In Silico Screening of Metal-Organic Frameworks and Zeolites for He/N2 Separation.

In silico screening of 10,143 metal-organic frameworks (MOFs) and 218 all-silica zeolites for adsorption-based and membrane-based He and N2 separation was performed. As a result of geometry-based prescreening, structures having zero accessible surface area (ASA) and pore limiting diameter (PLD) less than 3.75 Å were eliminated. So, both gases can be adsorbed and pass-through MOF and zeolite pores. The Grand canonical Monte Carlo (GCMC) and equilibrium molecular dynamics (EMD) methods were used to estimate the Henry's constants and self-diffusion coefficients at infinite dilution conditions, as well as the adsorption capacity of an equimolar mixture of helium and nitrogen at various pressures. Based on the obtained results, adsorption, diffusion and membrane selectivities as well as membrane permeabilities were calculated. The separation potential of zeolites and MOFs was evaluated in the vacuum and pressure swing adsorption processes. In the case of membrane-based separation, we focused on the screening of nitrogen-selective membranes. MOFs were demonstrated to be more efficient than zeolites for both adsorption-based and membrane-based separation. The analysis of structure-performance relationships for using these materials for adsorption-based and membrane-based separation of He and N2 made it possible to determine the ranges of structural parameters, such as pore-limiting diameter, largest cavity diameter, surface area, porosity, accessible surface area and pore volume corresponding to the most promising MOFs for each separation model discussed in this study. The top 10 most promising MOFs were determined for membrane-based, vacuum swing adsorption and pressure swing adsorption separation methods. The effect of the electrostatic interaction between the quadrupole moment of nitrogen molecules and MOF atoms on the main adsorption and diffusion characteristics was studied. The obtained results can be used as a guide for selection of frameworks for He/N2 separation.

Neuronal Bases of Systemic Organization of Behavior.

Despite the years of studies in the field of systems neuroscience, functions of neural circuits and behavior-related systems are still not entirely clear. The systems description of brain activity has recently been associated with cognitive concepts, e.g. a cognitive map, reconstructed via place-cell activity analysis and the like, and a cognitive schema, modeled in consolidation research. The issue we find of importance is that a cognitive unit reconstructed in neuroscience research is mainly formulated in terms of environment. In other words, the individual experience is considered as a model or reflection of the outside world and usually lacks a biological meaning, such as describing a given part of the world for the individual. In this chapter, we present the idea of a cognitive component that serves as a model of behavioral interaction with environment, rather than a model of the environment itself. This intangible difference entails the need in substantial revision of several well-known phenomena, including the long-term potentiation.The principal questions developed here are how the cognitive units appear and change upon learning and performance, and how the links between them create the whole structure of individual experience. We argue that a clear distinction between processes that provide the emergence of new components and those underlying the retrieval and/or changes in the existing ones is necessary in learning and memory research. We then describe a view on learning and corresponding neuronal activity analysis that may help set this distinction.

Sodium valproate, a histone deacetylase inhibitor, enhances the efficacy of vinorelbine-cisplatin-based chemoradiation in non-small cell lung cancer cells.

AIM: To enhance the anticancer activity of vinorelbine, cisplatin and ionizing radiation (IR) combination against non-small cell lung cancer (NSCLC) cells by co-administration of sodium valproate (VPA), a histone deacetylase inhibitor, and to elucidate molecular events underpinning treatment efficacy. MATERIALS AND METHODS: The NSCLC A549 cell line was treated with cisplatin (0.2 µg/ml), vinorelbine (2 nM), VPA (1 mM) and IR (2.5 Gy) alone, or in combination. Cell proliferation, cell-cycle distribution, apoptosis, and levels of DNA double-strand breaks, activated DNA damage checkpoint kinases pCHK1, pCHK2, cell-cycle inhibitors p21CIP1/WAF1 and p27KIP1 were assessed. RESULTS: VPA markedly enhanced the DNA-damaging effect of the cisplatin-vinorelbine-IR combination and induced increased DSBs, and expression of pCHK2, pCHK1, p21CIP1/WAF1 and p27KIP1. These molecular changes led to cell-cycle arrest and increased apoptosis and consequently markedly curtailed cancer cell growth. CONCLUSION: VPA markedly enhances the anticancer activity of cisplatin-vinorelbine-IR combination. This finding has translational implications for enhancing the efficacy of anticancer treatment and for reducing side-effects by reducing doses of radiation and drugs.

Kidney function and retinol status in type 2 diabetes mellitus patients.

