胼胝体损伤预测临床孤立综合征的复发

背景:大多数多发性硬化(MS)患者的首发症状为临床孤立综合征(GIS).目前MS的诊断主要依据临床表现、Barkhof MRI指标和脑脊液分析.     

BGC20-1531, a novel,potent and selective prostanoid EP4 receptor antagonist: a putative new treatment for migraine headache

Background and purpose:

Prostanoid EP₄ receptor antagonists may have therapeutic utility in the treatment of migraine since EP₄ receptors have been shown to be involved in prostaglandin (PG)E₂-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP₄ receptor antagonist.

Experimental approach:

BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP₄ receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.

Key results:

BGC20-1531 exhibited high affinity at recombinant human EP₄ receptors expressed in cell lines (pK_B 7.6) and native EP₄ receptors in human cerebral and meningeal artery (pK_B 7.6–7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE₂-induced vasodilatation of human middle cerebral (pK_B 7.8) and meningeal (pK_B 7.6) arteries in vitro, but had no effect on responses induced by PGE₂ on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1–10 mg·kg⁻¹ i.v.) caused a dose-dependent antagonism of the PGE₂-induced increase in canine carotid blood flow in vivo.

Conclusions and implications:

BGC20-1531 is a potent and selective antagonist at EP₄ receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.     

The vascular effects of different arginase inhibitors in rat isolated aorta and mesenteric arteries

Background and purpose

Arginase and nitric oxide (NO) synthase share the common substrate L-arginine, and arginase inhibition is proposed to increase NO production by increasing intracellular levels of L-arginine. Many different inhibitors are used, and here we have examined the effects of these inhibitors on vascular tissue.

Experimental approach

Each arginase inhibitor was assessed by its effects on isolated rings of aorta and mesenteric arteries from rats by: (i) their ability to preserve the tolerance to repeated applications of the endothelium-dependent agonist acetylcholine (ACh); and (ii) their direct vasorelaxant effect.

Key results

In both vessel types, tolerance (defined as a reduced response upon second application) to ACh was reversed with addition of L-arginine, (S)-(2-boronethyl)-L-cysteine HCl (BEC) or N^G-Hydroxy-L-arginine (L-NOHA). On the other hand, N^ω-hydroxy-nor-L-arginine (nor-NOHA) significantly augmented the response to ACh, an effect that was partially reversed with L-arginine. No effect on tolerance to ACh was observed with L-valine, nor-valine or D,L, α-difluoromethylornithine (DFMO). BEC, L-NOHA and nor-NOHA elicited endothelium-independent vasorelaxation in both endothelium intact and denuded aorta while L-valine, DFMO and nor-valine did not.

Conclusions and implications

BEC and L-NOHA, but not nor-NOHA, L-valine, DFMO or nor-valine, significantly reversed tolerance to ACh possibly conserving L-arginine levels and therefore increasing NO bioavailability. However, both BEC and L-NOHA caused endothelium-independent vasorelaxation in rat aorta, suggesting that these inhibitors have a role beyond arginase inhibition alone. Our data thus questions the interpretation of many studies using these antagonists as specific arginase inhibitors in the vasculature, without verification with other methods.     

How does home management of asthma exacerbations by parents of inner-city children differ from NHLBI guideline recommendations? National Heart, Lung, and Blood Institute

OBJECTIVES: 1) To describe the asthma morbidity, primary care practices, and asthma home management of inner-city children with asthma; 2) to determine the responses of parental caretakers to asthma exacerbations in their child; and 3) to compare these responses to the recommendations of the National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines for home management of acute exacerbations of asthma. DESIGN AND METHODS: A 64-item telephone survey was administered between July 1996 and June 1997 to 220 parental caretakers of 2- to 12-year-old children who had been hospitalized with asthma at an inner-city medical center from January, 1995 to February, 1996. Sociodemographics, primary care practices, asthma morbidity, and asthma home management were assessed. Parents were asked what they would do if their child "began wheezing and breathing faster than usual." RESULTS: Morbidity measures indicated that there were an average of 2.5 +/- 4.5 emergency department visits for asthma in the last 6 months, 1.6 +/- 2.2 hospitalizations for asthma in the last 12 months, and 18.1 +/- 17.9 asthma-related school absences in the previous school year. Most, but not all, of the families had primary care providers and most had phone access to them. Half of the families (51%) reported having been given a written asthma action plan. Only 30% of families with children age 5 years and older had peak flow meters. In contrast, almost all families (97%) had equipment for inhalation of beta-agonists. Only 39% of the 181 children with persistent symptoms were receiving daily antiinflammatory agents as recommended in the guidelines of the NHLBI. In response to the scenario of an acute exacerbation of asthma, no one mentioned that they would refer to a written plan, only 1 caretaker would measure peak flow and 36% would give beta-agonists. Two percent would give oral steroids initially, and 1 additional person would do so if wheezing continued 40 minutes later. Only 4% responded that they would contact their clinician. Reports of actual practice differed from the scenario responses in that more people began beta-agonists and oral steroids in response to an exacerbation in the past 6 months than said they would in response to the scenario. CONCLUSION: In this population of previously hospitalized inner-city children with asthma, the NHLBI guidelines for the home management of asthma exacerbations are not being followed. Interventions are needed to affect both clinician and caretaker practices.     

