection of various toxic substances and evaluation of their biochemical properties. In this concise review article, we discuss the recent research focused on the scientific value of ANNs in evaluation and prediction of toxicity of chemical compounds. • Artificial neural networks have a huge potential in toxicology research. • They can be used for toxicity prediction and classification of toxic compounds. • We discuss the use of perceptrons, convolutional neural networks and Bayesian networks. • We also focus on the limitations of artificial intelligence in toxicology. [ABSTRACT FROM AUTHOR]

Abstract: The effects of phenothiazine-class antipsychotics (chlorpromazine, fluphenazine, phenothiazine, promazine, thioridazine, and triflupromazine) upon the function of the cloned α7 subunit of the human nicotinic acetylcholine receptor expressed in Xenopus oocytes were tested using the two-electrode voltage-clamp technique. Fluphenazine, thioridazine, triflupromazine, chlorpromazine, and promazine reversibly inhibited acetylcholine (100μM)-induced currents with IC50 values of 3.8; 5.8; 6.1; 10.6 and 18.3μM, respectively. Unsubstituted phenothiazine did not have a significant effect up to a concentration of 30μM. Inhibition was further characterized using fluphenazine, the strongest inhibitor. The effect of fluphenazine was not dependent on the membrane potential. Fluphenazine (10μM) did not affect the activity of endogenous Ca2+-dependent Cl− channels, since the extent of inhibition by fluphenazine was unaltered by intracellular injection of the Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing 2mM Ba2+. Inhibition by fluphenazine, but not by chlorpromazine was reversed by increasing acetylcholine concentrations. Furthermore, specific binding of [125I] α-bungarotoxin, a radioligand selective for α7-nicotinic acetylcholine receptor, was inhibited by fluphenazine (10μM), but not by chlorpromazine in oocyte membranes. In hippocampal slices, epibatidine-evoked [3H] norepinephrine release was also inhibited by fluphenazine (10μM) and chlorpromazine (10μM). Our results indicate that phenothiazine-class typical antipsychotics inhibit, with varying potencies, the function of α7-nicotinic acetylcholine receptor. [Copyright &y& Elsevier]

Abstract: Phytochemical compounds and histone deacetylase (HDAC) inhibitors are emerging as a new generation of anticancer agents with limited toxicity in cancer patients. We investigated the impact of luteolin, a dietary flavonoid, on survival, migration, invasion of cancer cells in vitro, and tumor growth in vivo. Luteolin (25–200μM) decreased the viability of human cancer cell lines originating from the lung (LNM35), colon (HT29), liver (HepG2) and breast (MCF7/6 and MDA-MB231-1833). Luteolin effectively increased the sub-G1 (apoptotic) fraction of cells through caspase-3 and -7 dependent pathways. We provide evidence that luteolin at sub-lethal/non-toxic concentrations inhibited the invasive potential of LNM35, MCF-7/6 and MDA-MB231-1833 cancer cells using Matrigel as well as the chick heart and Oris invasion assays. Moreover, we demonstrate for the first time that luteolin is a potent HDAC inhibitor that potentiates the cytotoxicity of cisplatin in LNM35 cells and decreases the growth of LNM35 tumor xenografts in athymic mice after intraperitoneal injection (20mg/kg/day for 18days) Thus, luteolin, in combination with standard anticancer drugs such as cisplatin, may be a promising HDAC inhibitor for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Abstract: The effects of anandamide transport inhibitor AM404 were investigated on depolarization-induced 45Ca2+ fluxes in transverse tubule membrane vesicles from rabbit skeletal muscle and on Ba2+ currents through L-type voltage-dependent Ca2+ channels in rat myotubes. AM404, at the concentration of 3μM and higher, caused a significant inhibition of 45Ca2+ fluxes. Radioligand binding studies indicated that the specific binding of [3H]Isradipine to transverse tubule membranes was also inhibited significantly by AM404. In controls and in presence of 10μM AM404, B max values were 51±6 and 27±5pM/mg, and KD values were 236±43 and 220±37pM, respectively. Inhibitory effects of AEA and arachidonic acid on 45Ca2+ flux and [3H]Isradipine binding reported in earlier studies, were also enhanced significantly in the presence of AM404. In the presence of VDM11 (1μM), another anandamide transport inhibitor, AM404 continued to inhibit 45Ca2+ fluxes and [3H]Isradipine binding. In rat myotubes, Ca2+ currents through L-type Ca2+ channels recorded in whole-cell configuration of patch clamp technique were inhibited by AM404 in a concentration-dependent manner with an IC50 value of 3.2μM. In conclusion, results indicate that AM404 inhibits directly the function of L-type voltage-dependent Ca2+ channels in mammalian skeletal muscles. [Copyright &y& Elsevier]

