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Background: The introduction of second-generation antipsychotics (SGAs) over the past 2 decades generated considerable optimism that better antipsychotic treatments for schizophrenia and bipolar disorder were possible. SGAs offer several tolerability benefits over first-generation antipsychotics (FGAs), particularly with respect to extrapyramidal symptoms. However, SGAs can induce serious metabolic dysregulations, especially in drug-naive, first-episode, and child and adolescent populations, with olanzapine and clozapine having the highest propensity to cause these abnormalities. In this context, newer SGAs were developed to further improve the adverse effect burden of available agents. However, until now, the metabolic risk profile of the newly approved SGAs - asenapine, iloperidone, lurasidone and paliperidone (paliperidone extended release and paliperidone palmitate) - has not been compared. Objective: The objective of this systematic review and exploratory meta-analysis was to assess the effects of asenapine, iloperidone, lurasidone and paliperidone on body weight and other metabolic parameters (cholesterol, triglycerides and glucose), as this information is relevant to guide clinical decision making. Method: A systematic literature search (1966-March 2012), using the Cochrane Central Register of Controlled Trials and MEDLINE, CINAHL and EMBASE databases, was conducted for randomized, placebo-controlled and head-to-head clinical trials of asenapine, iloperidone, lurasidone and paliperidone. Published and unpublished data on changes in body weight and glucose and lipid metabolism parameters were extracted. For placebocontrolled, short-term (<12 weeks) and longer-term (>12 weeks) trials with available data on >7% weight increase compared with pre-treatment weight, or mean weight change with standard deviation, a formal meta-analysis was performed, estimating the pooled effect size (represented as relative risk [RR], numbers-needed-to-harm [NNH] and weighted mean difference [WMD]). An exploratory meta-analysis was also performed for the other metabolic variables (cholesterol, triglycerides and glucose). Data from active- and placebocontrolled studies were used for a pooled comparison of simple mean changes in weight, cholesterol, triglyceride and glucose levels. Results: Fifty-six trials (n = 21691) in schizophrenia (N = 49, n= 19299) or bipolar disorder (N = 7, n = 2392) were identified (asenapine: N = 9, iloperidone: N=ll, lurasidone: N = 8, paliperidone: N = 28). Most of the trials (64.3%) were of <12 weeks' duration. In the short-term trials, compared with placebo, a >7% weight increase was statistically significantly (p<0.05) most prevalent for asenapine (5 trials, n= 1360, RR = 4.09, 95% confidence interval [CI] 2.25, 7.43, NNH = 17), followed by iloperidone (4 trials, n= 1931, RR = 3.13, 95% CI 2.08, 4.70, NNH =11) and paliperidone (12 trials, n = 4087, RR = 2.17, 95% CI 1.64, 2.86, NNH = 20). The effect of lurasidone on body weight (6 trials, n=1793, RR =1.42, 95% CI 0.87, 2.29) was not statistically significant. Short-term weight gain was statistically significantly (p<0.001) greater than placebo with iloperidone (1 trial, n = 300, +2.50kg, 95% CI 1.92, 3.08), paliperidone (15 trials, n = 3552, +1.24 kg, 95% CI 0.91, 1.57), asenapine (3 trials, n = 751, +1.16 kg, 95% CI 0.83, 1.49), as well as with lurasidone (5 trials, n = 999, +0.49 kg, 95% CI 0.17, 0.81, p<0.01). Sufficient meta-analysable, longer-term, weight change data were only available for asenapine and paliperidone, showing statistically significantly (p< 0.001) greater weight gain versus placebo for both drugs (asenapine, 3 trials, n = 311, + 1.30kg, 95% CI 0.62,1.98; paliperidone, 6 trials, n= 1174, +0.50kg, 95% CI 0.22, 0.78). Although statistically significant, in general, no clinically meaningful differences were observed between the four newly approved SGAs and placebo regarding the mean change from baseline to endpoint in cholesterol levels in short-term trials, with the exception of iloperidone for total cholesterol (1 trial, n= 300, +11.60mg/dL, 95% CI 4.98, 18.22, p<0.001), high-density cholesterol (1 trial, n = 300, +3.6 mg/dL, 95% CI 1.58,5.62, p < 0.001) and lowdensity cholesterol (1 trial, n= 300, +10.30mg/dL, 95% CI 4.94,15.66, p<0.001) and with the exception of lurasidone for high-density cholesterol (5 trials, n= 1004,+1.50mg/dL, 95% CI 0.56,2.44, p<0.01). Asenapine increased total cholesterol statistically significantly (p<0.05) during longer-term treatment (1 trial, n=194, +6.53mg/dL, 95% CI 1.17, 11.89). Regarding triglycerides, only short-term (3 trials, n= 1152, +1.78mg/dL, 95% CI 0.40, 3.17, p<0.01) and longer-term treatment with paliperidone (4 trials, n = 791, -0.20mg/dL, 95% CI -0.40, -0.01, p< 0.05) had a statistically, but not clinically, significant effect. Statistically significant changes in glucose levels were noticed during short-term treatment with asenapine (2 trials, n = 379, -3.95mg/dL, 95% CI -7.37, -0.53, p<0.05) and iloperidone (1 trial, n=300, +6.90mg/dL, 95% CI 2.48, 11.32, p<0.01), and during long-term treatment with paliperidone (6 trials, n= 1022, +3.39mg/dL, 95% CI 0.42, 6.36, p<0.05). Conclusion: While preliminary data suggest the lowest weight gain potential with lurasidone and potentially relevant short-term metabolic effects for asenapine and iloperidone, data are still too sparse to comprehensively evaluate the metabolic safety of the newly approved SGAs. Therefore, there is a clear need for further controlled studies to evaluate whether these agents are less problematic regarding treatment-emergent weight gain and metabolic disturbances than other currently available antipsychotics. [ABSTRACT FROM AUTHOR]

