[PREVALENCE OF TOBACCO SMOKING AMONG MENTAL HEALTH INPATIENTS IN ISRAEL].

INTRODUCTION: Tobacco smoking is the worldwide leading preventable cause of morbidity [1]. The prevalence of current smoking among individuals with mental illnesses is more than twice as that of the general population [2]. Despite it being a primary cause of morbidity and mortality in Israel too, there is little information and research on the features of smoking among people with mental illnesses in Israel. OBJECTIVES: To present an up-to-date estimation of the prevalence of smoking among hospitalized patients with mental illness in Israel and to compare the prevalence of comorbidities among smokers and non-smokers in this population. METHODS: Analyzing data obtained from an electronic medical-records database, consisting of 4646 patients with mental illness, aged 18-90 years, who were hospitalized at Geha Mental Health Center during 2005-2013. RESULTS: The smoking rate among hospitalized patients with mental illness was significantly higher than the general population (51.3% versus 19.7%, respectively). The smoking rate among male hospitalized patients with mental illness was higher than that of the females (58.2% versus 42.7%, respectively), however, the difference between men and women is smaller compared to this difference in the general population. Smoking rates were highest among those with personality disorder (65.1%), bipolar disorder (58.8%) and schizophrenia (53.81%). The prevalence of comorbid substance use (alcohol or drug abuse) among hospitalized patients with mental illness was found to be higher in the smokers group than in the non-smokers group (37.4% versus 4.6%, respectively, p<0.0001). CONCLUSIONS: The prevalence of smoking among hospitalized patients with mental illness in Israel is 2.74 times that of the general population in 2013, in line with the reported worldwide rate. In addition, among hospitalized patients with mental illness the prevalence of comorbid substance use (alcohol or drug abuse) was higher among the smokers than among the non-smokers.

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.

Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6), which is metabolically stable and has the potential to become a peripheral painkiller being a full µ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6), we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6).

Phase-Amplitude Markers of Synchrony and Noise: A Resting-State and TMS-EEG Study of Schizophrenia.

The electroencephalogram (EEG) of schizophrenia patients is known to exhibit a reduction of signal-to-noise ratio and of phase locking, as well as a facilitation of excitability, in response to a variety of external stimuli. Here, we demonstrate these effects in transcranial magnetic stimulation (TMS)-evoked potentials and in the resting-state EEG. To ensure veracity, we used 3 weekly sessions and analyzed both resting-state and TMS-EEG data. For the TMS responses, our analysis verifies known results. For the resting state, we introduce the methodology of mean-normalized variation to the EEG analysis (quartile-based coefficient of variation), which allows for a comparison of narrow-band EEG amplitude fluctuations to narrow-band Gaussian noise. This reveals that amplitude fluctuations in the delta, alpha, and beta bands of healthy controls are different from those in schizophrenia patients, on time scales of tens of seconds. We conclude that the EEG-measured cortical activity patterns of schizophrenia patients are more similar to noise, both in alpha- and beta-resting state and in TMS responses. Our results suggest that the ability of neuronal populations to form stable, locally, and temporally correlated activity is reduced in schizophrenia, a conclusion, that is, in accord with previous experiments on TMS-EEG and on resting-state EEG.

Treatment of combined traumatic brain injury and hemorrhagic shock with fractionated blood products versus fresh whole blood in a rat model.

