Recent Advances in Structure-Based Virtual Screening of G-Protein Coupled Receptors

In addition to the rhodopsin crystal structure, high-resolution crystal structures of ligand-mediated G-protein-coupled receptors (GPCRs) have recently become available, and these have become attractive templates for developing homology models of several GPCRs of therapeutic interest. These crystal structures and the homology models derived from them have provided significant insights into ligand–receptor interactions. Moreover, several studies have demonstrated that the structural models are indeed suitable for virtual screening of compound databases to identify new ligands for various GPCRs. Recent examples of such virtual screening against GPCRs are discussed in this review.     

试析陆懋修从阳明论治温病之特色

陆懋修（1818-1886），又名免研，字九芝，号江左下工，又号林屋山人，江苏元和（今江苏吴县）人，为清代后期著名的医学家。陆氏出身于官宦之家，儒医兼通，陆氏秉承家学，对先人的医学成就颇为敬重。他曾三十余年坚持潜心研究《内经》、《伤寒》等医学经典著作，终于贯通医理而成为一代名医。陆氏一生博览群书之余，著述不断，     

Feasibility of treating hyperfibrinogenemia with intermittently administered batroxobin in patients with ischemic stroke/transient ischemic attack for secondary prevention.

This study evaluated the safety and efficacy of batroxobin in treating hyperfibrinogenemia for secondary stroke prevention. Patients with ischemic stroke or transient ischemic attack (TIA) were measured for plasma fibrinogen levels. Selected participants had concomitant hyperfibrinogenemia (plasma fibrinogen > or = 3.0 g/l). Patients enrolled between 1 July 2003 and 31 December 2004 were treated with batroxobin; patients enrolled between 1 January 2002 and 30 June 2003 were treated without batroxobin. Batroxobin was administered intermittently via intravenous injection at 3-monthly intervals. Patients in both groups were followed for 1 year. Any cerebrovascular events and suspected adverse events were recorded. In total, 112 ischemic stroke/TIA patients with concomitant hyperfibrinogenemia were enrolled, 52 being treated with batroxobin and 60 without batroxobin. Six patients (11.5%) with batroxobin and 16 patients (26.7%) without batroxobin had recurrent cerebral ischemic events during follow-up. Stroke/TIA recurrence in patients without batroxobin was higher than that in patients with batroxobin (P < 0.05). Two patients with batroxobin and two patients without batroxobin developed hemorrhagic stroke during follow-up. There were five deaths (9.6%) in the batroxobin group, and seven deaths (11.7%) in the nonbatroxobin group during follow-up (P > 0.05). Intermittent intravenous injection of batroxobin can efficiently reduce the risk for stroke/TIA recurrence in patients with concomitant hyperfibrinogenemia.     

Presence of lysine at aa 335 of the hemagglutinin-neuraminidase protein of mumps virus vaccine strain Urabe AM9 is not a requirement for neurovirulence

The recent global resurgence of mumps has drawn attention to the continued need for robust mumps immunization programs. Unfortunately, some vaccines derived from inadequately attenuated vaccine strains of mumps virus have caused meningitis in vaccinees, leading to withdrawal of certain vaccine strains from the market, public resistance to vaccination, or in some cases, cessation of national mumps vaccination programs. The most widely implicated mumps vaccine in cases of postvaccination meningitis is derived from the Urabe AM9 strain, which remains in use in some countries. The Urabe AM9 vaccine virus has been shown to exhibit a considerable degree of nucleotide and amino acid heterogeneity. Some studies have specifically implicated variants containing a lysine residue at amino acid position 335 in the hemagglutinin-neuraminidase (HN) protein with neurotoxicity, whereas a glutamic acid residue at this position was associated with attenuation. To test this hypothesis we generated two modified Urabe AM9 cDNA clones coding either for a lysine or a glutamic acid at position 335 in the HN gene. The two viruses were rescued by reverse genetics and characterized in vitro and in vivo. Both viruses exhibited similar growth kinetics in neuronal and non-neuronal cell lines and were of similar neurotoxicity when tested in rats, suggesting that amino acid 335 is not a crucial determinant of Urabe AM9 growth or neurovirulence.     

Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine.

The present study was undertaken to examine whether the second generation antibiotic drug minocycline attenuates behavioral changes (eg, acute hyperlocomotion and prepulse inhibition (PPI) deficits) in mice after the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (dizocilpine). Dizocilpine (0.1 mg/kg)-induced hyperlocomotion was significantly attenuated by pretreatment with minocycline (40 mg/kg). Furthermore, the PPI deficits after a single administration of dizocilpine (0.1 mg/kg) were attenuated by pretreatment with minocycline (10, 20, or 40 mg/kg), in a dose-dependent manner. Moreover, in vivo microdialysis study in the free-moving mice revealed that pretreatment with minocycline (40 mg/kg, i.p.) significantly attenuated the increase of extracellular dopamine (DA) levels in the frontal cortex and striatum after administration of dizocilpine (0.1 mg/kg), suggesting that the inhibition of dizocilpine-induced DA release by minocycline may, at least in part, be implicated in the mechanism of action of minocycline with respect to dizocilpine-induced behavioral changes in mice. These findings suggest that minocycline could attenuate behavioral changes in mice after the administration of the NMDA receptor antagonist dizocilpine. Therefore, it is possible that minocycline would be a potential therapeutic drug for schizophrenia.     

复发性鼻腔及鼻窦恶性肿瘤的挽救性治疗

目的 探讨鼻腔及鼻窦恶性肿瘤复发后的临床表现、与复发有关的因素、再手术的意义及缺损组织的修复。方法 排除原发性鼻腔鼻窦恶性肿瘤，仅收集治疗后复发并且有再手术意义的病例。应用乘积极限法估计生存率，Stata7．0统计软件进行统计运算。结果 1993～2002年共有25例患者符合要求。男19例，女6例，年龄13～66岁，平均46．1岁。所有患者均有至少1次手术或放射治疗史。末次治疗至复发的时间2周～46个月，中位时间18个月，80％的患者肿瘤复发出现于末次治疗后2年内。术后随访1～65个月。再手术中无死亡病例。5例健在无肿瘤复发；局部复发2例，颈部淋巴结转移1例，经过1刀或手术治疗后2例健在、1例带瘤生存；死于局部复发13例，死于肺转移1例，死于无关疾病1例，失访2例。1年生存率62．5%，2年生存率43．7％，3年生存率29．1％，中位生存时间18个月。术后发生脑脊液漏3例次，中枢性尿崩症1例次，皮瓣部分坏死1例次。手术修补脑脊液漏l例。结论 鼻腔及鼻窦恶性肿瘤局部复发多发生于末次治疗后2年之内，主要症状是头痛及局部隆起。肿瘤的类型和分化程度与复发密切相关。合理、及时的综合治疗有助于减少复发。运用有效修复手段的再手术可改善晚期患者的生活质量，延长生命。并发症主要是脑脊液漏，多数可通过保守方法治愈。