Background: α-TEA (RRR-α-tocopherol ether-linked acetic acid analog), a derivative of RRR-α-tocopherol (vitamin E) exhibits anticancer actions in vitro and in vivo in variety of cancer types. The objective of this study was to obtain additional insights into the mechanisms involved in α-TEA induced apoptosis in human breast cancer cells. Methodology/Principal Findings: α-TEA induces endoplasmic reticulum (ER) stress as indicated by increased expression of CCAAT/enhancer binding protein homologous protein (CHOP) as well as by enhanced expression or activation of specific markers of ER stress such as glucose regulated protein (GRP78), phosphorylated alpha subunit of eukaryotic initiation factor 2 (peIF-2α), and spliced XBP-1 mRNA. Knockdown studies using siRNAs to TRAIL, DR5, JNK and CHOP as well as chemical inhibitors of ER stress and caspase-8 showed that: i) α-TEA activation of DR5/caspase-8 induces an ER stress mediated JNK/ CHOP/DR5 positive amplification loop; ii) α-TEA downregulation of c-FLIP (L) protein levels is mediated by JNK/CHOP/DR5 loop via a JNK dependent Itch E3 ligase ubiquitination that further serves to enhance the JNK/CHOP/DR5 amplification loop by preventing c-FLIP's inhibition of caspase-8; and (iii) α-TEA downregulation of Bcl-2 is mediated by the ER stress dependent JNK/CHOP/DR5 signaling. Conclusion: Taken together, ER stress plays an important role in α-TEA induced apoptosis by enhancing DR5/caspase-8 proapoptotic signaling and suppressing anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase- 8 signaling. [ABSTRACT FROM AUTHOR]

The non-natural amino acids (R)- and (S)-2-amino-3-fluoro-2-methylpropanoic acid 5and (R)- and (S)-3-fluoro-2-methyl-2-N-(methylamino)propanoic acid 8were synthesized in shorter reaction sequences than in the original report starting from enantiomerically pure (S)- and (R)-α-methyl-serine, respectively. The reaction sequence provided the cyclic sulfamidate precursors for radiosynthesis of (R)- and (S)-[18F]5and (R)- and (S)-[18F]8in fewer steps than in the original report. (R)- and (S)-[18F]5and(R)- and (S)-[18F]8were synthesized by no-carrier-added nucleophilic [18F]fluorination in 52−66% decay-corrected yields with radiochemical purity over 99%. The cell assays showed that all four compounds were substrates for amino acid transport and enter 9L rat gliosarcoma cells in vitro at least in part by system A amino acid transport. The biodistribution studies demonstrated that in vivo tumor to normal brain ratios for all compounds were high with ratios of 20:1 to115:1 in rats with intracranial 9L tumors. The (R)-enantiomers of [18F]5and [18F]8demonstrated higher tumor uptake in vivo compared to the (S)-enantiomers. [ABSTRACT FROM AUTHOR]