INTRODUCTION: Treatment of combined traumatic brain injury and hemorrhagic shock, poses a particular challenge due to the possible conflicting consequences. While restoring diminished volume is the treatment goal for hypovolemia, maintaining adequate cerebral perfusion pressure and avoidance of secondary damage remains a treatment goal for the injured brain. Various treatment modalities have been proposed, but the optimal resuscitation fluid and goals have not yet been clearly defined. A growing body of evidence suggests that in hypovolemic shock, resuscitation with fresh whole blood (FWB) may be superior to component therapy without platelets (which are likely to be unavailable in the pre-hospital setting). Nevertheless, the effects of this approach have not been studied in the combined injury. Previously, in a rat model of combined injury we have found that mild resuscitation to MABP of 80 mmHg with FWB is superior to fluid resuscitation or aggressive resuscitation with FWB. In this study, we investigate the physiological and neurological outcomes in a rat model of combined traumatic brain injury (TBI) and hypovolemic shock, submitted to treatment with varying amounts of FWB, compared to similar resuscitation goals with fractionated blood products-red blood cells (RBCs) and plasma in a 1:1 ratio regimen. MATERIALS AND METHODS: 40 male Lewis rats were divided into control and treatment groups. TBI was inflicted by a free-falling rod on the exposed cranium. Hypovolemia was induced by controlled hemorrhage of 30% blood volume. Treatment groups were treated either with fresh whole blood or with RBC + plasma in a 1:1 ratio, achieving a resuscitation goal of a mean arterial blood pressure (MAP) of 80 mmHg at 15 min. MAP was assessed at 60 min, and neurological outcomes and mortality in the subsequent 24 h. RESULTS: At 60 min, hemodynamic parameters were improved compared to controls, but not significantly different between treatment groups. Survival rates at 48 h were 100% for both of the mildly resuscitated groups (MABP 80 mmHg) with FWB and RBC + plasma. The best neurological outcomes were found in the group mildly resuscitated with FWB and were better when compared to resuscitation with RBC + plasma to the same MABP goal (FWB: Neurological Severity Score (NSS) 6 ± 2, RBC + plasma: NSS 10 ± 2, p = 0.02). CONCLUSIONS: In this study, we find that mild resuscitation with goals of restoring MAP to 80 mmHg (which is lower than baseline) with FWB, provided better hemodynamic stability and survival. However, the best neurological outcomes were found in the group resuscitated with FWB. Thus, we suggest that resuscitation with FWB is a feasible modality in the combined TBI + hypovolemic shock scenario, and may result in improved outcomes compared to platelet-free component blood products.

Vitamin D Supplementation in Chronic Schizophrenia Patients Treated with Clozapine: A Randomized, Double-Blind, Placebo-controlled Clinical Trial.

BACKGROUND: While accumulating evidence suggests that vitamin D deficiency may be involved in the risk to develop schizophrenia and its outcome, there are no studies on vitamin D supplementation in this context. We sought to assess the effect of vitamin D supplementation on psychiatric, cognitive and metabolic parameters in chronic clozapine-treated schizophrenia patients. METHODS: This eight-week, randomized, double-blind, placebo-controlled clinical trial, recruited schizophrenia patients who had been maintained on clozapine treatment for at least 18weeks and had low levels of vitamin D (<75nmol/l) and total PANSS scores >70 (to ascertain the presence of residual symptoms). Patients were randomly allocated to either weekly oral drops of vitamin D (14,000IU) or placebo and subsequently assessed at two-week intervals for psychosis severity, mood, cognition and metabolic profile. RESULTS: Twenty four patients were randomly assigned to vitamin D (aged 39.4±9.6years, 75% males) and the other 23 patients to the placebo arm (aged 42.5±11.2years, 60.9% males). After eight weeks, the vitamin D group exhibited a significant increase in vitamin D levels (31.4 vs -0.4nmol/l, p<0.0001). There was no significant effect of vitamin D on psychotic, depressive or metabolic parameters. However, in the vitamin D group, there was a trend towards improved cognition (effect size=0.17, significance lost following Bonferroni correction). CONCLUSIONS: Vitamin D supplementation was associated with a trend towards improved cognition, but did not affect psychosis, mood or metabolic status. It is possible that the robust decrease in the PANSS scores in both groups may have obscured an effect of vitamin D supplementation.

[THE PSYCHIATRIC DIAGNOSIS GUIDE - DSM-5 - INNOVATIONS AND CRITICISM].

