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Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications. [ABSTRACT FROM AUTHOR]

Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant mechanisms of adjusting the body temperature to the value set by the internal thermostat exist. The neural circuitry of temperature control and the neurotransmitters involved are reviewed. The GABAergic inhibitory output from the brain thermostat in the preoptic area POA to subaltern neural circuitry of temperature control (Nucleus Raphe Dorsalis and Nucleus Raphe Pallidus) is a function of the balance between the (opposite) effects mediated by the transient receptor potential receptor TRPM2 and EP3 prostaglandin receptors. Activation of TRPM2-expressing neurons in POA favors hypothermia, while inhibition has the opposite effect. Conversely, EP3 receptors induce elevation in body temperature. Activation of EP3-expressing neurons in POA results in hyperthermia, while inhibition has the opposite effect. Agonists at TRPM2 and/or antagonists at EP3 could be beneficial in hyperthermia control. Activity of the neural circuitry of temperature control is modulated by a variety of 5-HT receptors. Based on the theoretical model presented the "ideal" antidote against serotonin syndrome hyperthermia appears to be an antagonist at the 5-HT receptor subtypes 2, 4 and 6 and an agonist at the receptor subtypes 1, 3 and 7. Very broadly speaking, such a profile translates in a sympatholytic effect. While a compound with such an ideal profile is presently not available, better matches than the conventional antidote cyproheptadine (used off-label in severe serotonin syndrome cases) appear to be possible and need to be identified. [ABSTRACT FROM AUTHOR]

Sir Louis Francis Knuthsen (1869–1957), the physician who painstakingly listed almost all treatments known for obstinate hiccough, ascribes the holding of breath method to Philip Henry Pye-Smith, FRS (1840–1914), consultant at Guy's Hospital in London. In fact, the strategy is much older and was mentioned by greats such as Francis Bacon (1561–1626), Aristoteles (384–322 BC), and Eryximachus (late-fifth century bce). Hypoventilation to reduce central nervous system excitability was used in antiquity as evidenced by Cyriacus' treatment of Artemia, the daughter of Emperor Diocletian (≈ 244–311). She was suffering from (among others) seizures that Cyriacus was apparently controlling by tightening a scarf around her neck, as depicted by Mathias Grünewald (1460–1528) on a wing of the so-called Heller Altar now on display at the Historical Museum, Frankfurt, Germany. In modern times, around 1920, inducing hypercapnia by CO2 inhalation as therapy for hiccups was suggested and tried by a number of anesthetists, such as Americans Russel Firth Sheldon (1885–1960) and Brian Collins Sword (1889–1956) in Boston; Briton Christopher Langton Hewer (1896–1986) at St. Bartholomew's Hospital in London; Austrian Karl Doppler (1887–1947) in Vienna; and the German/Polish Arthur Dzialoszynski (1893–1977) in Berlin. Although various authors assign the scientific primate to any of them, the first mention of carbon dioxide inhalation as treatment of singultus in the scientific literature is of French origin and was made by Paris pharmacist Henri Bocquillon-Limousin (1856–1917) in his 1892 Formulaire des médicaments nouveaux et des médications nouvelles. [ABSTRACT FROM AUTHOR]

A multitude of nonpharmacological interventions to terminate hiccup belong to the public-domain hiccup “mythology” or have been described in the medical literature as case reports. While usually effective in terminating bouts of acute hiccup, they are mostly ineffective in cases of hiccupping that have been present for an extended period. The common denominator of most of these therapeutic maneuvers (some also used to terminate paroxysmal supraventricular tachycardia) is their ability to directly or indirectly increase efferent vagal activity. Among the best known “vagal maneuvers” are the oculo-cardiac reflex (Dagnini-Aschner), the carotid sinus massage, the Valsalva maneuver, stimulation of the ear/auditory canal, ice ingestion, and induction of emesis. This short report provides an overview on hiccups and attempts to identify the lesser known personalities who pioneered its treatment by vagal maneuvers. The recent introduction of electrical vagus nerve stimulation for therapy-resistant hiccup is the ultimate compliment to these pioneers. [ABSTRACT FROM PUBLISHER]

