P2X7 receptor mediated phosphorylation of p38MAP kinase in the hippocampus

This study was designed to explore the effect of P2X7 receptor (P2X7R) activation on the expression of p38 MAP kinase (p38 MAPK) enzyme in hippocampal slices of wild-type (WT) and P2X7R^−/− mice using the Western blot technique and to clarify its role in P2X7 receptor mediated [³H]glutamate release. ATP (1 mM) and the P2X7R agonist BzATP (100 μM) significantly increased p38 MAPK phosphorylation in WT mice, and these effects were absent in the hippocampal slices of P2X7R^−/− mice. Both ATP- and BzATP-induced p38 MAPK phosphorylations were sensitive to the p38 MAP kinase inhibitor, SB203580 (1 μM). ATP elicited [³H]glutamate release from hippocampal slices, which was significantly attenuated by SB203580 (1 μM) but not by the extracellular signal-regulated kinase (ERK1/2) inhibitor, PD098095 (10 μM). Consequently, we suggest that P2X7Rs and p38 MAPK are involved in the stimulatory effect of ATP on glutamate release in the hippocampal slices of WT mice.     

Preventing Olanzapine-Induced Weight Gain Using Betahistine: A Study in a Rat Model with Chronic Olanzapine Treatment

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H₁ receptors (H₁R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H₁R agonist and H₃R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H₁R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP₁ and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H₁R, pAMPKα, BAT UCP₁ and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.     

Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice

The mutation L159R apoA-I or apoA-I_L159R (FIN) is a single amino acid substitution within the sixth helical repeat of apoA-I. It is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Mice lacking both mouse apoA-I and LDL receptor (LDL^−/−, apoA-I^−/−) (double knockout or DKO) were crossed > 9 generations with mice transgenic for human FIN to obtain L159R apoA-I, LDLr^−/−, ApoA-I^−/− (FIN-DKO) mice. A similar cross was also performed with human wild-type (WT) apoA-I (WT-DKO). In addition, FIN-DKO and WT-DKO were crossed to obtain WT/FIN-DKO mice. To determine the effects of the apoA-I mutations on atherosclerosis, groups of each genotype were fed either chow or an atherogenic diet for 12 weeks. Interestingly, the production of dysfunctional HDL-like particles occurred in DKO and FIN-DKO mice. These particles were distinct with respect to size, and their enrichment in apoE and cholesterol esters. Two-dimensional gel electrophoresis indicated that particles found in the plasma of FIN-DKO mice migrated as large α₃-HDL. Atherosclerosis analysis showed that FIN-DKO mice developed the greatest extent of aortic cholesterol accumulation compared to all other genotypes, including DKO mice which lack any apoA-I. Taken together these data suggest that the presence of large apoE enriched HDL particles containing apoA-I L159R lack the normal cholesterol efflux promoting properties of HDL, rendering them dysfunctional and pro-atherogenic. In conclusion, large HDL-like particles containing apoE and apoA-I_L159R contribute rather than protect against atherosclerosis, possibly through defective efflux properties and their potential for aggregation at their site of interaction in the aorta. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).     

Cholesterol reduction ameliorates glucose-induced calcium handling and insulin secretion in islets from low-density lipoprotein receptor knockout mice

Aims/hypothesis

Changes in cellular cholesterol level may contribute to beta cell dysfunction. Islets from low density lipoprotein receptor knockout (LDLR^−/−) mice have higher cholesterol content and secrete less insulin than wild-type (WT) mice. Here, we investigated the association between cholesterol content, insulin secretion and Ca^2 + handling in these islets.

Methods

Isolated islets from both LDLR^−/− and WT mice were used for measurements of insulin secretion (radioimmunoassay), cholesterol content (fluorimetric assay), cytosolic Ca^2 + level (fura-2AM) and SNARE protein expression (VAMP-2, SNAP-25 and syntaxin-1A). Cholesterol was depleted by incubating the islets with increasing concentrations (0–10 mmol/l) of methyl-beta-cyclodextrin (MβCD).

Results

The first and second phases of glucose-stimulated insulin secretion (GSIS) were lower in LDLR^−/− than in WT islets, paralleled by an impairment of Ca^2 + handling in the former. SNAP-25 and VAMP-2, but not syntaxin-1A, were reduced in LDLR^−/− compared with WT islets. Removal of excess cholesterol from LDLR^−/− islets normalized glucose- and tolbutamide-induced insulin release. Glucose-stimulated Ca^2 + handling was also normalized in cholesterol-depleted LDLR^−/− islets. Cholesterol removal from WT islets by 0.1 and 1.0 mmol/l MβCD impaired both GSIS and Ca^2 + handling. In addition, at 10 mmol/l MβCD WT islet showed a loss of membrane integrity and higher DNA fragmentation.