Safety and immunogenicity of a booster dose of Staphylococcus aureus types 5 and 8 capsular polysaccharide conjugate vaccine (StaphVAX) in hemodialysis patients

StaphVAX, an unadjuvanted, bivalent vaccine composed of Staphylococcus aureus (S. aureus) capsular polysaccharides (CPS) types 5 and 8 bound to the mutant non-toxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA) conferred approximately 60% protection for 10 months against bacteremia caused by this pathogen in hemodialysis patients. A protective level of 80 microg/ml was estimated based upon geometric mean (GM) antibody levels at the end of the efficacy period. To extend the duration of protection conferred by StaphVAX in hemodialysis patients, recipients of the vaccine were reinjected in a randomized double-blinded, placebo-controlled study. Vaccinees received StaphVAX and a saline placebo injection 14 days apart according to the randomization schedule. The booster dose of StaphVAX was administered an average of 958 days (753-1167 days) after the first injection. There were no serious adverse reactions. Antibody levels at day 14, 28, 92, and 182 post-injection were measured by ELISA. Maximal levels of IgG anti-CPS were observed at the 28-day interval. For type 5, GM antibody levels increased from 73 microg/ml at day 0 to 162 microg/ml (P < 0.001) and for type 8 from 59 microg/ml to 133 microg/ml (P < 0.001). Anti-CPS antibody levels of approximately 80 microg/ml to type 5 and type 8 were achieved in 72.4 and 74.3% of vaccinees, respectively. There was excellent correlation between the level of anti-CPS and opsonic titer (r = 0.93). Moreover, the decline of anti-CPS antibody levels at six months was significantly less rapid than that observed from the first immunization (P < 0.001). We conclude that a booster immunization to maintain protective levels of specific antibodies for an extended period of time is feasible for patients at continuous risk for S. aureus bacteremia.     

Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates

Tauopathies are neurodegenerative disorders characterized by aberrant intracellular aggregation of hyperphosphorylated tau. It has been shown that aggregated tau is phosphorylated at serine, threonine, and tyrosine residues. However, the occurrence of tyrosine phosphorylation on tau proteins at different states of tau aggregation has not been shown. In this report, we utilized the tauopathy mouse model JNPL3 that expresses human 0N4R tau isoform bearing the missense P301L mutation to study the occurrence of tau tyrosine phosphorylation in the course of the development of tau aggregation. These mice develop behavioral and motor deficits and form sarkosyl-insoluble hyperphosphorylated tau in an age-dependent manner. Mass spectrometry analyses of immunopurified brain tau proteins from JNPL3 and Alzheimer's disease affected individual uncovered novel tau tyrosine-phosphorylated sites. Further studies demonstrated that the abundance of tyrosine-phosphorylated tau increases in an age-dependent manner in JNPL3 mice. Tyrosine-phosphorylated tau was detected in both soluble and sarkosyl-insoluble preparations derived from brain and spinal cord, and localized in neurons containing aggregated tau. The phosphorylation of tyrosine residues in tau appeared to occur along with that of serine and threonine residues and was not detectable in non-transgenic littermates and transgenic mice expressing 0N4R wild-type human tau. The results suggest that tyrosine phosphorylation is as important as phosphorylation of other residues in tauopathy.     

Intravenous administration of ONYX-015, a selectively replicating adenovirus, induces antitumoral efficacy.

Replication-incompetent viral vectors are being developed for the gene therapy of cancer. Although some of these may eventually be proven to have significant localized antitumoral activity, none to date have been shown to infect and cause regression of established tumors following i.v. administration. Because cancer is a systemic disease in almost all fatal cases, the lack of i.v. efficacy is a major limitation to treatment with replication-incompetent viral vectors. ONYX-015 (d11520) is an attenuated adenovirus that replicates in and causes selective lysis of cancer cells. We carried out i.v. efficacy and distribution studies in nude mice with s.c. and intraparenchymal tumor xenografts. ONYX-015 infected and replicated efficiently within tumors following i.v. administration. Viral titers in livers were relatively high 3 h after administration but decreased rapidly, becoming undetectable after 24 h. Effective antitumor doses were not associated with hepatic toxicity. Viral replication within tumors was associated with regressions in several tumor models. Selectively replicating viruses like ONYX-015 hold promise as agents to treat metastatic cancer.     

环磷酰胺对大鼠早期胚胎发育里程的影响

目的：为探索烷化剂对哺乳动物早期胚胎发育里程的影响及其可能的机制。方法：孕大鼠第３ 天ｉｐ 环磷酰胺（Ｃｙｃ １０ 、２０ 、４０ｍｇ／ｋｇ） ,孕第４ 天评价胚胎的胚胎化作用,胚胎发育时相,及蜕变胚胎率;同时显微外科分离胚胎内细胞团及滋养层细胞,评价两群细胞受损情况。结果：在Ｃｙｃ １０ｍｇ／ｋｇ 时,胚胎的胚泡化作用,胚胎发育时相均未受明显影响;４０ｍｇ／ｋｇ 时,蜕变胚胎率明显提高。胚泡化率及胚胎细胞数呈剂量依赖性减少,其中内细胞团细胞减少尤甚。结论：Ｃｙｃ 在未引起早期胚胎蜕变率显著增加时,可影响细胞周期,但不影响发育里程;高剂量时,显著影响发育里程并伴蜕变率显著增加