During intrauterine life, hiccups are universally present, their incidence peaking in the third trimester. Alfons Mermann (1852–1908), a gynecologist from Mannheim, Germany, best known for having established the Luisenheim Woechnerinnenasyl [lying-in asylum] there in 1887, is viewed as the first physician to name and describe singultus foetalis [fetal hiccups] in a modern peer-reviewed scientific publication. This short report attempts to shed some light on the work of Dr. Mermann and to explore whether or not he was indeed the first to recognize this phenomenon. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a dramatically increasing problem affecting many individuals as well as the health system. As we have no causal treatment for the loss of memory, symptomatic treatment is needed. Influencing the ACh system is a generally accepted approach, although other therapeutic treatments are in various stages of development. The multiple target drug approach using hybrid compounds may be another optimized move forward for the treatment of cognitive disorders. Since the complex neuronal regulation is slowly being decoded, there is hope that ways will be found to stop neuronal loss and to generate new synapses. [ABSTRACT FROM AUTHOR]

Pyridostigmine (PSTG) is a carbamate inhibitor of cholinesterases. Carbamates are known to confer some protection from the lethal effects of (some) organophosphorus compounds. Recently, based on animal data, the FDA approved oral PSTG for pre-exposure treatment of soman. The purpose of the study was to quantify in vivo the effect of PSTG pre-treatment on survival in rats exposed to the organophosphate paraoxon (POX) with and without subsequent reactivator (pralidoxime) treatment. POX is a highly toxic non-neuropathic ethyl organophospate. Pralidoxime (PRX) is the enzyme reactivator used by some NATO armies. The prospective, controlled animal (rat) study included Group 1 that received 1 μmol POX (≈LD75); Group 2 that received 1 μmol PSTG followed 30 min later by 1 μmol POX; Group 3 that received 1 μmol PSTG followed 30 min later by 1 μmol POX and 50 μmol PRX; Group 4 that received 1 μmol POX and 50 μmol PRX; Group 5 that received 1 μmol PSTG; Group 6 that received 50 μmol PRX and Group 7 that received 1 μmol PSTG followed 30 min later by 50 μmol PRX. Each group contained six rats. The experiment was repeated twelve times (12 cycles). All substances were applied i.p. From surviving animals of eight cycles tail blood was taken for red blood cell acetylcholinesterase (RBC-AChE) measurements. The animals were monitored for 48 h and mortality (survival time) was recorded. RBC-AChE activities were determined. Mortality was analysed using Kaplan–Meier plots. Both PSTG and PRX statistically significantly decreased organophosphate induced mortality in the described model. While the same applies to their combination the decrease in mortality when using both PSTG and PRX is less than that achieved with their single use (but not significantly so). While certainly further work using different organophosphorus compounds and animal species are needed before a final conclusion is reached, the animal data presented does not support the combined use of PSTG and PRX. [ABSTRACT FROM AUTHOR]

Weak and reversible inhibitors of cholinesterase, when co-administered in large doses, can act in a protective manner against more potent inhibitors such as organophosphates. The clinically widely used histamine type 2 (H2) receptor blocker ranitidine is among H2 blockers the most potent inhibitor of acetylcholinesterase but roughly three to four orders of magnitude less potent than paraoxon (an irreversible organophosphate esterase inhibitor) or pyridostigmine (a reversible carbamate esterase inhibitor). We have previously shown that in vitro ranitidine confers some protection against inhibition of cholinesterases by paraoxon and that in vivo it both increases the number of rats surviving an acute paraoxon exposure and also protects to some degree the cholinesterases from organophosphate inhibition. The purpose of the study was to compare in a prospective non-blinded study, in a rat model of acute high-dose paraoxon exposure, ranitidine with pyridostigmine either administered simultaneously or 30 min. before exposure. There were 36 rats in each of the 5 groups. All substances were applied intraperitoneally. Additional analysis included data from a similar experiment carried out in 2005, in which 54 rats were exposed to paraoxon only (G1) and 54 to paraoxon+ranitidine simultaneously (G2). All groups (except controls; G6 & G7) received 1 μMol paraoxon (≈LD75); groups 2–5 received in addition to paraoxon: G2: 50 μMol ranitidine within 1 min. of paraoxon, G3: 1 μMol pyridostigmine within 1 min. of paraoxon, G4: 50 μMol ranitidine 30 min. before paraoxon, G5: 1 μMol pyridostigmine 30 min. before paraoxon. Groups 6 & 7 received only ranitidine and pyridostigmine respectively, group G1 received only paraoxon. Mortality was recorded at 30 min., 1, 2, 3, 4, 24 and 48 hr. Mortality data were compared using Kaplan-Meier plots and logrank tests. No Bonferroni correction for multiple comparisons was applied and an α≤0.05 was considered significant. All statistical analysis was performed by using SPSS 12.0 statistical software (SPSS Inc., Chicago, IL, USA). Simultaneous administration of ranitidine or pyridostigmine with paraoxon does not significantly affect mortality. Pretreatment (30 min. before) with both ranitidine or pyridostigmine statistically and significantly reduced mortality. When administered before paraoxon, pyridostigmine is statistically significantly superior to ranitidine. Both ranitidine and pyridostigmine are protective against acute paraoxon toxicity provided they are administered before paraoxon. Pyridostigmine results are statistically significantly superior to ranitidine (≤0.05). [ABSTRACT FROM AUTHOR]