RRR-a-tocopherol derivative α-TEA (RRR-α-tocopherol ether-linked acetic acid analog) has been shown to be a potent antitumor agent both in vivo and in vitro. In this study, we investigated the effects of α-TEA on the expression of epidermal growth factor receptor (EGFR) family members, ErbB1, 2 and 3, and the role of ErbB 2 and 3 in α-TEA-induced apoptosis and suppression of Akt, FLIP and survivin in the cisplatin-sensitive (A2780S) and -resistant (A2780/CP70R) human ovarian cancer cell lines. Data show that α-TEA's ability to induced apoptosis was associated with reduced expression of ErbB1 (cisplatin-resistant cells), 2 and 3 (both cell types) and reduced levels of the phosphorylated (active) form of Akt; as well as, reduced levels of FLIP and survivin proteins in both cell types. Ectopic overexpression and siRNA knockdown studies showed that ErbB2, ErbB3, Akt, FLIP and survivin are involved in α-TEA-induce apoptosis and that α-TEA downregulates FLIP and survivin via suppression of pAkt, which is mediated by ErbB2 and ErB3. Thus, α-TEA is a potent pro-apoptotic agent for both cisplatin-sensitive and -resistant ovarian cancer cell lines in cell culture and it produces cell death, at least in part, by downregulation of members of the EGFR family. [ABSTRACT FROM AUTHOR]

Background: Alpha-tocopherol ether-linked acetic acid (α-TEA), an analog of vitamin E (RRR-alpha-tocopherol), is a potent and selective apoptosis-inducing agent for human cancer cells in vivo and in vitro. α-TEA induces apoptosis via activation of extrinsic death receptors Fas (CD95) and DR5, JNK/p73/Noxa pathways, and suppression of antiapoptotic mediators Akt, ERK, c-FLIP and survivin in breast, ovarian and prostate cancer cells. Results: In this study, we demonstrate that α-TEA induces the accumulation of cell surface membrane ceramide, leading to co-localization with Fas, DR5, and FADD, followed by activation of caspases-8 and -9 and apoptosis in human MDA-MB-231 breast cancer cells. α-TEA treatment leads to increased acid sphingomyelinase (ASMase) activity by 30 min, peaking at 4 hrs, which is correlated with ASMase translocation from cytosol to the cell surface membrane. Functional knockdown of ASMase with either the chemical inhibitor, desipramine, or siRNA markedly reduces α-TEA-induced cell surface membrane accumulation of ceramide and its co-localization with Fas, DR5, and FADD, cleavage of caspases-8 and -9 and apoptosis, suggesting an early and critical role for ASMase in α-TEAinduced apoptosis. Consistent with cell culture data, immunohistochemical analyses of tumor tissues taken from a- TEA treated nude mice bearing MDA-MB-231 xenografts show increased levels of cell surface membrane ceramide in comparison to tumor tissues from control animals. Conclusion: Taken together, these studies demonstrate that ASMase activation and membrane ceramide accumulation are early events contributing to α-TEA-induced apoptosis in vitro and perhaps in vivo. [ABSTRACT FROM AUTHOR]

Both enantiomers of 2-amino-2-methyl-4-iodo-3-( E)-butenoic acid (IVAIB, 5) were radioiodoinated in 65−72% yield. ( S)-IVAIB entered 9L gliosarcoma cells primarily via A-type transport in vitro with higher uptake than ( R)-IVAIB. Biodistribution studies in rats with 9L gliosarcoma brain tumors demonstrated higher tumor to brain ratios with ( S)-IVAIB (75:1 at 1 h) than ( R)-IVAIB (7.7:1). In this model, ( S)-IVAIB is superior to ( R)-IVAIB and is a promising radiotracer for brain tumor imaging. [ABSTRACT FROM AUTHOR]