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is published by the American Psychiatric Association (APA) as a guide for diagnosing psychiatric diseases and enables the alignment of psychiatric diagnoses with those of the psychologists, the social workers, the nursing staff and other mental health professionals. In addition, it helps bring cohesion to research, public health policy, education, the field of insurance and compensation and the legal system. After 14 years of hard work, the updated version of the DSM, the DSM-5, was published on May 2013. The current review aims to update the readers on the essence of the DSM and the methods of psychiatric diagnosing and to present the main changes in the field, as expressed in the 5th edition of the guide. In addition to details of those changes we included discussions of the criticisms brought against them. We hope that the review will contribute to broadening the readers' knowledge, broaden exposure and familiarity with the psychiatric lingo and to strengthening the professional ties between psychiatrists and professionals in other, tangential, medical fields.

Severe traumatic brain injury and controlled hemorrhage in rats: quest for the optimal mean arterial blood pressure after whole fresh donor blood resuscitation.

Treatment of combined traumatic brain injury and hypovolemic shock poses a particular challenge due to the possible conflicting consequences. While restoring diminished volume is the treatment goal for hypovolemia, maintaining and adequate cerebral perfusion pressure and avoidance of secondary damage remain a treatment goal for the injured brain. Various treatment modalities have been proposed, but the optimal resuscitation fluid and goals have not yet been clearly defined. In this study, we investigate the physiological and neurological outcomes in a rat model of combined traumatic brain injury and hypovolemic shock, submitted to treatment with varying amounts of fresh blood. Forty-eight male Lewis rats were divided into control and treatment groups. Traumatic brain injury was inflicted by a free-falling rod on the exposed cranium. Hypovolemia was induced by controlled hemorrhage of 30% blood volume. Treatment groups were treated by fresh whole blood with varying volumes, reaching resuscitation goals of a mean arterial blood pressure (MAP) of 80, 100, and 120 mmHg at 15 min. Mean arterial blood pressure was assessed at 60 min and neurological outcomes and mortality in the subsequent 48 h. At 60 min, MAP was highest for the group resuscitated most aggressively. Neurological outcomes and mortality inversely correlated with the aggressiveness of resuscitation. In this study, we find that mild resuscitation with goals of restoring MAP to 80 mmHg (which is lower than baseline) provided best results when considering hemodynamic stability, survival, and neurological outcomes. An aggressive resuscitation may be detrimental, inducing processes that eventually cause a significant decrease in survival.

NF-kappaB activity in endothelial cells is modulated by cell substratum interactions and influences chemokine-mediated adhesion of natural killer cells.

Because changes in subendothelial matrix composition are associated with alterations of the endothelial immune phenotype, we sought to understand if cytokine-induced NF-kappaB activity and downstream effects depend on substrate adherence of endothelial cells (EC). We compared the upstream phosphorylation cascade, activation of NF-kappaB, and expression/secretion of downstream effects of EC grown on tissue culture polystyrene plates (TCPS) with EC embedded within collagen-based matrices (MEEC). Adhesion of natural killer (NK) cells was quantified in vitro and in vivo. NF-kappaB subunit p65 nuclear levels were significantly lower and p50 significantly higher in cytokine-stimulated MEEC than in EC-TCPS. Despite similar surface expression of TNF-alpha receptors, MEEC had significantly decreased secretion and expression of IL-6, IL-8, MCP-1, VCAM-1, and ICAM-1. Attenuated fractalkine expression and secretion in MEEC (two to threefold lower than in EC-TCPS; p < 0.0002) correlated with 3.7-fold lower NK cell adhesion to EC (6,335 +/- 420 vs. 1,735 +/- 135 cpm; p < 0.0002). Furthermore, NK cell infiltration into sites of EC implantation in vivo was significantly reduced when EC were embedded within matrix. Matrix embedding enables control of EC substratum interaction. This in turn regulates chemokine and surface molecule expression and secretion, in particular of those compounds within NF-kappaB pathways, chemoattraction of NK cells, local inflammation, and tissue repair.

The effect of three-dimensional matrix-embedding of endothelial cells on the humoral and cellular immune response.

