Analysis of the immune response induced by a scorpion venom sub-fraction, a pure peptide and a recombinant peptide, against toxin Cn2 of Centruroides noxius Hoffmann.

Three different immunogens from the venom of the Mexican scorpion Centruroides noxius Hoffmann were used to study protective antibody response in mice and rabbits, challenged with toxin Cn2, one of the most abundant toxic peptide of this venom. The immunogens were: Cn5, a crustacean specific toxin; a recombinant protein containing the peptide Cn5 linked to the maltose transporter and a sub-fraction (F.II.5) containing 25 distinct peptides, among which is Cn5. Mice immunized with these three preparations, when directly challenged with Cn2 presented no apparent protection, whereas anti-sera produced in rabbits with these three immunogens were capable of partially neutralizing the effect of Cn2, when injected into naive mice. Cn5 rabbit anti-serum showed a better protective effect on mice, than the rabbit sera obtained against the two other antigens. The subcutaneous route of challenging mice was shown to be better than intraperitoneal injections. Comparative structural analysis of Cn5 with other toxins of this venom showed that our results are important to be taken into consideration, when choosing appropriate immunogens aimed at the production of better anti-venoms or for the rational design of possible vaccines.     

Food, health, the environment and consumers' dietary choices

The aim of this paper is to examine some of the issues that surround food and the environment, particularly conventional and organic agriculture and food distribution, and to look at some of the health implications. It is argued that the links between food, health and the environment are strong. Consumers have the power to have an impact positively or negatively on the environment via their dietary choices. By providing information and advice about the environmental as well as the health impact of food choices, health and nutrition professionals could increase consumers' awareness of such issues.     

循证病例报告 原发性脑出血患者是否应该进行抗血小板或抗凝治疗？

原发性脑出血伴有血栓危险因素的患者治疗比较棘手，如以下病例：老年男性，55岁，因右侧肢体无力入院。既往患有难治陛高血压、Ⅱ型糖尿病、心绞痛及高脂血症。约10年前右侧肢体曾有一次轻微卒中。入院时所服药物为：阿司匹林75mg，1次／日；阿托伐他汀10mg，1次／日；苄氟噻嗪2．5mg，1次／日；雷米普利2．5mg，1次／日；氨氯地平5mg，1次／日；     

Testing and implementing signal impact analysis in a regulatory setting: results of a pilot study.

BACKGROUND AND AIM: Statistical signal detection methods such as proportional reporting ratios (PRRs) detect many drug safety signals when applied to databases of spontaneous suspected adverse drug reactions (ADRs). Impact analysis is a tool that was developed as an aid to prioritisation of such signals. This paper describes a pilot project whereby impact analysis was simultaneously introduced into practice in a regulatory setting and tested in comparison with the existing approach. METHODS: Impact analysis was run on signals detected during a 26-week period from the UK Adverse Drug Reactions On-line Information Tracking (ADROIT) database of spontaneous ADRs that met minimum criteria (PRR>or=3.0, chi2>or=4.0 and >or=3 reported cases) and related to established drugs (i.e. those that have been available for at least 2 years and no longer carry the 'black triangle' symbol). The current method of signal prioritisation (i.e. the collective judgement at a weekly meeting) was initially performed without knowledge of the findings of impact analysis. Subsequently, the meeting was presented with the findings and, where appropriate, given the opportunity to reconsider the judgement made. The categories arising from the two methods were compared and the ultimate action recorded. Inter-observer variation between scientists performing impact analysis was also assessed. RESULTS: Eighty-six separate signals were analysed by impact analysis, of which 5% were categorised as high priority (A), 14% as requiring further information (B), 31% as low priority (C) and 50% as no action required (D). In general, the new method tended to give a higher level of priority to signals than the existing approach. Overall, there was 59% agreement between the impact analysis and the collective judgement at the meetings (kappa statistic=0.30). There was slightly greater agreement between impact analysis and the final action taken (kappa statistic=0.39), indicating that the findings of an impact analysis had an influence on the outcome. Assessment of inter-observer variation demonstrated that the method is repeatable (kappa statistic for overall category=0.77). Almost 70% of those who participated in the pilot study believed that impact analysis represented an improvement in how signals were prioritised. CONCLUSIONS: Impact analysis is a repeatable method of signal prioritisation that tended to give a higher level of priority to signals than the standard approach and which had an influence on the ultimate outcome.     