Presents a study which examined the utility of paraoxon sensitive phenylvalerate hydrolase to assess the severity of acute poisoning of paraoxon, an organosphophorous compound. Materials and methods; Results; Discussion.

We examined the influence of an experimental venous and arterial air embolism on the hearing level in laboratory mini pigs. Before and after the injection of air a threshold ABR was measured in anaesthetized mini pigs (n=15). A venous air embolism was performed in 6 animals: no changes in the hearing level or in the interpeak latencies Jewett wave V-I were observed in any of the animals before, during or after the application of air. In 9 animals the arterial embolism was done, 2 animals died and had to be excluded. In 6 animals out of 7 a hearing loss was observed starting after the injection of 40 ml air and finally ending in deafness for these 6 animals. The detected hearing loss is probably of cochlear origin, as no prolongations of the interpeak latencies of Jewett wave V-I at 90 dB HL were observed prior to the deafness. Our results show that air bubbles in the arterial circulation lead to cochlear damage ending in deafness. Our research indicates that decompression sickness, which is comparable to the arterial air embolism, is more often the cause of a sensorineural hearing loss after diving than previously believed. [ABSTRACT FROM AUTHOR]

The author discusses a report about abolishing the venous-arterial carbon dioxide gradient as treatment for singultus. Topics discussed include the capacity of carbon dioxide to modulate excitability, inducement of hypercapnia as therapy for hiccups, and reduction in excitability due to the increase in arterial carbon dioxide needed to remove the venous-arterial carbon dioxide gradient.

Presents several letters to the editor. Appreciation on the article about poisoning with organophosphorus compounds; Topics about hemodynamics; Views on the use of oxime reactivators.

Previous studies on biocatalytic transformations of pinenes by cytochrome P450 (CYP) enzymes reveal the formation of different oxygenated products from a single substrate due to the multistate reactivity of CYP and the many reactive sites in the pinene scaffold. Up until now, the detailed mechanism of these biocatalytic transformations of pinenes have not been reported. Hereby, we report a systematic theoretical study of the plausible hydrogen abstraction and hydroxylation reactions of α- and β-pinenes by CYP using the density functional theory (DFT) method. All DFT calculations in this study were based on B3LYP/LAN computational methodology using the Gaussian09 software. We used the B3LYP functional with corrections for dispersive forces, BSSE, and anharmonicity to study the mechanism and thermodynamic properties of these reactions using a bare model (without CYP) and a pinene-CYP model. According to the potential energy surface and Boltzmann distribution for radical conformers, the major reaction products of CYP-catalyzed hydrogen abstraction from β-pinene are the doublet trans (53.4%) and doublet cis (46.1%) radical conformer at delta site. The formation of doublet cis/trans hydroxylated products released a total Gibbs free energy of about 48 kcal/mol. As for alpha pinene, the most stable radicals were trans-doublet (86.4%) and cis-doublet (13.6%) at epsilon sites, and their hydroxylation products released a total of ~50 kcal/mol Gibbs free energy. Our results highlight the likely C-H abstraction and oxygen rebounding sites accounting for the multi-state of CYP (doublet, quartet, and sextet spin states) and the formation of different conformers due to the presence of cis/trans allylic hydrogen in α-pinene and β-pinene molecules. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) relates to an abrupt reduction in renal function resulting from numerous conditions. Morbidity, mortality, and treatment costs related to AKI are relatively high. This condition is strongly associated with damage to proximal tubule cells (PTCs), generating distinct patterns of transcriptional and epigenetic alterations that result in structural changes in the nuclei of this epithelium. To this date, AKI-related nuclear chromatin redistribution in PTCs is poorly understood, and it is unclear whether changes in PTC chromatin patterns can be detected using conventional microscopy during mild AKI, which can progress to more debilitating forms of injury. In recent years, gray level co-occurrence matrix (GLCM) analysis and discrete wavelet transform (DWT) have emerged as potentially valuable methods for identifying discrete structural changes in nuclear chromatin architecture that are not visible during the conventional histopathological exam. Here we present findings indicating that GLCM and DWT methods can be successfully used in nephrology to detect subtle nuclear morphological alterations associated with mild tissue injury demonstrated in rodents by inducing a mild form of AKI through ischemia–reperfusion injury. Our results show that mild ischemic AKI is associated with the reduction of local textural homogeneity of PTC nuclei quantified by GLCM and the increase of nuclear structural heterogeneity indirectly assessed with DWT energy coefficients. This rodent model allowed us to show that mild ischemic AKI is associated with the significant reduction of textural homogeneity of PTC nuclei, indirectly assessed by GLCM indicators and DWT energy coefficients. [ABSTRACT FROM AUTHOR]

