Phe(1)Psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2) does not antagonize orphaninFQ/nociceptin-induced prolactin release

The specificity of the orphaninFQ (OFQ)/nociceptin (N)-induced prolactin increase was determined in male and female rats by pretreating animals with different doses of [Phe(1)Psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2), a compound originally reported to be a specific OFQ/N antagonist. In addition, the effect of naloxone pretreatment on OFQ/N-induced prolactin release was examined to determine if OFQ/N's effects were mediated by opiate receptors. Furthermore, dose response studies using [Phe(1)Psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2) only were performed to determine potential agonist activity of this drug. Finally, growth hormone (GH) levels were determined as an index of specificity of the prolactin response. Our results confirm previous findings that OFQ/N potently stimulates prolactin release and that a gender difference exists in the magnitude of the response, with females showing a much greater response than male rats. The endocrine response is specific because OFQ/N potently stimulated prolactin, but not GH secretion. The prolactin response is not mediated by actions at opiate receptors because naloxone did not inhibit OFQ/N's effects on prolactin release. However, [Phe(1)Psi(CH(2)-NH) Gly2]NC(1-13) NH(2) did not antagonize OFQ/N's effects on prolactin release. Indeed, this drug acted as a potent agonist. Demonstrating pharmacological specificity of OFQ/N's effects on prolactin release awaits the development of more selective, specific antagonists.     

Source localization (LORETA) of the error-related-negativity (ERN/Ne) and positivity (Pe)

We investigated error processing of 39 subjects engaging the Eriksen flanker task. In all 39 subjects a pronounced negative deflection (ERN/Ne) and a later positive component (Pe) were observed after incorrect as compared to correct responses. The neural sources of both components were analyzed using LORETA source localization. For the negative component (ERN/Ne) we found significantly higher brain electrical activity in medial prefrontal areas for incorrect responses, whereas the positive component (Pe) was localized nearby but more rostral within the anterior cingulate cortex (ACC). Thus, different neural generators were found for the ERN/Ne and the Pe, which further supports the notion that both error-related components represent different aspects of error processing.     

Allosteric regulation of alpha(IIb)beta(3) by beta(3) 95-105

The linear recognition sequences of an anti-beta(3) antibody that blocked platelet aggregation were identified using beta(3) tryptic peptides. Two of these recognition sequence-containing peptides were mapped to beta(3) 92-105, and antibodies affinity purified using these peptides blocked platelet aggregation. Examining the structure of alpha(IIb)beta(3) identified beta(3) 95-105 as the solvent accessible sequence within beta(3) 92-105. A peptide corresponding to beta(3) 95-105 was synthesized and used to affinity purify the beta(3) antibody. Anti-beta(3) 95-105 completely blocked platelet aggregation and agonist-induced fibrinogen binding to platelets, but had no effect on cyclic-RGD binding. Binding of anti-beta(3) 95-105 to alpha(IIb)beta(3) also did not alter the structure of the alpha(IIb) cap subdomain, as measured by anti-alpha(IIb) 201-217 binding. beta(3) 95-105 and peptides spanning two adjacent sequences in the structure of beta(3) did not bind fibrinogen and were ineffectual in blocking agonist-induced platelet aggregation. Structure analysis revealed that beta(3) 95-105 is adjacent to one of the two hinges in beta(3) that allows for the outward swing of the hybrid and PSI domains which is central to the conversion of alpha(IIb)beta(3) from a low into a high affinity state. Thus, the binding of an antibody to beta(3) 95-105 could serve as a fulcrum for allosteric regulation of alpha(IIb)beta(3) by regulating the movement of the hybrid-PSI domain.     

对映异构聚乳酸/聚乙二醇空间异构复合水凝胶的药物释放及形貌和细胞毒性

背景：目前生物降解水凝胶已被广泛应用于抗癌药物及生物活性大分子的装载,但为了保护生物活性大分子的活性,需要得到凝胶化条件更温和,凝胶化时间更短的凝胶体系。 目的：制备对映异构聚乳酸∕聚乙二醇的空间异构复合水凝胶,使其具有更短的凝胶化时间,实现对模拟药物溶菌酶的装载和控释。 方法：以聚乙二醇为引发剂,辛酸亚锡为催化剂,丙交酯与聚乙二醇发生开环聚合反应,得到聚乳酸/聚乙二醇的三嵌段共聚物(PLLA-PEG-PLLA 和 PDLA-PEG-PDLA)。用1H NMR,FT-IR 和 XRD表征三嵌段共聚物。10% PLLA20-PEG227-PLLA20的水溶液和10%PDLA21-PEG227-PDLA21的水溶液在室温下混合,12 h后形成凝胶。通过XRD考察凝胶化机制,以溶菌酶为模拟药物,考察凝胶的释药特性,通过扫描电镜考察凝胶的形貌,采用MTT法考察凝胶的细胞毒性。 结果与结论：成功得到聚乳酸/聚乙二醇的三嵌段共聚物,在嵌段共聚物中,聚乳酸嵌段和聚乙二醇嵌段都能结晶,但以聚乙二醇嵌段的结晶为主。通过XRD证明凝胶中存在空间异构复合作用,溶菌酶在凝胶中通过凝胶的溶蚀和降解行为,在7 d之内释放完全。通过扫描电镜观察到冻干的水凝胶呈三维贯穿的多孔结构,空隙尺寸在50~100 μm 之间。鼠成纤维细胞与浓度为100%的凝胶浸提液共培养72 h之后,细胞的存活率为99.3%。     