Kidneys play an important role in retinol turnover. We postulated that retinol homeostasis is disturbed in diabetic nephropathy. The aim of this research was to study the effect of kidney impairment on urinary excretion and on serum concentrations of retinol in type 2 diabetes mellitus patients. For this purpose, 41 type 2 diabetes patients and 9 sex -and age-matched healthy subjects were enrolled. Serum and urinary retinol and retinol-binding protein (RBP) were assessed by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. The study showed that 17 out of 41 diabetic patients (41.5%) and none of the controls excreted retinol in urine (P < 0.02). Retinol excretion in the urine in these patients was 1.5-fold more prevalent than hypercreatininemia. Urinary retinol significantly correlated with clinically diagnosed nephropathy (P = 0.02). All but one of the patients with hypercreatininemia excreted retinol in the urine. Serum retinol and RBP in patients with hypercreatininemia were higher than in controls (P < 0.002). Values of urinary retinol, unlike urinary RBP, albumin and total protein, did not overlap between patients and controls. Our results indicate that (i) urinary retinol is a specific sign of tubular damage in type 2 diabetic patients and (ii) urinary retinol enables a more clear-cut identification of proximal tubule dysfunction in type 2 diabetes patients than urinary RBP or albumin.

A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells.

Radiotherapy is one of the curative treatment options for prostate cancer (PCa). However, effective doses of ionizing radiation (IR) have a high risk of side effects. To increase sensitivity of PCa to IR we pretreated human androgen-refractory DU145 PCa cells with a combination of sodium valproate (VPA), a well-tolerated drug with histone deacetylases inhibiting activity, and 1,25-dihydroxyvitamin D3, 1,25(OH)2D3, the active metabolite of vitamin D, a well known anticancer agent. The results show that irradiation (4Gy) of DU145 PCa cells pretreated with a combination of 1 mM VPA and 100 nM 1,25(OH)2D3 efficiently suppressed (87.9%) PCa cell proliferation. IR after combined pretreatment resulted in increased DNA double-strand breaks expressed as levels of phosphorylated histone H2A.X, compared with non-treated cells the increase was 58.1% in pretreated cells and 11.8% in non-pretreated cells (p<0.002). Combined pretreatment enhanced IR-induced activation of DNA damage checkpoint kinase Chk2, 39.0% in pretreated cells compared to 23.8% in non-pretreated cells (p<0.05). These molecular changes led to DNA replication blockade, S-phase cell-cycle arrest and enhanced apoptosis. Cumulatively, the results indicate that combined pretreatment with VPA and 1,25(OH)2D3 followed by IR is a highly effective treatment for human PCa cells. This observation may have important implications for reducing doses of radiation administered to cancer patients thus limiting the severity of side effects.

Efficient dual treatment of the hormone-refractory prostate cancer cell line DU145 with cetuximab and 1,25-dihydroxyvitamin D3.

BACKGROUND: Targeting of the epidermal growth factor receptor (EGFR) pathway is a promising treatment strategy for aggressive androgen-refractory prostate cancer (PCa). The effect of treating the androgen-resistant PCa cell line DU145 with a combination of the anti-EGFR drug cetuximab and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) was evaluated. MATERIALS AND METHODS: DU145 cells were treated with 5 nM cetuximab, 100 nM 1,25(OH)2D3 or a combination of both. The effect of the treatments on cell growth, cell-cycle and apoptosis was evaluated. RESULTS: Single-drug treatments decreased DU145 cell growth by up to 25% and caused a 1.5-to 1.7-fold increase of apoptosis, but did not affect the cell-cycle distribution. However, dual treatment with a combination of cetuximab and 1,25(OH)2D3 inhibited DU145 cell proliferation by 40%, caused considerable cell-cycle arrest in the Go/Gl-phase, and enhanced apoptosis by 2.5-fold (compared to the control, p < 0. 0001, p <0. 006 and p <0. 0001, respectively). CONCLUSION: A combination of cetuximab and 1,25(OH)2D3 efficiently suppresses hormone-resistant PCa cell growth and could provide a basis for its clinical application.

The combined treatment of 1,25-dihydroxyvitamin D3 and a non-steroid anti-inflammatory drug is highly effective in suppressing prostate cancer cell line (LNCaP) growth.