The endothelium is a unique immunologic target. The first host-donor reaction in any cell, tissue or organ transplant occurs at the blood-tissue interface, the endothelium. When endothelial cells are themselves the primary component of the implant a second set of immunologic reactions arises. Injections of free endothelial cell implants elicit a profound major histocompatibility complex (MHC) II dominated immune response with significant sensitivity, cascade enhancement and immune memory. Endothelial cells embedded within three-dimensional matrices retain all the biosecretory capacity of quiescent endothelial cells. Perivascular implants of such cells are the most potent inhibitor of intimal hyperplasia and thrombosis following controlled vascular injury, but without any immune reactivity. Allo- and even xenogeneic endothelial cells evoke no significant humoral or cellular immune response in immunocompetent hosts when embedded within matrices. Moreover, endothelial implants are immunomodulatory, reducing the extent of the memory response to previous free cell implants. Attenuated immunogenicity results in muted activation of adaptive and innate immune cells. These findings point toward a pivotal role of matrix-cell-interconnectivity for the cellular immune phenotype and might therefore assist in the design of extracellular matrix components for successful tissue engineering.

Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity.

The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability. This peptide was detected in the brain following oral administration to rats. A single oral dose of 0.5 mg/kg in mice led to reduced food consumption (up to 48% vs the control group) that lasted for 5 h. Repetitive once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain. Backbone cyclization was shown to produce a potential drug lead for treating obesity.

Implications on emergence of antimicrobial resistance as a critical aspect in the design of oral sustained release delivery systems of antimicrobials.

PURPOSE: To assess the effects of the unabsorbed fraction of an orally administered antimicrobial drug which enters the colon on the emergence of resistance among the natural microflora, a phenomenon largely overlooked so far despite its clinical importance, especially when sustained release formulations are used. METHODS: Effects of an orally administered model beta-lactam antibiotic (amoxicillin) on emergence of resistant bacteria were assessed using a microbiological assay for qualitative and quantitative determination of resistant bacteria in fecal samples of rats following gastric administration of the drug to rats for 4 consecutive days. Time- and site-controlled administration of a beta-lactamase to the rat colon was assessed as a potential strategy for prevention the emergence of resistant bacteria following oral administration of incompletely absorbed antimicrobials. RESULTS: Emergence of resistant bacteria was demonstrated following oral administration of amoxicillin to rats, whereas de-activation of the beta-lactam prior to entering the colon, by infusion of a beta-lactamase into the lower ileum, was shown to prevent the emergence of resistant colonic bacteria. CONCLUSIONS: This study illustrates the need to consider the emergence of antimicrobial resistance as a goal equally important to microbiological and clinical cure, when designing oral sustained-release delivery systems of antimicrobial drugs.

Effect of structural and conformation modifications, including backbone cyclization, of hydrophilic hexapeptides on their intestinal permeability and enzymatic stability.

A library of 18 hexapeptide analogs was synthesized, including sub-libraries of N- or C-methylation of the parent hexapeptide Phe-Gly-Gly-Gly-Gly-Phe, as well as backbone cyclized analogs of each linear analog with various ring sizes. N- or C-methylation as well as cyclization (but not backbone cyclization) have been suggested to improve intestinal permeability and metabolic stability of peptides in general. Here we aimed to assess their applicability to hydrophilic peptides. The intestinal permeability (Papp) of the 18-peptide library was in the range of 0.2-6.8 x 10-6 cm/sec. Based on several tests, we concluded that the absorption mechanism of all tested analogs is paracellular, regardless of the structural or conformational modifications. In all cases, backbone cyclization increased Papp (5-fold) in comparison to the linear analogs due to the smaller 3D size and also dramatically decreased peptide proteolysis by brush border enzymes. N- or C-methylation did not enhance the permeability of the linear analogs in this series.

Endothelial immunogenicity--a matter of matrix microarchitecture.