The effect of [Phe(1)psi(CH(2)-NH)Gly(2)]-nociceptin(1-13)NH(2) on feeding and c-Fos immunoreactivity in selected brain sites

Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand of the ORL1 receptor. N/OFQ, when administered centrally, stimulates feeding in a fashion similar to other opioids. Intracerebroventricular administration of N/OFQ induces changes in c-Fos immunoreactivity in several feeding-related brain sites. A synthetic pseudopeptide, [Phe(1)iota(CH(2)-NH)Gly(2)]-nociceptin(1-13)-NH(2) (hereafter: [FG]N/OFQ(1-13)NH(2)), has been labeled both as an ORL1 agonist and antagonist. The present study was designed to examine the influence of [FG]N/OFQ(1-13)NH(2) on food intake in rats. We also evaluated c-Fos immunoreactivity in those areas of the brain which have been shown to exhibit altered c-Fos expression upon N/OFQ administration. We found that [FG]N/OFQ(1-13)NH(2) increases food consumption in satiated rats. This effect is short-lasting and can be reversed by the opioid antagonist naloxone. Co-administration of [FG]N/OFQ(1-13)NH(2) does not affect orexigenic response to N/OFQ. Intracerebroventricularly-injected [FG]N/OFQ(1-13)NH(2) induces c-Fos expression in the nucleus of the solitary tract, hypothalamic paraventricular and supraoptic nuclei, central nucleus of amygdala, lateral septal and lateral habenular nuclei-brain areas that have been shown to be activated by N/OFQ. These results support the hypothesis that [FG]N/OFQ(1-13)NH(2) acts as an agonist of ORL1 receptor in vivo.     

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in amyotrophic lateral sclerosis (ALS)

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, responsible for the integrity of the basement membrane (BM) via degradation of extracellular matrix and BM components. These enzymes are presented in central and peripheral nervous system. They are considered to be involved in the pathogenesis of several neurological diseases, including amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disease, leading to muscle atrophy, paralysis and death within 3–5 years from diagnosis. Currently, there is no treatment that can substantially prolong life of ALS patients. Despite the fact that MMPs are not specific for ALS, there is also strong evidence that these enzymes are involved in the pathology of ALS. MMPs are able to exert direct neurotoxic effects, or may cause cell death by degrading matrix proteins. The objective of this paper is to provide an updated and comprehensive review concerning the role of MMPs and their tissue inhibitors (TIMPs) in the pathology of ALS with an emphasis on the significance of MMP-2 and MMP-9 as well as their tissue inhibitors as potential biomarkers of ALS. Numerous hypotheses have been proposed regarding the role of selected MMPs and TIMPs in ALS pathogenesis. Moreover, selective MMPs’ inhibitors might be potential targets for therapeutic strategies for patients with ALS. However, future investigations are necessary before some of those non-specific for ALS enzymes could finally be used as biomarkers of this disease.     

Negative priming (cognitive inhibition) in obsessive-compulsive disorder (OCD)

Cognitive disinhibition has been implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Negative priming (NP) is regarded to tap into this function. While early studies indeed found reduced negative priming in OCD, attempts to replicate are both scarce and equivocal. Moreover, several studies in favor of the disinhibition hypothesis are plagued by methodological limitations. For the present investigation, 18 participants with OCD and 28 healthy controls underwent a computerized NP experiment with varying response-stimulus intervals. In addition, a variant of the paradigm with concurrent item presentation was employed to rule out the confounding impact of memory. Negative priming was comparable between groups yielding small between-group effect sizes. The present study challenges broad claims of disinhibition in OCD. In our view, the disinhibition account faces theoretical problems. Instead, theories implicating cognitive biases as well as metacognitive problems may more parsimoniously explain the idiosyncratic nature of OCD symptoms.     

