Concentrations of nucleotides, nucleosides, purine bases, oxypurines, uric acid, and neuron-specific enolase in the cerebrospinal fluid of children with sepsis

To determine the effects of sepsis on cerebral energy metabolism, the cerebrospinal fluid adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, hypoxanthine, xanthine, and urate concentrations were determined by high-performance liquid chromatography and the neuron-specific enolase levels by means of an enzyme immunoassay method in 32 children with sepsis, without meningitis, aged between 2 months and 13 years, and in 160 age-matched controls. The septic group had significantly higher cerebrospinal fluid concentrations of inosine, adenosine, xanthine, and urate than controls. These results suggest that sepsis could provoke some degree of neuronal hypoxia and significant alterations of cerebral energy metabolism homeostasis.     

Estradiol enhances endothelial cell interactions with extracellular matrix proteins via an increase in integrin expression and function

Premenopausal women have a lower cardiovascular risk and a higher incidence of several autoimmune diseases involving blood vessels than men. Although the precise effects of estrogens on the cardiovascular system are largely unknown, recent data suggest that estrogens can exert direct regulatory effects on endothelial cells. In the present study, we show that 17β-estradiol increases human umbilical vein endothelial cell attachment to the extracellular matrix proteins laminin-1, type IV collagen, type I collagen, and fibronectin. Estradiol enhanced adhesion most significantly to laminin-1 and to fibronectin-derived synthetic peptides containing an RGD sequence. Upon exposure to estradiol, an increase in β1, α5 and α6 integrin mRNA was observed in subconfluent cells which was abrogated by treatment with cycloheximide. This increase was followed by a later enhancement in surface expression of the above integrins. In addition, integrin-mediated signaling was also enhanced by estrogens since an increase in tyrosine-phosphorylation of focal adhesion kinase induced by cell attachment was observed in estrogen-treated endothelial cells. Since integrins have an important role in mediating endothelial cell attachment, migration and differentiation, the increase in integrin expression and function induced by estradiol may be an important mechanism through which estrogens can promote neovascularization and vessel repair. This revised version was published online in June 2006 with corrections to the Cover Date.     

Ligands for the common allosteric site of acetylcholine M2-receptors: development and application

Ligands for the allosteric site of acetylcholine M2 receptors are able to retard the dissociation of simultaneously bound ligands for the orthosteric site. This effect promotes receptor occupation by the orthosteric ligand. The allosteric effect opens various therapeutic perspectives, e.g., in organophosphorus poisoning. The aim of our studies was to optimize the affinity of the modulators for the common allosteric binding site of muscarinic M2 receptors, the orthosteric site of which was liganded with the N-methylscolopamine. The phthalimido substituted hexane-bisammonium compound W84 served as a starting point. Previous molecular modelling studies revealed two positive charges and two aromatic imides in a sandwich-like arrangement to be essential for a high allosteric potency. A three-dimensional quantitative structure activity relationship (3D QSAR) analysis predicted compounds with substituents of increasing size on the lateral imide moieties to enhance the affinity for the allosteric binding site. Thus, we synthesized and pharmacologically evaluated compounds bearing "saturated" phthalimide moieties as well as phthalimidines with substituents of systematically increasing size in position 3 or on the aromatic ring at one or both ends of the molecule. Within each series, QSAR could be derived: 1. "Saturation" of the aromatic ring of the phthalimide moiety results in less potent compounds. 2. Increasing the size of the substituents in position 3 of the phthalimide enhances the potency. 3. Putting substituents on the aromatic part of the phthalimide increases the potency more effectively: the introduction of a methyl group in position 5 gave a compound with a potency in the nanomolar concentration range which was subsequently developed as the first radioligand for the allosteric binding site.     

Structure-activity relationships in a series of bisquaternary bisphthalimidine derivatives modulating the muscarinic M(2)-receptor allosterically

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are well-established ligands of the common allosteric binding site of muscarinic M(2) receptors. Previous structure-activity relationships (SAR) revealed two positively charged centers and two lateral phthalimide moieties in a defined arrangement to be essential of a high allosteric potency. The purpose of this study was to replace one carbonyl group of the phthalimides with hydrogens, hydroxy, alkoxy, phenyl, benzyl, and benzylidene groups in order to check the influence of these substituents on the allosteric activity in antagonist-linked receptors. The analysis of the quantitative SAR indicated that a high allosteric potency is related to a certain amount of rigidity as well as polarizibility and the ability to form hydrophobic interactions.     

半肢骨骺发育异常1例

１　病例报告　男,７岁．因双下肢不等长,右膝及右踝关节骨性肿大就诊．无明显外伤史,亦无红、肿、热、痛病史．查体：发育正常,营养良好．双下肢不等长,左６０ｃｍ,右６４ｃｍ,有跛行．右膝及右踝内侧肿大,肤色正常,关节活动无异常．Ｘ线：右侧半身诸关节（肩、肘、腕、髋、膝、踝）骨骺及干骺发育均较左侧增大,肢体较长,骨骺出现亦较对侧提早．如右尺骨茎突骨骺较左侧提早出现（图１）．右肘关节肱骨小头骨骺较左侧增大（图２）．右髋臼发育浅平,边缘毛糙,右股骨头骨骺较左侧明显增大,其距泪滴之距离较左侧大１．０ｃｍ,呈…     

丁公藤碱Ⅱ类似物的合成及其生物活性

本文设计合成了丁公藤碱Ⅱ的C_2脱氧和C_8电子等排类似物。药理结果表明,丁公藤碱Ⅱ的C_2羟基是保持其缩瞳活性的关键部分之一;目的物2和4各自分别具有拟和抗胆碱活性;电子等排目的物16和17既无拟也无抗胆碱作用。