Randomized trial of two intravenous schedules of the topoisomerase I inhibitor liposomal lurtotecan in women with relapsed epithelial ovarian cancer: a trial of the national cancer institute of Canada clinical trials group.

PURPOSE: Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS: Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS: Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION: The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.     

Comprehensive analysis of CDKN2A status in microdissected urothelial cell carcinoma reveals potential haploinsufficiency, a high frequency of homozygous co-deletion and associations with clinical phenotype.

PURPOSE: There are significant differences in reported frequencies, modes of inactivation, and clinical significance of CDKN2A in urothelial cell carcinoma (UCC). We aimed to address these issues by investigating all possible modes of inactivation and clinicopathologic variables in a single tumor panel. EXPERIMENTAL DESIGN: Fifty microdissected UCCs were examined. CDKN2A gene dosage (quantitative real-time PCR), allelic status (microsatellite analysis), hypermethylation (methylation-specific PCR), mutation status (denaturing high-performance liquid chromatography and sequencing), protein expression (immunohistochemistry), and clinicopathologic variables (stage, grade, and disease recurrence during follow-up) were assessed. RESULTS: Exon 2 was underrepresented in 20 of 46 (43%) and exon 1beta in 21 of 46 (46%) of cases. Underrepresentation of exon 2 was accompanied by loss of heterozygosity (LOH) of 9p in 6 of 18 (30%) and of exon 1beta in 11 of 19 assessable cases (58%). Overall, LOH of 9p was identified in 15/41 (37%). Homozygous deletion of exons 2 and 1beta was detected in 16 of 46 (35%) and 10 of 46 tumors (22%), respectively. Co-deletion was most common, but exon 2-specific homozygous deletion was also detected. In tumors without homozygous deletion, p16 promoter hypermethylation was detected in 1 of 18 (6%). Hypermethylation of the p14ARF promoter or mutations in CDKN2A were not observed. Homozygous deletion of exon 2 or LOH on 9p were associated with invasion. Homozygous deletion of exon 2 or exon 1beta was associated with recurrent disease. CONCLUSIONS: These results confirm CDKN2A as a clinically relevant target for inactivation in UCC and show that the true frequency of alteration is only revealed by comprehensive analysis. Our results suggest that CDKN2A may be haploinsufficient in human cancer.     

Increased susceptibility to adult paraoxon exposure in mice neonatally exposed to nicotine.

Low-dose exposure of neonatal mice to nicotine has earlier been shown to induce an altered behavioral response to nicotine in adulthood. Organophosphorus insecticides are known to affect the cholinergic system by inhibition of acetylcholinesterase. This study was undertaken to investigate whether neonatal exposure to nicotine makes mice more susceptible to a known cholinergic agent. Neonatal, 10-day-old, male mice were exposed to nicotine-base (33 microg/kg body weight) or saline s.c. twice daily on five consecutive days. At 5 months of age the animals were exposed to paraoxon (0.17 or 0.25 mg/kg body weight [29% and 37% inhibition of cholinesterase, respectively]) or saline sc every second day for 7 days. Before the first paraoxon injection, the animals were observed for spontaneous motor behavior. The spontaneous motor behavior test did not reveal any differences in behavior between the treatment groups. Immediately after the spontaneous behavior test, the animals received the first injection of paraoxon and were observed for acute effects of paraoxon on spontaneous motor behavior. The acute response to paraoxon in the spontaneous motor behavior test was a decreased level of activity in mice neonatally exposed to nicotine. Control animals showed no change in activity. Two months after the paraoxon treatment, the animals were again tested for spontaneous motor behavior. Animals neonatally exposed to nicotine and exposed to paraoxon as adults showed a deranged spontaneous motor behavior, including hyperactivity and lack of habituation.