Background: The pollution of drinking water, e.g. from rivers and pools, has long been recognized to be associated with an increased risk for colorectal cancer (CRC), but there are few direct prospective cohort studies related to person-years on the relative risks of different sources of drinking water for CRC, hence the reason for our study. Methods: Based on a screening for CRC among residents aged 30 years and over in Jiashan County, Zhejiang Province, China, a total of 64,115 residents were classified into five cohorts by their source of drinking water and followed-up from 1st May 1990 to 1st January 2001. Person-years was calculated for every cohort member and Poisson regression was used to control potential confounding variables including demographic variables and smoking history, and to attain crude and adjusted relative risks based on person-years. Results: A trend was seen toward increasing incidence rates for CRC from the drinking water sources of municipal, river, ditch, mixed water to well in turn as shown by relative risk rates of 29.61, 32.67, 33.45, 40.87 and 58.67 per 100,000 inhabitants. Only the role in risk of well water was significantly different from municipal water (P < 0.05). After the confounding variables were adjusted, the significant risk from well water could be seen for colon cancer, rectal cancer as well as CRC. The relative risks were 1.741 [95% confidence interval (CI) 1.001-3.029], 2.228 (95% CI 1.432-3.466) and 2.022 (95% CI 1.432-2.854), respectively. Conclusion: Drinking well water over a long period was identified as playing a role in the risk for CRC, especially for rectal cancer. [ABSTRACT FROM AUTHOR]

Vitamin E is a term that describes a group of compounds with similar yet unique chemical structures and biological activities. One interesting property possessed by certain vitamin E compounds-namely, delta-tocotrienol, RRR-alpha-tocopheryl succinate [vitamin E succinate (VES), a hydrolyzable ester-linked succinic acid analogue of RRR-alpha-tocopherol], and a novel vitamin E analogue referred to as alpha-TEA (alpha-tocopherol ether linked acetic acid analogue, which is a stable nonhydrolyzable analogue of RRR-alpha-tocopherol)-is their ability to induce cancer cells but not normal cells to undergo a form of cell death called apoptosis. In contrast, the parent compound, RRR-alpha-tocopherol, also referred to as natural or authentic vitamin E and known for its antioxidant properties, does not induce cancer-cell apoptosis. Efforts to understand how select vitamin E forms can induce cancer cells to undergo apoptosis have identified several nonantioxidant biological functions, including restoration of pro-death transforming growth factor-beta and Fas signaling pathways. Recent studies with alpha-TEA show it to be a potent inducer of apoptosis in a wide variety of epithelial cancer cell types, including breast, prostate, lung, colon, ovarian, cervical, and endometrial in cell culture, and to be effective in significantly reducing tumor burden and metastasis in a syngeneic mouse mammary tumor model, as well as xenografts of human breast cancer cells. Studies also show that alpha-TEA, in combination with the cyclooxygenase-2 inhibitor celecoxib and the chemotherapeutic drug 9-nitro-camptothecin decreases breast cancer animal model tumor burden and inhibits metastasis significantly better than do single-agent treatments. [ABSTRACT FROM AUTHOR]

Vitamin E derivative, RRR-α-tocopheryl succinate (vitamin E succinate, VES), is a potent pro-apoptotic agent, inducing apoptosis by restoring both transforming growth factor-β (TGF-β) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptos is. Objectives of these studies were to characterize signaling events involved in the pro-apoptotic actions of a naturally occurring form of vitamin E, δ-tocotrienol, and a novel vitamin E analog, α-tocopherol ether acetic acid analog [α-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, α-TEA and δ-tocotrienol induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells to undergo high levels of apoptosis in a concentration- and time-dependent fashion. Like VES, the two compounds induced either no o1" lower levels of apoptosis in normal human mammary epithelial cells and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic mechanisms triggered by the structurally distinct α-TEA and δ-tocotrienol were identical to those previously reported for VES, that is, α-TEA-and δ-tocotrienol-induced apoptosis involved up-regulation of TGF-β receptor II expression and TGF-β-, Fas- and JNK-signaling pathways. These data provide a better understanding of the anticancer actions of a dietary form of vitamin E (δ-tocotrienol) and a novel nonhydrolyzable vitamin E analog (α-TEA). [ABSTRACT FROM AUTHOR]

Presents information on a study which developed a method to prepare ceramic coatings by making use of plasma energy produced from the pulsed discharge between electric conductor and aqueous electrolyte. Methodology of the study; Results and discussion on the study; Conclusions.