Abstract: There is evidence for migrational disturbances in the entorhinal cortex (ERC) in schizophrenia that supports a neurodevelopmental origin of the disorder. Since impaired myelin basic protein (MBP) gene expression during the migration phase could lead to abnormalities in final laminar position, we performed layer specific measurements of MBP expression in the ERC and hypothesised that migrational disturbances of pre-alpha-cell clusters relate to decreased MBP expression. Paraffin embedded sections of the left entorhinal cortex of 16 schizophrenia patients and 10 control subjects were stained for MBP using routine immunohistochemistry. On each section representative regions of interest were scanned to attain optimal quality images of the gray matter. Results were correlated to previous published disturbed dispersion of pre-alpha-cell clusters in adjacent brain sections. Mean MBP stain-intensity was significantly reduced in schizophrenia patients. Absolute MBP stain-intensity was significantly reduced in layers III and IV in patients. A significant correlation of MBP stain-intensity with the distance of the deep pole of the pre-alpha-cell cluster from the gray–white matter junction was observed in the ERC of schizophrenia patients. The present data provide evidence for reduced MBP expression in the ERC in schizophrenia, which implies deficits in axonal myelination and disturbed connectivity. MBP gene is expressed in oligodendrocytes and neuronal populations during embryonic development, which are important in establishing the structure of the cerebral cortex. Correlation between reduced MBP as a sign of down-regulated MBP gene expression and disorganization of pre-alpha-cell clusters supports a neurodevelopmental origin of pathological processes in schizophrenia. [Copyright &y& Elsevier]

Background: Membrane lipids are important mediators of neuronal function. In a postmortem study, we measured membrane lipid components in the left thalamus of schizophrenic patients. This region might play an important role in the pathophysiology of schizophrenia and has not been studied thus far with respect to its membrane lipid composition.Methods: The study included 18 chronic schizophrenic patients and 23 healthy control subjects. Using lipid extraction and thin-layer chromatography, we measured membrane phospholipids, galactocerebrosides 1 and 2, and sulfatides in thalamus homogenate.Results: The main membrane phospholipid phosphatidylcholine and the major myelin membrane components sphingomyelin and galactocerebrosides 1 and 2 were found to be decreased in schizophrenic patients. In contrast, phosphatidylserine was increased. These lipid contents did not correlate with postmortem intervals and medication doses. There was no difference in the membrane phospholipids lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol or in sulfatides.Conclusions: Our results confirm findings of magnetic resonance imaging, postmortem, and gene expression studies. They support the notion of an increased phospholipid breakdown in schizophrenia as a sign for decreased myelination and oligodendrocyte dysfunction. [Copyright &y& Elsevier]

Background: Emergency oral tracheal intubations in the pre-hospital setting can be more difficult because the rescuer''s position with respect to a patient lying on the ground may not provide optimal conditions for intubation. Since optimal visualisation of the larynx often depends on the force generated during laryngoscopy, we measured the pressure required for intubation (Pi) as well as the maximum pressure (Pmax) that can be generated with the laryngoscopy blade in seven intubator positions. Methods: Nineteen hospital personnel with intubation experience participated in this study. A modified #3 Macintosh laryngoscope blade was used to measure the pressure exerted on the tongue of a manikin placed on the ground during intubation. The following positions were studied: standard, sitting, prone, kneeling, left and right lateral decubitus and straddling. Results: Intubating in the straddling position required the lowest Pi, as a percent of Pmax (68±14%). This was significantly less than the prone, right lateral decubitus and sitting positions. (Tukey''s W procedure, P<0.05) Conclusion: The straddling position affords the intubator significantly more reserve force than the prone, right lateral decubitus or sitting position. We suggest that the straddling position may be an advantageous position for pre-hospital intubations especially when visualisation of the glottis is difficult. [Copyright &y& Elsevier]