Conclusion

Abnormally high (LDLR^−/− islets) or low cholesterol content (WT islets treated with MβCD) alters both GSIS and Ca^2 + handling. Normalization of cholesterol improves Ca^2 + handling and insulin secretion in LDLR^−/− islets.     

Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis

Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term efficacy of antipsychotic drugs in acutely ill patients using network meta-analysis. We searched the Cochrane Schizophrenia Group register up to March 6, 2022 for randomized, blinded trials of at least 6-month duration on all second-generation and 18 first-generation antipsychotics. The primary outcome was change in overall symptoms of schizophrenia; secondary outcomes were all-cause discontinuation; change in positive, negative and depressive symptoms; quality of life, social functioning, weight gain, antiparkinson medication use, akathisia, serum prolactin level, QTc prolongation, and sedation. Confidence in the results was assessed by the CINeMA (Confidence in Network Meta-Analysis) framework. We included 45 studies with 11,238 participants. In terms of overall symptoms, olanzapine was on average more efficacious than ziprasidone (standardized mean difference, SMD=0.37, 95% CI: 0.26-0.49), asenapine (SMD=0.33, 95% CI: 0.21-0.45), iloperidone (SMD=0.32, 95% CI: 0.15-0.49), paliperidone (SMD=0.28, 95% CI: 0.11-0.44), haloperidol (SMD=0.27, 95% CI: 0.14-0.39), quetiapine (SMD=0.25, 95% CI: 0.12-0.38), aripiprazole (SMD=0.16, 95% CI: 0.04-0.28) and risperidone (SMD=0.12, 95% CI: 0.03-0.21). The 95% CIs for olanzapine versus aripiprazole and risperidone included the possibility of trivial effects. The differences between olanzapine and lurasidone, amisulpride, perphenazine, clozapine and zotepine were either small or uncertain. These results were robust in sensitivity analyses and in line with other efficacy outcomes and all-cause discontinuation. Concerning weight gain, the impact of olanzapine was higher than all other antipsychotics, with a mean difference ranging from –4.58 kg (95% CI: –5.33 to –3.83) compared to ziprasidone to –2.30 kg (95% CI: –3.35 to –1.25) compared to amisulpride. Our data suggest that olanzapine is more efficacious than a number of other antipsychotic drugs in the longer term, but its efficacy must be weighed against its side effect profile.     

Mifepristone Reduces Weight Gain and Improves Metabolic Abnormalities Associated With Risperidone Treatment in Normal Men

Antipsychotic medications are associated with significant weight gain, type 2 diabetes mellitus, dyslipidemia, and increased cardiovascular risk. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, could prevent risperidone‐induced weight gain. Using a 2:2:1 randomization scheme, 76 lean, healthy men (BMI 18–23 kg/m²) age 18–40 years were randomized to risperidone (n = 30), risperidone plus mifepristone (n = 30) or mifepristone (n = 16) daily for 28 days in an institutional setting. Subjects were provided food ad libitum. Body weight was measured daily. Metabolic measures were taken at study onset, midpoint, and end. Analyses of covariance indicated that the group receiving risperidone plus placebo gained significantly more weight (P < 0.001) and exhibited a significantly greater increase in waist circumference (P < 0.05) than the group receiving risperidone plus mifepristone. Significant differences were also observed for metabolic measures including fasting insulin (P < 0.001) and triglyceride levels (P < 0.05). Mifepristone attenuated increases in weight and reduced the metabolic changes induced by risperidone use, replicating results from a prior study of olanzapine‐induced weight gain. These findings suggest mechanistic involvement of the hypothalamic‐pituitary‐adrenal axis in the weight and cardiometabolic side effects of antipsychotic medications. Future research should continue to test the potential of glucocorticoid antagonists to alleviate the deleterious side effects associated with use of antipsychotic medications.     

Apolipoprotein M promotes mobilization of cellular cholesterol in vivo

Objective

The HDL associated apolipoprotein M (apoM) protects against experimental atherosclerosis but the mechanism is unknown. ApoM increases preβ-HDL formation. We explored whether plasma apoM affects mobilization of cholesterol from peripheral cells in mice.