Discusses the mechanism of action of vitamin E as tumor cell growth inhibitors. Structure and nomenclature of vitamin E compounds; Apoptotic activity of vitamin E compounds; Vitamin E succinate induction of apoptosis of human cancer cells.

The authors comment on a study by A. J. Mitchell and D. Lawrence which claims that schizophrenics and people with other mental illnesses have lower invasive coronary intervention rates following acute coronary syndrome. According to the authors, the main limitation of the study by Mitchell and Lawrence is that the data analyzed were from observational studies conducted in the U.S. They add that, despite this limitation, it emphasizes the need for more research on low quality of care.

Crocin, extracted and purified from Gardenia jasminoids Ellis in our laboratory, has been reported to have antioxidative, hypolipidaemic and anti-atherosclerorotic effects. However, the underlying molecular mechanisms by which crocin acts as a cytoprotective agent remain to be elucidated. In the present study, we examined the mechanisms of crocin, the digentiobiosyl ester of crocetin, on bovine aortic endothelial cell apoptosis induced by hydrogen peroxide (H2O2). The cells were obtained from the thoracic aorta of newborn calves, and apoptosis was induced by 200 µM H2O2. Before addition of H2O2, the cells were pretreated with different concentrations of crocin for 6 hr. After incubation of the cells with H2O2, a comparative reverse transcriptase–polymerase chain reaction-based repeated amplification protocol assay was used to determine the ratio of bcl-2/bax mRNA expression, and cells loaded with fluo-3/AM were subjected to laser scanning confocal microscopy for detection of intracellular calcium ([Ca2+]i) levels. Treatment of the cells with H2O2 alone decreased the ratio of bcl-2/bax expression to almost twice of those of untreated cells (from 0.33 ± 0.05 to 0.16 ± 0.02). In the presence of 1 and 10 µM crocin, the ratios were enhanced when compared with H2O2 alone respectively (from 0.16 ± 0.02 to 0.58 ± 0.04, 1.18 ± 0.13). The treatment of cells with crocin alone had little effect on the value of this ratio. In the presence or absence of extracellular Ca2+, H2O2 could induce intracellular calcium elevation not only in the elevation presence of extracellular Ca2+ (Hanks), but also without extracellular calcium present (D-Hanks). But the extent of [Ca2+]i under conditions lacking extracellular calcium is less. Crocin concentration dependently inhibited the [Ca2+]i elevation induced by H2O2 under these two conditions. Our data suggest that crocin may exert anti-atherosclerotic effects by increasing the expression ratio of bcl-2/bax, as a result, inhibiting the bovine aortic endothelial cell apoptosis that plays an important role in the initiation and progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) can increase up to 1000-fold in blood and form complexes with very low density lipoproteins (VLDL). These complexes are associated with worse outcomes for septic patients, and this suggests a potential pathological role in sepsis. Complex formation is heightened when CRP is over 200 mg/l and levels are associated with the severity of sepsis and blood bacterial culture positivity. Using a mouse bacteremia model, blood bacterial clearance can be delayed by i.v. injection of CRP-VLDL complexes. Complexes are more efficiently taken up by activated U937 cells in vitro and Kupffer cells in vivo than VLDL alone. Both in vitro-generated and naturally occurring CRP-VLDL complexes reduce phagocytosis of bacteria by activated U937 cells. Fcg and scavenger receptors are involved and a competitive mechanism for clearance of CRP-VLDL complexes and bacteria is demonstrated. Interaction of phosphocholine groups on VLDL with CRP is the major driver for complex formation and phosphocholine can disrupt the complexes to reverse their inhibitory effects on phagocytosis and bacterial clearance. Increased formation of CRP-VLDL complexes is therefore harmful and could be a novel target for therapy in sepsis. [ABSTRACT FROM AUTHOR]