A response from Dietrich E. Lorke and colleagues to a letter to the editor on their article "Efficacy of two new asymmetric bispyridinium oximes (K-27 and K-48) in rats exposed to diisopropylfluorophosphate: Comparison with pralidoxime, obidoxime, trimedoxime, methoxime, and HI6," is presented.

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples. [ABSTRACT FROM AUTHOR]

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]

Exposure to or ingestion of turpentine can alter the scent of urine, conferring it a flowery, violet-like scent. Turpentine's effect on urine was initially noticed after its use either as medicine or as a preservative in winemaking. Regardless of the source of exposure, the phenomenon requires metabolic conversion of turpentine component(s) to ionone, the molecule mainly responsible for the scent of violets. The purpose of this study was to identify the presence of ionone in the urine of rats that received β-pinene, and thus to demonstrate that the postulated conversion occurs. We treated rats intraperitoneally with normal saline (negative control), β-ionone (positive control), low-dose β-pinene (1/3 of LD50), and high-dose β-pinene (1/2 of LD50). Urine samples were collected up to 72 h after administration of the compounds, followed by gas chromatography/mass spectrometry identification of the presence of ionone. β-Ionone was found in the urine of rats exposed to both low and high doses of β-pinene. In contrast, α-ionone appears unlikely to have been formed in rats exposed to either low or high doses of β-pinene. β-pinene was converted to β-ionone, followed by partial excretion in the urine of rats. β-Ionone is a minor metabolite of β-pinene. [ABSTRACT FROM AUTHOR]

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]

Organs On-a-Chip represent novel platforms for modelling human physiology and disease. The lymph node (LN) is a relevant immune organ in which B and T lymphocytes are spatially organized in a complex architecture, and it is the place where the immune response initiates. The present study addresses the utility of a recently designed LN-on-a-chip to dissect and understand the effect of drugs delivered to cells in a fluidic multicellular 3D setting that mimics the human LN. To do so, we analyzed the motility and viability of human B and T cells exposed to hydroxychloroquine (HCQ). We show that the innovative LN platform, which operates at a microscale level, allows realtime monitoring of co-cultured B and T cells by imaging, and supports cellular random movement. HCQ delivered to cells through a constant and continuous flow induces a reduction in T cell velocity while promotes persistent rotational motion. We also find that HCQ increases the production of reactive oxygen species in T cells. Taken together, these results highlight the potential of the LN-on-a-chip to be applied in drug screening and development, and in cellular dynamics studies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 24 million people worldwide and represents an immense medical, social and economic burden. While a vast array of active pharmaceutical ingredients (API) is available for the prevention and possibly treatment of AD, applicability is limited by the selective nature of the blood-brain barrier (BBB) as well as by their severe peripheral side effects. A promising solution to these problems is the incorporation of anti-Alzheimer drugs in polymeric nanoparticles (NPs). However, while several polymeric NPs are nontoxic and biocompatible, many of them are not biodegradable and thus not appropriate for CNS-targeting. Among polymeric nanocarriers, chitosan-based NPs emerge as biodegradable yet stable vehicles for the delivery of CNS medications. Furthermore, due to their mucoadhesive character and intrinsic bioactivity, chitosan NPs can not only promote brain penetration of drugs via the olfactory route, but also act as anti-Alzheimer therapeutics themselves. Here we review how chitosan-based NPs could be used to address current challenges in the treatment of AD; with a specific focus on the enhancement of blood-brain barrier penetration of anti-Alzheimer drugs and on the reduction of their peripheral side effects. [ABSTRACT FROM AUTHOR]

Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigatedin silicoandin vitroand compared with an experimental oxime (kamiloxime; K-27) and pralidoxime.In silicothe molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated.In vitrothe intrinsic ability of the oximes to inhibit AChE (IC50) and their reactivation potency (R50) when used in paraoxon inhibited human RBC-AChE was determined. Molecular docking revealed that K378 and K727 bind to the peripheral site(s) with high binding energies in contrast to the central binding of K-27 and pralidoxime. LogP values indicating that the novel compounds are significantly less hydrophilic than K-27 or pralidoxime. IC50of K378 and K727 were comparable (0.9 and 1 µM, respectively) but orders of magnitude lower than comparators.R50values revealed their inability to reactivate paraoxon inhibited AChE. It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful. Thein silicoandin vitrostudies described allow avoidance of unnecessaryin vivoanimal work and contribute to the reduction of laboratory animal use. [ABSTRACT FROM PUBLISHER]

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]

Claims that the inventor of the oesophageal detector device B.J. Pollard, is Australian and not British as earlier claimed. History of the invention of the device; Uses of the device; Profile on Bollard.

Abstract: Derivatization of phenothiazine (PTZ, 1) has been a commonly used method to develop drugs with various pharmacological properties. In the present study, a series of PTZ derivatives 1–11 were investigated on the inhibition of the cloned α7 subunit of the human nicotinic acetylcholine receptor (α7-nAChR) expressed in Xenopus oocytes by using the two-electrode voltage-clamp technique. In the first series of experiments, the effect of unsubstituted phenothiazine 1 on α7-nAChRs was compared with that of the N3,N7-diaminophenothiazin-5-ium derivative 2, and of sequentially methylated derivatives 3–6. In the second set of experiments, the effects of N3,N7-tetra-ethyl- to n-hexylphenothiazin-5-ium derivatives 7–11 were tested. Despite the lack of activity found for 1, a reversible inhibition of α7-nAChRs, ranging from moderate to potent, was observed as a result of a sequential amine- and methylamine substitution of 1. The inhibition of ACh (100μM)-induced currents was concentration-dependent with IC50 values ranging from 0.4 to 16.8μM. However, an optimal inhibitory activity was achieved by prolongation of alkyl chains up to propyl size, as found in PTZ derivative 8, whereas further lengthening of alkyl chains to n-butyl-, n-pentyl-, or n-hexyl groups resulted in inactive derivatives 9–11. The results evidently suggest the presence of a lipophilic binding pocket of narrow tolerability on the receptor protein. These results emphasize the importance of amine and/or alkylamine moieties for the inhibitory effect of PTZ derivatives and provide further insights for the development of novel antagonists targeting α7-nAChRs. [Copyright &y& Elsevier]