Methods and results

ApoM-enriched HDL from apoM-transgenic mice increased the in vitro efflux of ³H-cholesterol from macrophages by 24 ± 3% (p < 0.05) as compared with HDL from wild type (WT) mice, thus confirming previous findings. However, apoM-free HDL was not poorer than that of WT HDL to mobilize ³H-cholesterol. ³H-cholesterol-labeled foam cells were implanted in the peritoneal cavity of apoM^−/−, WT and apoM-transgenic mice to assess the mobilization of cholesterol from foam cells in vivo and subsequent excretion into feces. The results showed a statistically non-significant trend towards increased mobilization of cellular cholesterol to plasma with increasing plasma apoM. However, the apoM-genotype did not affect the excretion of ³H-cholesterol in feces. Nevertheless, when apoM^−/−, apoM-transgenic and WT mice received a constant intravenous infusion of ¹³C₂-cholesterol/intralipid for 5 h, the rate of enrichment of blood free cholesterol with free ¹³C₂-cholesterol was significantly lower (consistent with an increase in flux of unlabeled free cholesterol into the plasma) in the apoM-transgenic (3.0 ± 0.9‰/h) as compared to WT (5.7 ± 0.9‰/h, p < 0.05) and apoM^−/− (6.5 ± 0.6‰/h, p < 0.01) mice.

Conclusion

The present data indicate that the plasma apoM levels modulate the ability of plasma to mobilize cellular cholesterol, whereas apoM has no major effect on the excretion of cholesterol into feces.     

Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents

Objective: To characterize a model of atypical antipsychotic drug‐induced obesity and evaluate its mechanism. Research Methods and Procedures: Chronically, olanzapine or clozapine was self‐administered via cookie dough to rodents (Sprague‐Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance. Results: Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting ～24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted. Discussion: A model of olanzapine‐induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug‐induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine‐induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.     

Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents

We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethyl-urea), a D₃/D₂ dopamine receptor partial agonist with ∼10-fold preference for the D₃ receptor. Oral bioavailability of cariprazine at a dose of 1 mg/kg in rats was 52% with peak plasma concentrations of 91 ng/mL. Cariprazine 10 mg/kg had good blood-brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [³H](+)-PHNO, a dopamine D₃ receptor-preferring radiotracer, in the D₃ receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED₅₀ = 0.27 mg/kg) was sustained for 8 h. Cariprazine blocked amphetamine-induced hyperactivity (ED₅₀ = 0.12 mg/kg) and conditioned avoidance response (CAR) (ED₅₀ = 0.84 mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED₅₀ = 0.049 mg/kg) and phencyclidine (ED₅₀ = 0.09 mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED₅₀ = 0.11 mg/kg) and rats (ED₅₀ = 0.18 mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED₅₀ value. Cariprazine 0.02-0.08 mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D₃ receptors versus currently marketed typical and atypical antipsychotics.     

Temporary upregulation of anti-inflammatory cytokine IL-13 expression in the brains of CD14 deficient mice in the early stage of prion infection

CD14 deficient (CD14^−/−) mice survived longer than wild-type (WT) C57BL/6J mice when inoculated with prions intracerebrally, accompanied by increased expression of anti-inflammatory cytokine IL-10 by microglia in the early stage of infection. To assess the immune regulatory effects of CD14 in detail, we compared the gene expression of pro- and anti-inflammatory cytokines in the brains of WT and CD14^−/− mice infected with the Chandler strain. Gene expression of the anti-inflammatory cytokine IL-13 in prion-infected CD14^−/− mice was temporarily upregulated at 75 dpi, whereas IL-13 gene expression was not upregulated in prion-infected WT mice. Immunofluorescence staining showed that IL-13 was mainly expressed in neurons of the thalamus at 75 dpi. These results suggest that CD14 can suppress IL-13 expression in neurons during the early stage of prion infection.     

