DNA adducts formed by ring-oxidation of the carcinogen 2-naphthylamine with prostaglandin H synthase in vitro and in the dog urothelium in vivo

The presence of relatively high levels of prostaglandin H synthase(PHS) in the dog urinary bladder and its ability to mediatethe activation of carcinogenic arylamines to DNA-bound productsin vitro suggests the involvement of this enzyme in arylamine-inducedbladder carcinogenesis. Since the PHS-dependent metabolism of2-naphthylamine (2-NA) had been shown to yield both ring- andN-oxidation products in vitro, we compared the reactivity of³H-labeled N-hydroxy-2-naphthylamine (N-OH-2-NA), 2-nitrosonaphthalene,and 2-amino-1-naphthol (2-AN) toward DNA and protein. In thePHS-incubation system, all three derivatives bound at high levelsto protein, but only N-OH-2-NA and 2-AN bound appreciably toDNA. Though ring-oxidation has usually been considered a detoxificationpathway, the covalent binding of [³H]2-AN to DNA was found tooccur readily under aerobic conditions and was enhanced at acidicpH. At pH 5 in air, the reactivity of [³H]2-AN with nucleicacids and protein was in the order: serum albumin > tRNA> poly G > poly C > DNA > poly A > rRNA >poly U. Enzymatic hydrolysis of DNA reacted with [³H]2-AN andsubsequent analysis by h.p.l.c. indicated the presence of severalcarcinogen-nucleoside adducts. The major product was characterizedas N⁴-(deoxyguanosin-N²-yl)-2-amino-1,4-naphthoquinoneimine;and two minor products were tentatively identified as N⁴-(deoxyadenosin-N⁶-yl)-2-amino-1,4-naphthoquinoneimineand a deoxyguanosin-N²-yl adduct of a naphthoquinoneimine dimer.These adducts accounted for 60% of the total DNA binding obtainedby incubation of [³H]2-NA with PHS in vitro and for 20% of the[³H]2-NA bound to dog urothelial DNA in vivo. The remainingadducts were identical to those previously reported as productsof the reaction of N-OH-2-NA with DNA. These results suggestthat a minor proportion of the DNA adducts found in vivo maybe formed by PHS-activation of 2-NA in the target tissue. Furthermore,the reactivity of 2-AN with cellular nucleophiles, presumablythrough formation of 2-imino-1-naphthoquinone or a protonated4-naphthocarbenium ion, indicates that ring-oxidation productsof arylamines and of other carcinogenic aryl compounds shouldbe evaluated as proximate carcinogenic metabolites.     

Characterization of and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity.

Helicobacter pylori infection is strongly associated with histologic gastritis and peptic ulcer disease. Broth culture supernatants from a subset of H. pylori strains induce vacuolization in cultured cells, a phenomenon that has been attributed to cytotoxin activity. Concentrated culture supernatants from 15 of 28 (53.6%) H. pylori strains tested induced vacuolization in HeLa cells in titers ranging from 1:10 to 1:180. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining of supernatants from these 28 strains and 2 control strains demonstrated an 82-kilodalton (kDa) protein band in 3 of 16 supernatants with vacuolizing activity, but in none of 14 supernatants without vacuolizing activity. By immunoblotting with human sera, a 128-kDa band was recognized in all 16 supernatants with vacuolizing activity, compared with 9 of 14 (64%) supernatants without vacuolizing activity (P = 0.014). Serologic recognition of the 128-kDa band in H. pylori culture supernatants was more prevalent among persons infected with vacuolizing H. pylori strains than among persons infected with nonvacuolizing strains, but the difference was not statistically significant (80 versus 45%; P = 0.079); human serologic recognition of the 82-kDa band was less common. The 128-kDa band was recognized by 100% of 31 serum samples from H. pylori-infected patients with duodenal ulcer disease, compared with 60.8% of 74 serum samples from H. pylori-infected persons without peptic ulcer disease (P = 0.0001). These data indicate that antigenic 128- and 82-kDa proteins are present in H. pylori broth culture supernatants with vacuolizing activity and that serologic responses to the 128-kDa protein are more prevalent among H. pylori-infected persons with duodenal ulceration than among infected persons without peptic ulceration.     