Antipsychotic medications can induce cardiovascular and metabolic abnormalities (such as obesity, hyperglycemia, dyslipidemia and the metabolic syndrome) that are associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. Controversy remains about the contribution of individual antipsychotic drugs to this increased risk and whether they cause sudden cardiac death through prolongation of the corrected QT interval. Although some drug receptor-binding affinities correlate with specific cardiovascular and metabolic abnormalities, the exact pharmacological mechanisms underlying these associations remain unclear. Antipsychotic agents with prominent metabolic adverse effects might cause abnormalities in glucose and lipid metabolism via both obesity-related and obesity-unrelated molecular mechanisms. Despite existing guidelines and recommendations, many antipsychotic-drug-treated patients are not assessed for even the most easily measurable metabolic and cardiac risk factors, such as obesity and blood pressure. Subsequently, concerns have been raised over the use of these medications, especially pronounced in vulnerable pediatric patients, among whom their use has increased markedly in the past decade and seems to have especially orexigenic effects. This Review outlines the metabolic and cardiovascular risks of various antipsychotic medications in adults and children, defines the disparities in health care and finally makes recommendations for screening and monitoring of patients taking these agents. [ABSTRACT FROM AUTHOR]

The Liqian people in north China are well known because of the controversial hypothesis of an ancient Roman mercenary origin. To test this hypothesis, 227 male individuals representing four Chinese populations were analyzed at 12 short tandem repeat (STR) loci and 12 single nucleotide polymorphisms (SNP). At the haplogroup levels, 77% Liqian Y chromosomes were restricted to East Asia. Principal component (PC) and multidimensional scaling (MDS) analysis suggests that the Liqians are closely related to Chinese populations, especially Han Chinese populations, whereas they greatly deviate from Central Asian and Western Eurasian populations. Further phylogenetic and admixture analysis confirmed that the Han Chinese contributed greatly to the Liqian gene pool. The Liqian and the Yugur people, regarded as kindred populations with common origins, present an underlying genetic difference in a median-joining network. Overall, a Roman mercenary origin could not be accepted as true according to paternal genetic variation, and the current Liqian population is more likely to be a subgroup of the Chinese majority Han. [ABSTRACT FROM AUTHOR]

Background: The impact of uridine diphosphate glucuronosyltransferase 1A7 (UGT1A7) polymorphisms on genetic susceptibility to digestive system cancer has received close attention since the discovery by Guillemette, the polymorphisms of which may alter enzyme activity. To clarify the allele frequency distribution and its association with risk of colorectal cancer, a population-based case–control study was carried out in Chinese population. Methods: A total of 140 patients with colorectal cancer and 280 cancer-free frequency-matched controls from a follow-up cohort population established in 1989, were enrolled. For the UGT1A7 polymorphisms analysis, polymerase chain reaction (PCR)-based genotyping techniques including semi-nested PCR, allele-specific PCR and PCR-restriction fragment length polymorphism (RFLP) were developed. Results: The variant allele frequencies in patients and controls were 50.0% and 38.6%, respectively, which were significantly associated with risk of colorectal cancer (odds ratio [OR]: 1.59; 95% confidence interval [CI]: 1.19–2.13). For the variant genotypes analysis, *2/*2 and *3/*3 exhibited a significant association with risk of colorectal cancer (OR: 7.80, 95%CI: 2.66–22.87; OR: 3.47, 95%CI: 1.51–7.97, respectively). Stratification analysis indicated that in previous–current cigarette smoking (cigarette smoking history), current cigarette smoking (current cigarette smoking status), previous–current alcohol drinking (alcohol drinking history) or current alcohol drinking individuals (current alcohol drinking status), the risk developing colorectal cancer increased: OR (95%CI), 2.81 (0.97–8.11), 3.39 (1.19–9.67), 2.89 (0.99–8.46) and 3.14 (1.09–9.09), respectively. Conclusions: UGT1A7 polymorphisms may have a significant modifying effect on colorectal cancer risk, which may interact with environmental factors, cigarette smoking and alcohol drinking in colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]