Effect of chitosan on UASB treating POME during a transition from mesophilic to thermophilic conditions

The effects of chitosan addition on treatment of palm oil mill effluent were investigated using two lab-scale upflow anaerobic sludge bed (UASB) reactors: (1) with chitosan addition at the dosage of 2 mg chitosan per g volatile suspended solids on the first day of the operation (R1), (2) without chitosan addition (the control, R2). The reactors were inoculated with mesophilic anaerobic sludge which was acclimatized to a thermophilic condition with a stepwise temperature increase of 5 °C from 37 to 57 °C. The OLR ranged from 2.23 to 9.47 kg COD m⁻³ day⁻¹. The difference in biogas production rate increased from non-significant to 18% different. The effluent volatile suspended solids of R1 was 65 mg l⁻¹ lower than that of R2 on Day 123. 16S rRNA targeted denaturing gradient gel electrophoresis (DGGE) fingerprints of microbial community indicated that some methanogens in the genus Methanosaeta can be detected in R1 but not in R2.     

Structure and solution behaviour of cyclooctadiene complexes of platinum(II)

The substitution behaviour of [PtCl(R)(COD)] (R⁻ = Me and Fc) complexes, by the stepwise addition of phosphine ligands, L (L = PPh₃, PEt₃ and P(NMe₂)₃), were investigated in situ by ¹H and ³¹P NMR spectroscopy. Addition of less than two equivalents of the phosphine ligand results in the formation of dimeric molecules with the general formula trans-[Pt(R)(μ-Cl)(L)]₂ for the sterically demanding systems where R⁻ = Me/L = P(NMe₂)₃ and R⁻ = Fc/L = PEt₃, PPh₃ and P(NMe₂)₃ while larger quantities resulted in cis- and trans mixtures of mononuclear complexes being formed. In the case of the relatively small steric demanding, strongly coordinating, PEt₃ ligand the trans-[PtCl(R)(PEt₃)₂] mononuclear complexes were exclusively observed in both cases. The crystal structures of the two substrates, [PtCl(R)(COD)] (R⁻ = Me or Fc), as well as the cis-[PtCl(Fc)(PPh₃)₂] substitution product are reported.     

Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.     

Salinity induced changes in haemolymph osmolality and total metabolic rate of the mud crab Rhithropanopeus harrisii Gould, 1841 from Baltic coastal waters

The specific metabolic rate (SMR) and haemolymph osmolality (HO) of the mud crab Rhithropanopeus harrisii Gould, 1841 from Baltic brackish waters were measured at a habitat salinity of 7 psu (T = 15 °C, full air saturation) and after step-wise acclimation to a salinity range of 3-27 psu. Values of SMR at 7 psu varied between 0.40 and 3.89 J g^− 1 WW h^− 1 (n = 25, wet weight range 0.051-1.142 g) and were significantly (p < 0.05) related to the specimen's wet weight (WW) according to the power regression SMR = 0.94 WW^− 0.41 (R² = 0.68). The SMR of females did not differ significantly (p > 0.05) from those of males. When exposed to higher salinities, the SMR of R. harrisii decreased significantly (p < 0.05) and reached a minimum value at 23 psu (0.55 ± 0.05 J g^− 1 WW h^− 1, n = 6). Mean haemolymph osmolality at 7 psu amounted to 581 ± 26 mOsm kg^− 1 (n = 5) and was 2.9 times higher than that of the external medium. R. harrisii hyperosmoregulated its body fluids up to 24 psu (727 mOsm kg^− 1) at which salinity the isosmotic point was reached.     

A Role for Hypothalamic AMP-Activated Protein Kinase in the Mediation of Hyperphagia and Weight Gain Induced by Chronic Treatment with Olanzapine in Female Rats

Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine.     

Reactive oxygen species on bone mineral density and mechanics in Cu,Zn superoxide dismutase (Sod1) knockout mice

Reactive oxygen species (ROS) play a role in a number of degenerative conditions including osteoporosis. Mice deficient in Cu,Zn-superoxide dismutase (Sod1) (Sod1^−/− mice) have elevated oxidative stress and decreased muscle mass and strength compared to wild-type mice (WT) and appear to have an accelerated muscular aging phenotype. Thus, Sod1^−/− mice may be a good model for evaluating the effects of free radical generation on diseases associated with aging. In this experiment, we tested the hypothesis that the structural integrity of bone as measured by bending stiffness (EI; N/mm²) and strength (MPa) is diminished in Sod1^−/− compared to WT mice. Femurs were obtained from male and female WT and Sod1^−/− mice at 8 months of age and three-point bending tests were used to determine bending stiffness and strength. Bones were also analyzed for bone mineral density (BMD; mg/cc) using micro-computed tomography. Femurs were approximately equal in length across all groups, and there were no significant differences in BMD or EI with respect to gender in either genotype. Although male and female mice demonstrated similar properties within each genotype, Sod1^−/− mice exhibited lower BMD and EI of femurs from both males and females compared with gender matched WT mice. Strength of femurs was also lower in Sod1^−/− mice compared to WT as well as between genders. These data indicate that increased oxidative stress, due to the deficiency of Sod1 is associated with decreased bone stiffness and strength and Sod1^−/− mice may represent an appropriate model for studying disease processes in aging bone.     