The endothelium is a highly specialized active interface between blood and the underlying tissues, maintaining vascular tone, thrombo-resistance and selective permeability to cells and proteins. It is also an important regulator of inflammatory diseases, and endothelial-leukocyte interactions often herald complex diseases with an inflammatory component. Yet, the exact mechanisms promoting immune activation of endothelial cells (EC) are incompletely understood. Knowledge is accumulating that the immediate environment defines the cellular phenotype, whereby matrix composition and spatial formation (three- versus two-dimensional) seem to act as pivotal mediators. Here we summarize current findings denoting a key role of matrix environment in regulating endothelial immunogenicity. The immune response to three-dimensional matrix-embedded EC stands in stark contrast to the response engendered by injection of these same cells in their free state. Matrix-embedding confers a quiescent endothelial state with reduced expression levels of chemokines, adhesion, costimulatory, and major histocompatibility complex II molecules. Compared to EC grown on two-dimensional tissue culture plates, cytokine-stimulation of matrix-embedded EC results in significantly reduced adhesion of natural killer cells and proliferation of co-cultivated allogeneic T cells. On the contrary, matrix-embedded EC induce an immune-inhibitory phenotype of dendritic cells and T regulatory cells to a greater extent than non-embedded EC. As vascular diseases are associated with profound changes in basement membrane composition and overall tissue architecture, our results indicate that the immediate environment of EC might play a pivotal role in initiating and regulating of different vascular diseases. Cell-matrix interconnections appear to govern endothelial immunogenicity and interactions between EC and immune cells.

Endothelial cell-matrix interactions determine maturation of dendritic cells.

The fate of allo- and xenogeneic endothelial cell (EC) implants is regulated by EC-matrix interactions. While free EC are destroyed by a vigorous immune reaction, EC embedded within 3D collagen cells are well tolerated. Given the critical role DC serve in immune reactivity, we hypothesized that EC-driven DC maturation depends on EC-matrix contact. In marked contrast to DC co-cultured with a cytokine cocktail or with allo- and xenogeneic EC grown to confluence on 2D tissue culture plates, DC exposed to 3D matrix-embedded allo- and xenogeneic EC failed to mature, retaining their endocytic activity and exhibiting significantly reduced expression of maturation markers (costimulatory molecules, HLA-DR, CD83; p <0.01). Matrix-embedded EC also limited cytokine-induced maturation and activity of DC. Incubation with matrix-embedded EC inhibited DC induction of allogeneic lymphocyte proliferation (p <0.002) and EC cross-activation (ICAM-1, VCAM-1, HLA-DR, TLR2 and 4; p <0.01). The endothelium in its quiescent state is confluent and substrate adherent. The former ensures secretion of growth inhibitors rather than promoters, and the latter may ensure immune acceptance. We now demonstrate for the first time that interactions of EC with an underlying 3D matrix affect the ability of EC to drive DC maturation.

Investigation of the enhancing mechanism of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate effect on the intestinal permeability of polar molecules utilizing a voltage clamp method.

Oral administration of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) has been reported to increase the bioavailability of various macromolecules. The present study was aimed to study the effect of SNAC on the intestinal tissue permeability of polar charged molecules, using 6-carboxy-fluorescein (6-CF) as a model. The effects of SNAC on rat intestinal permeability was investigated ex vivo by utilizing voltage clamp experiments in a side-by-side diffusion chamber model in comparison with the effect of EDTA (10mM). The intestinal permeability of 6-CF was increased two-fold in the presence of 33-66 mM SNAC, and by 6.5-fold in the presence of 10mM EDTA. The voltage clamp experiments show that the effect of SNAC was particularly on the transcellular 7-folds increase (that was five times larger than the paracellular transport of the model agent). While EDTA affected predominantly paracellular pathway transport, SNAC 33-66 mM had no effect on [(3)H]-mannitol transport or any toxic effect on tissue integrity measured by TEER values. In conclusion, this study demonstrates that SNAC can facilitate passive transport of polar charged molecules through the membrane of epithelial enterocytes. This is noteworthy in view of the very low tendency of a charged molecule to permeate across the lipophilic inter-phase of the enterocytes membrane.