BACKGROUND AND PURPOSE Methylene blue (MB) is commonly employed as a treatment for methaemoglobinaemia, malaria and vasoplegic shock. An increasing number of studies indicate that MB can cause 5-HT toxicity when administered with a 5-HT reuptake inhibitor. MB is a potent inhibitor of monoamine oxidases, but other targets that may contribute to MB toxicity have not been identified. Given the role of the 5-HT transporter (SERT) in the regulation of extracellular 5-HT concentrations, the present study aimed to characterize the effect of MB on SERT. EXPERIMENTAL APPROACH Live cell imaging, in conjunction with the fluorescent SERT substrate 4-(4-(dimethylamino)-styryl)- N-methylpyridinium (ASP+), [3H]5-HT uptake and whole-cell patch-clamp techniques were employed to examine the effects of MB on SERT function. KEY RESULTS In EM4 cells expressing GFP-tagged human SERT (hSERT), MB concentration-dependently inhibited ASP+ accumulation (IC50: 1.4 ± 0.3 µM). A similar effect was observed in N2A cells. Uptake of [3H]5-HT was decreased by MB pretreatment. Furthermore, patch-clamp studies in hSERT expressing cells indicated that MB significantly inhibited 5-HT-evoked ion currents. Pretreatment with 8-Br-cGMP did not alter the inhibitory effect of MB on hSERT activity, and intracellular Ca2+ levels remained unchanged during MB application. Further experiments revealed that ASP+ binding to cell surface hSERT was reduced after MB treatment. In whole-cell radioligand experiments, exposure to MB (10 µM; 10 min) did not alter surface binding of the SERT ligand [125I]RTI-55. CONCLUSIONS AND IMPLICATIONS MB modulated SERT function and suggested that SERT may be an additional target upon which MB acts to produce 5-HT toxicity. [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]

The cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival. [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]

One important risk gene in schizophrenia is neuregulin-1 ( NRG1), which is expressed in different isoforms in the brain. To determine if alterations of NRG1 are present in schizophrenia, we measured gene expression of NRG1 and its main isoforms as well as the impact of genetic variation of NRG1 in an exploratory study examining three brain regions instead of only one as published so far. In all, we examined post-mortem samples from 11 schizophrenia patients and eight normal subjects. We investigated gene expression of total NRG1 and isoforms I, II and III by real-time PCR in the prefrontal cortex (Brodmann areas 9 and 10) and right hippocampal tissue. For the genetic study, we genotyped the NRG1 polymorphism SNP8NRG221533, which is within the core haplotype of the original publication. Compared to controls, gene expression of the NRG1 isoform I was decreased and isoform II increased in the prefrontal cortex (BA10) of schizophrenia patients. There were no statistically significant differences between individuals carrying at least one C allele of SNP8NRG221533 compared to individuals homozygous for the T allele. The decreased expression of NRG1 isoform I and overexpression of isoform II may be related to deficits in receptor function as well as abnormal migration and myelination. However, our study sample was small and results of this exploratory study should be verified in a larger sample. [ABSTRACT FROM AUTHOR]

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]

Lung cancer is the most common form of cancer in the world, and 90% of patients die from their disease. The angiotensin converting enzyme (ACE) inhibitors are used widely as antihypertensive agents, and it has been suggested that they decrease the risk of some cancers, although available data are conflicting. Accordingly, we investigated the anticancer activity of the ACE inhibitor, captopril, in athymic mice injected with highly tumorigenic LNM35 human lung cells as xenografts. Using this model, we demonstrated that daily IP administration of captopril (2.8 mg/mouse) for 3 weeks resulted in a remarkable reduction of tumor growth (58%, P < 0.01) and lymph node metastasis (50%, P= 0.088). There were no undesirable effects of captopril treatment on animal behavior and body weight. In order to determine the mechanism by which captopril inhibited tumor growth, we investigated the impact of this drug on cell proliferation, apoptosis, and angiogenesis. Immunohistochemical analysis demonstrated that captopril treatment significantly reduced the number of proliferating cells ( Ki-67) in the tumor samples but was not associated with inhibition of tumor angiogenesis (CD31). Using cell viability and fluorescent activated cell sorting analysis tests, we demonstrated that captopril inhibited the viability of LNM35 cells by inducing apoptosis, providing insight about the mechanisms underlying its antitumorigenic activities. In view of these experimental findings, we conclude that captopril could be a promising option for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

A simple and reliable reversed-phase TLC method was used to determine the lipophilicity of ACE inhibitors. The TLC silica plates were saturated with paraffin using continuous development with 10% paraffin in hexane for 18 hours. The TLC silica particles covered with the paraffin are used as an inexpensive substituent of the usual RP-18 TLC stationary phase. [ABSTRACT FROM AUTHOR]