BACKGROUND: The active metabolite of vitamin D3, 1,25(OH)2D3, is known to possess anti-proliferative and pro-differentiative activities in prostate cancer (PCa) cells. However, its clinical use is limited because of the risk of hypercalcemia. Concurrent administration of lower doses of 1,25(OH)2D3 together with other anticancer drugs may help to overcome this obstacle and lead to an effective and tolerable therapy. In the present in vitro study, we investigated the combined anti-cancer effect of 1,25(OH)2D3 and ibuprofen, a well-known non-steroidal anti-inflammatory drug (NSAID) that is also recognized for its ability to reduce prostate cancer development. MATERIALS AND METHODS: An androgen-sensitive prostate cancer cell line (LNCaP), grown in medium containing androgen (5alpha-dihydrotestosterone (DHT)) or without it, was treated with 1,25(OH)2D3 or ibuprofen alone or with a combination of both drugs. The effects of the treatments on LNCaP cell proliferation, cell cycle and apoptosis were evaluated by the thymidine incorporation method, the propidium iodide method and ELISA, respectively. The unpaired t-test was used for statistical analysis. RESULTS: Simultaneous treatment of LNCaP cells grown without DHT with 10 nM 1,25(OH)2D3 and 0.2 mM ibuprofen decreased cell growth by 42% (p<0.001, compared to the control cells). This effect was found to be additive since each single drug reduced cell proliferation by only 24%. On the other hand, highly significant synergistic cell growth inhibition (67%, p<0.001) was achieved by combined treatment of 1,25(OH)2D3 and ibuprofen in DHT-stimulated LNCaP cells. This combined treatment was also found to be effective in decreasing the cell transition from G1- to S-phase (p<0.003) and effective in enhancing apoptosis. CONCLUSION: Although both 1,25(OH)2D3 and ibuprofen demonstrate in vitro anti-carcinogenic activities as a single drug treatment, the present results showed that the combined use of 1,25(OH)2D3 with ibuprofen is superior to treatment with a single drug.

Urinary excretion of vitamin A in critically ill patients complicated with acute renal failure.

OBJECTIVE: Study the possible excretion of vitamin A in urine of critically ill patients complicated with acute renal failure. PATIENTS AND METHODS: Nine Intensive Care Unit patients, age 71.2 +/- 15.7 (mean +/- SD) with acute renal failure were studied. Urinary retinol, creatinine, protein, albumin, and serum creatinine were measured. RESULTS: All patients excreted retinol in urine; individual values ranged from 0.007 to 0.379 micromol retinol/mmol creatinine. There was no correlation of urinary retinol/creatinine ratio with serum creatinine or with urinary protein/creatinine and albumin/creatinine ratios. CONCLUSION: Excretion of retinol in urine may be indicative of acute renal failure in critically ill patients.

Urinary excretion of retinol in patients with multiple myeloma: a preliminary study.

Urinary excretion of vitamin A was studied in patients with multiple myeloma (MM). Eight of the 12 patients studied excreted retinol in urine; only one of them had elevated serum creatinine (115-150 micromol/L). There was a highly significant correlation between urinary retinol and serum creatinine (P < 0.0004). Urinary retinol correlated also with urine protein (P < 0.0001) and albumin (P = 0.001), but not with urinary immunoglobulin light chains. Urinary retinol excretion may be an early manifestation of renal dysfunction in MM patients. The effect of urinary retinol excretion on vitamin A homeostasis in MM deserves further study.

Transdermal delivery of paracetamol for paediatric use: effects of vehicle formulations on the percutaneous penetration.

Paracetamol is a safe and effective analgesic and antipyretic agent, and is one of the most widely used medications for infants and children. The formulations currently available have been designed for oral and rectal administration. However, they are not practical in young patients with vomiting and diarrhoea, or in those who refuse to take the full dose. An alternative route of administration would be a significant contribution to the paediatric pharmacopoeia. The aim of this study was to develop a new transdermal system for optional therapeutic administration of paracetamol in infants and children. In-vivo studies were carried out in animals using a transdermal system of high-loaded, soluble paracetamol in a hydrogel patch, which was also tested in-vitro for 8 h. Although the beneficial contribution of glyceryl oleate to the transdermal penetration of paracetamol seemed to be significant in-vitro, it was shown to be insufficient in-vivo. To improve the penetration of the drug, 4% PEG-40 stearate and 10% ethanol were incorporated as absorption enhancers into the dermal patches. A few hours after application of the improved patches to rats, plasma drug concentrations were elevated to levels comparable with those obtained after oral and subcutaneous administration of a high dose of paracetamol. Since plasma drug concentrations did not reach a constant steady state (as a peak or plateau) during the short-term animal experiments, longer pharmacokinetic studies in conscious animals are necessary.

LF 16-0687 Ms, a new bradykinin B2 receptor antagonist, improves neurologic outcome but not brain tissue prostaglandin E2 release in a rat model of closed head trauma combined with ethanol intoxication.