In vitro characterization of Ac-RYYRWK-NH(2), Ac-RYYRIK-NH(2) and [Phe1Psi(CH(2)-NH)Gly2] nociceptin(1-13)NH(2) at rat native and recombinant ORL(1) receptors

The pharmacology of ORL(1) compounds, [Phe1Psi(CH(2)-NH)Gly2]nociceptin(1-13)NH(2) (F/GNC13), Ac-RYYRIK-NH(2) and Ac-RYYRWK-NH(2) was evaluated at rat ORL(1) receptors in frontal cortex (CTX), transfected chinese hamster ovary (CHO) cells, vas deferens (VD) and anococcygeus (AC). Ranked affinities for the inhibition of [3H]nociceptin binding to CTX and CHO's were: Ac-RYYRWK-NH(2) identical withAc-RYYRIK-NH(2) identical withnociceptin>F/GNC13>Dynorphin A>naloxone.The full agonist, nociceptin stimulated [35S]GTPgammaS binding in CTX (E(max)=174%) and CHO's (E(max)=311%); all other ORL(1) peptides acted as partial agonists with the following rank order for E(max) values: Ac-RYYRWK-NH(2) (96% (CTX), 202% (CHO))>F/GNC13 (44% (CTX), 136% (CHO)) identical withAc-RYYRIK-NH(2) (44% (CTX), 115% (CHO)). Schild analysis generated pA(2) values in CTX of 8.59 (F/GNC13) and 9.13 (Ac-RYYRIK-NH(2)). cAMP production in CHO's was inhibited by 77% (nociceptin), 58% (Ac-RYYRWK-NH(2)), 55% (F/GNC13) and 49% (Ac-RYYRIK-NH(2)). Nociceptin inhibited electrically evoked contractions in isolated tissues by 95% (VD) and 98% (AC); partial inhibition was observed with Ac-RYYRWK-NH(2) (72% (VD), 66% (AC)) and Ac-RYYRIK-NH(2) (54% (VD); 37%(AC)).Ineffective in the VD, F/GNC13 caused a small inhibition in the AC that was reversed at higher concentrations. Schild analysis gave pA(2) affinities of 7.32(VD) and 7.34(AC) for F/GNC13 and 8.69(AC) for Ac-RYYRIK-NH(2).     

Middle latency auditory evoked potentials (MLAEPs) in (MS)

Middle latency auditory evoked potentials (MLAEPs) were studied in 30 definite multiple sclerosis (MS) patients in addition to brain-stem auditory evoked potentials (BAEPs). BAEP abnormalities were detected in 18 (60%) patients. MLAEPs were abnormal in 22 (73%) of them. In 15 patients BAEPs and MLAEPs were both abnormal. MLAEPs were found abnormal in 7 of the 12 patients with normal BAEPs. In 18 patients with abnormal BAEPs only 3 had normal MLAEPs. MLAEPs abnormalities are consistent with a rostral auditory pathway involvement. Therefore, they can be used in combination with BAEPs to examine the whole auditory system to improve the sensitivity.     

Eppendorfer Schizophrenie-Inventar (ESI) vs. Frankfurter Beschwerde-Fragebogen (FBF)

Zusammenfassung  Mit dieser Studie wurden erstmals 2 klinische Fragebögen direkt miteinander verglichen, die beide auf Selbstwahrnehmungen kognitiver Dysfunktionen bei Schizophrenie zielen: das Eppendorfer Schizophrenie-Inventar (ESI) und der Frankfurter Beschwerde-Fragebogen (FBF). Geprüft wurden (a) diagnostische Validität, (b) psychometrische Eigenschaften, (c) Interkorrelationen der Skalen sowie (d) faktorenanalytische Stabilität. Zu (a): Schizophrene (n=36) weisen in den ESI-Einzelskalen und im Gesamtscore hochsignifikant höhere Scores auf als die klinischen Vergleichsgruppen (Depressive, Alkoholiker, Zwangskranke, jeweils n>30), wohingegen der FBF keine systematischen Gruppenunterschiede aufzeigt. Zu (b): Die Reliabilitätskoeffizienten (Cronbach ) der ESI-Skalen liegen im Mittel bei r_tt=0,86, die der FBF-Skalen sind signifikant geringer. Zu (c): Die Korrelationen zwischen den ESI- und FBF-Skalen liegen im Mittel bei r_xy=0,56 (Minimum 0,29, Maximum 0,73), was einer durchschnittlichen gemeinsamen Varianz von etwa 31% entspricht. Zu (d): Die Faktorenanalyse ergab einen ESI- und einen FBF-Faktor; Varianzanalysen mit den Faktorwerten bestätigen die diagnostische Validität des ESI. Fazit: ESI und FBF bilden im Wesentlichen unterschiedliche Aspekte der schizophrenen Psychopathologie ab. Hinsichtlich Reliabilität und diagnostischer Validität ist das ESI dem FBF überlegen.