The chemical structures of certain drug candidates give only a minimum of lipophilicity. Investigation of their elution on reversed-phase materials was difficult, even when the water content of the mobile phase was changed. The dominative role of lipophilicity, either in the drugs' penetration or in the receptorial drug binding, is considered to be valid solely in the same chemical group of the various drugs. In the cases of extremely lipophobic (i.e., hydrophilic) compounds, both the determination or calculation of lipophilicity was difficult or impossible. This is the reason that a novel index, the TLC hydrophilicity parameter, should be introduced as a substitute for lipophilicity. Hydrophilicity can be preferrably determined using a planar stationary phase and an aqueous-organic mobile phase. Numerical data of hydrophilicity on silica stationary phase can be calculated using RM values, similar to the lipophilicity indices. [ABSTRACT FROM AUTHOR]

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]

Sneezing (sternutatio) is a poorly understood polysynaptic physiologic reflex phenomenon. Sneezing has exerted a strange fascination on humans throughout history, and induced sneezing was widely used by physicians for therapeutic purposes, on the assumption that sneezing eliminates noxious factors from the body, mainly from the head. The present contribution examines the various mixtures used for inducing sneezes (remedia sternutatoria) over the centuries. The majority of the constituents of the sneeze-inducing remedies are modulators of transient receptor potential (TRP) channels. The TRP channel superfamily consists of large heterogeneous groups of channels that play numerous physiological roles such as thermosensation, chemosensation, osmosensation and mechanosensation. Sneezing is associated with the activation of the wasabi receptor, (TRPA1), typical ligand is allyl isothiocyanate and the hot chili pepper receptor, (TRPV1), typical agonist is capsaicin, in the vagal sensory nerve terminals, activated by noxious stimulants. [ABSTRACT FROM AUTHOR]

The term ionone is derived from "iona" (Greek for violet) which refers to the violet scent and "ketone" due to its structure. Ionones can either be chemically synthesized or endogenously produced via asymmetric cleavage of β-carotene by β-carotene oxygenase 2 (BCO2). We recently proposed a possible metabolic pathway for the conversion of α-and β-pinene into α-and β-ionone. The differences between BCO1 and BCO2 suggest a unique physiological role of BCO2; implying that β-ionone (one of BCO2 products) is involved in a prospective biological function. This review focuses on the effects of ionones and the postulated mechanisms or signaling cascades involved mediating these effects. β-Ionone, whether of an endogenous or exogenous origin possesses a range of pharmacological effects including anticancer, chemopreventive, cancer promoting, melanogenesis, anti-inflammatory and antimicrobial actions. β-Ionone mediates these effects via activation of olfactory receptor (OR51E2) and regulation of the activity or expression of cell cycle regulatory proteins, pro-apoptotic and anti-apoptotic proteins, HMG-CoA reductase and pro-inflammatory mediators. α-Ionone and β-ionone derivatives exhibit anti-inflammatory, antimicrobial and anticancer effects, however the corresponding structure activity relationships are still inconclusive. Overall, data demonstrates that ionone is a promising scaffold for cancer, inflammation and infectious disease research and thus is more than simply a violet's fragrance. [ABSTRACT FROM AUTHOR]

Physiological Glucocorticoids are important regulators of the immune system. Pharmacological GCs are in widespread use to treat inflammatory diseases. Adrenalectomy (ADX) has been shown to exacerbate renal injury through inflammation and oxidative stress that results in renal impairment due to depletion of GCs. In this study, the effect of myrcene to attenuate renal inflammation and oxidative stress was evaluated in the adrenalectomized rat model. Rats were adrenalectomized bilaterally or the adrenals were not removed after surgery (sham). Myrcene (50 mg/kg body weight, orally) was administered post ADX. Myrcene treatment resulted in significant downregulation of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) compared to untreated ADX rats. In addition, myrcene resulted in significant downregulation of immunomodulatory factors (IFNγ and NF-κB) and anti-inflammatory markers (IL-4 and IL-10) in treated ADX compared to untreated ADX. Myrcene significantly increased the antioxidant molecules (CAT, GSH, and SOD) and decreased MDA levels in treated ADX compared to untreated. Moreover, myrcene treatment reduced the expression of COX-2, iNOS, KIM-1, and kidney functional molecules (UREA, LDH, total protein, and creatinine) in ADX treated compared to ADX untreated. These results suggest that myrcene could be further developed as a therapeutic drug for treatment of kidney inflammation and injury. [ABSTRACT FROM AUTHOR]

Aims: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome. Methods: Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure. Results: Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens. Conclusions: Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter. [ABSTRACT FROM AUTHOR]