Synthesis, structure and polymerization behavior of tri- and dichloroaminopyridinato complexes of titanium

Three 2-phenylaminopyridine (Ap) complexes of types ApTiCl₃ and Ap₂TiCl₂ were characterized with X-ray diffraction. The complexes were studied as polymerization catalysts using MAO as cocatalyst. In ethylene polymerization, the catalysts showed moderate activities between 65 and 285 kg PE mol⁻¹ Ti⁻¹ h⁻¹ and the molecular weight distributions were between 2.5 and 4.2, and the molar masses were between 135 000 and 804 000 kg/mol.     

Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds

Using radioligand binding assays and post-mortem normal human brain tissue, we obtained equilibrium dissociation constants (K(d)s) for nine new antipsychotic drugs (iloperidone, melperone, olanzapine, ORG 5222, quetiapine, risperidone, sertindole, ziprasidone, and zotepine), one metabolite of a new drug (9-OH-risperidone), and three older antipsychotics (clozapine, haloperidol, and pimozide) at nine different receptors (alpha1-adrenergic, alpha2-adrenergic, dopamine D2, histamine H1, muscarinic, and serotonin 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C receptors). Iloperidone was the most potent drug at the two adrenergic receptors. ORG 5222 was the most potent drug at dopamine D2 and 5-HT2c receptors, while ziprasidone was the most potent compound at three serotonergic receptors (5-HT1A, 5-HT1D, and 5-HT2A). At the remaining two receptors, olanzapine was the most potent drug at the histamine H1 receptor (Kd=0.087 nM); clozapine at the muscarinic receptor (Kd=9 nM). Certain therapeutic and adverse effects, as well as certain drug interactions can be predicted from a drug's potency for blocking a specific receptor. These data can provide guidelines for the clinician in the choice of antipsychotic drug.     

Laboratory experiments on the effects of variable suspended sediment concentrations on the ecophysiology of the porcelain crab Petrolisthes elongatus (Milne Edwards, 1837)

The porcelain crab Petrolisthes elongatus is a particulate suspension feeding species common to coastal areas of New Zealand (NZ). Consistent with the responses of other suspension feeding species, it is likely to be negatively influenced by elevated suspended sediment concentrations. Laboratory experiments were conducted to quantify the effect of temperature (12 °C, 15 °C and 18 °C) and suspended sediment concentration (total particulate matter (TPM): low < 100 mg L^− 1; medium 100-1000 mg L^− 1; high > 1000 mg L^− 1) on the clearance rate (CR in L h^− 1), oxygen uptake rate (VO₂ in mL h⁻¹), net absorption efficiency (AE), and net energy budget (NEB in J h^− 1) of P. elongatus across a range of sizes. Variation in CR and AE was independent of temperature and of body size, but were significantly different (P < 0.05) at low and medium suspended sediment concentrations compared with high suspended sediment concentrations. CR responded in a non-linear manner to changes in TPM, increasing with TPM up to a maximum value at medium-low concentrations (approximately 250 mg L^− 1) and then decreasing thereafter. CR had almost completely shut down at TPM concentrations of > 1000 mg L^− 1 and at particulate organic matter (POM) concentrations of > 250 mg L^− 1. AE was zero at approximate TPM and POM values of 1200 mg L^− 1 and 300 mg L^− 1, respectively. VO₂ was positively correlated with body size and with temperature, but was independent of TPM. NEB values for P. elongatus were low (approx 110 J g^− 1 h^− 1) at low sediment concentrations, were high (approx 320 J g^− 1 h^− 1) at medium sediment concentrations, and were negative (approx − 114 J g^− 1 h^− 1) at high sediment concentrations. These findings indicate that P. elongatus is likely to be food-limited at sediment concentrations of < 100 mg L^− 1, and severely negatively affected at sediment concentrations of > 1000 mg L^− 1, at least for the duration of such events which may persist for 2-3 days in coastal environments where this crab occurs.