BACKGROUND: LF 16-0687 Ms previously was reported to improve Neurological Severity Score (NSS) and decrease cerebral edema and prostaglandin E(2) (PGE(2)) release after closed head trauma (CHT) in rats. Here, we examined whether these beneficial effects of LF 16-0687 Ms are altered when CHT is accompanied by acute ethanol administration. METHODS: Six groups of rats (n = 8 per group) were examined during combination of the following experimental conditions: CHT versus sham operation, LF 16-0687 Ms 3 mg/kg subcutaneously versus saline, and ethanol 2 g/kg versus saline. RESULTS: After CHT, brain water content decreased and NSS improved with ethanol + LF 16-0687 Ms as compared with values after saline or ethanol. PGE(2) release decreased with ethanol (147 +/- 59 pg/mg tissue) but not with ethanol + LF 16-0687 Ms (286 +/- 194 pg/mg tissue). CONCLUSION: Ethanol does not affect the improvement of NSS and the decrease of cerebral edema seen with LF 16-0687 Ms after CHT, but does reverse the ability of LF 16-0687 Ms to minimize the increase of PGE(2) release. In intoxicated patients, bradykinin antagonist therapy may improve post-CHT outcome without altering PGE(2) release.

Unapproved prescriptions in two pediatric intensive care units in Israel.

BACKGROUND: Many medications prescribed to children worldwide have not been approved for pediatric use because the necessary clinical trials have not yet been performed. Children given these drugs have been shown to be at increased risk for adverse drug reactions. OBJECTIVE: The aim of this study was to assess the extent of unapproved (off label and/or unlicensed) use of medications in pediatric intensive care units (PICUs) in Israel. METHODS: Medications administered to patients treated in the PICUs of Soroka University Medical Center (SMC) and Assaf Harofe Medical Center (AHMC) were reviewed. Analyses were retrospective at SMC and prospective at AHMC. RESULTS: The records of 158 patients were included in the study-116 patients at SMC (73.4%; 62 boys, 54 girls; mean [SD] age, 38.9 [50.4] months) and 42 at AHMC (26.6%; 26 boys, 16 girls; mean [SD] age, 63.3 [69.3] months). They received a total of 123 different medications. Sedatives and antibiotics were the most frequently prescribed drug classes at SMC (15.2% and 6.5%, respectively), and antibiotics, acetaminophen, and antiasthmatic drugs were most frequently prescribed at AHMC (14.4%, 13.6%, and 6.8%, respectively). Sympathomimetic drugs, sedatives, and antibiotics were the drugs most commonly prescribed in an unlicensed or off-label manner at SMC (11.4%, 11.4%, and 6.5%, respectively); at AHMC, they were antiinfectives, sympathomimetics, antiasthmatic drugs, and acetaminophen (18.7%, 16.9%, 12.7%, 6.8%, respectively). The percentage of patients receiving unapproved medications (SMC, 93 [80.2%]; AHMC, 38 [90.5%]) and the percentage of unlicensed and off-label prescriptions (SMC, 243 [41.5%]; AHMC, 118 [41.0%], respectively) were similar between the 2 PICUs. Inappropriate age was the most common off-label category, followed by different dose, different indication, and different route. CONCLUSION: The results of this study of unapproved prescriptions in 2 PICUs in Israel show a high number of such prescriptions and indicate an urgent need to investigate the use of those medications in children.

Deliberate self-poisoning in adolescents.

BACKGROUND: Adolescent suicide has become increasingly more prevalent in recent years, with self-poisoning being a frequent means of suicide attempt. OBJECTIVE: To investigate the factors associated with adolescent self-poisoning. METHODS: Data on adolescents referred for intentional self-poisoning to the Adolescent Medical Unit during the years 1990-1998 were evaluated retrospectively. Data were obtained from the hospital medical records and included the following factors: sociodemographic data, educational status, agent and route of intake, motivation for overdose, and the extent of serious suicidal intent. RESULTS: We evaluated 324 cases of adolescent self-poisoners aged 12-18 years (mean +/- SD 14.8 +/- 1.5 years). The female/male ratio was 8:1. Most of the patients were attending school and lived in urban areas. Oral ingestion was the only route of intake; 84.5% of the patients ingested drugs and 10.5% non-medicinal compounds. The drug most commonly taken was acetaminophen. The non-medicinal compounds were mostly pesticides and household materials. The suicide attempts were most frequently associated with transient depression, stemming from defects in child-family communication. As based on clinical psychiatric evaluation, patients who had ingested polydrugs and non-medical compounds evidenced a significantly greater suicidal intent (chi 2 = 11.9, P < 0.001) compared to those who took only one or two kinds of drugs. CONCLUSIONS: We found that self-poisoning attempts occur most frequently in depressed females at junior high and high school, usually in the context of family dysfunction. Non-medicinal agents and polydrug ingestion are major risk factors for evaluating the seriousness of the suicidal intent.