Group interventions and the limits of behavioral medicine

A wide range of interventions has been devised to address health hazards in the social and physical environment. The authors propose a 2-dimensional matrix to organize these interventions. The timing of interventions is divided into 4 stages: preventing exposure to hazard (proactive primary prevention), preventing symptoms from appearing (reactive primary prevention), preventing early symptoms from becoming chronic or leading to disease (secondary prevention), and managing the disease (tertiary prevention). The level at which the intervention is targeted is divided into 2 categories: micro (individual or family) and macro (more aggregate social level). Large-scale interventions such as media campaigns can target either individual health behaviors (microlevel) or the environment (macrolevel). This typology is illustrated with interventions designed to prevent or ameliorate the health consequences of adverse employment changes such as job loss. The analysis concludes that behavioral medicine and public health approaches are differentially suited to different intervention types.     

Differential effects of calcium channel antagonists (ω-conotoxin GVIA,nifedipine, verapamil) on the electrically-evoked release of [3H]acetylcholine from the myenteric plexus,phrenic nerve and neocortex of rats

Summary Electrically-evoked release of [³H]acetylcholine from autonomic neurons (myenteric plexus), motoneurons (phrenic nerve) and the central nevous system (neocortex) was investigated in the presence and absence of the calcium channel antagonists -conotoxin GVIA, nifedipine and verapamil, whereby the same species (rat) was used in all experiments. Release of [³H]acetylcholine was measured after incubation of the tissue with [³H]choline.-Conotoxin GVIA markedly reduced (70%) the evoked release of [³H]acetylcholine from the myenteric plexus of the small intestine (IC₅₀: 0.7 nmol/l) with a similar potency at 3 and 10 Hz stimulation. An increase in the extracellular calcium concentration attenuated the inhibitory effect of -conotoxin GVIA. Release of [³H]acetylcholine from the rat neocortex was also inhibited (90%) by -conotoxin GVIA, but the potency was 19-fold lower (IC₅₀: 13 nmol/l). However, the release of [³H]acetylcholine from the phrenic nerve was not reduced by -conotoxin GVIA (100 nmol/l) at 1.8 mmol/l calcium (normal concentration), whereas -conotoxin GVIA inhibited evoked [³H]acetylcholine release by 47% at 0.9 mmol/l calcium. Neither nifedipine (0.1 and 1 mol/l) nor verapamil (0.1, 1 and 10 mol/l) modified the evoked release of [3H]acetylcholine from the myenteric plexus and the phrenic nerve.Acetylcholine release from different neurons appears to be regulated by different types of calcium channels. N-type channels play the dominant role in regulating acetylcholine release from both the myenteric plexus and the neocortex, whereas acetylcholine release from motor nerves is regulated by calcium channel(s) not yet characterized. Send offprint requests to I. Wessler at the above address     

病灶清除内固定植骨治疗胸椎结核

目的;探讨手术治疗胸椎结核的更好方法。方法;自１９９０年以来,对２１例胸椎结核导致椎柱不稳的患者,应用病灶清除,哈氏棒内固定,椎间及椎板植骨的手术方法。本组平均３３．２岁。胸７椎体６例,胸８椎体８例,胸１０椎体７例,椎体压缩〈１／２椎体高度１３例,〉１／２椎体高度８例,并不全瘫１４例。手术中先行病灶清除,然后哈氏棒内固一,撑开后再次清除病灶,取肋骨和髂骨行椎间及椎板上植骨。术后化疗１２～１５月。结     

Brain activity and language assessment using event-related potentials: development of a clinical protocol

To test the validity of a new computerized task to assess children's receptive vocabulary, event-related potentials (ERPs) were recorded from 56 typically developing children ranging in age from 5 to 12 years. This ERP-computerized vocabulary task does not require a child to give a verbal or motor (i.e. pointing) response. Single pictures, from an existing standardized test of receptive vocabulary, were presented on a computer screen and simultaneously named either correctly (congruent) or incorrectly (incongruent) via a computer. As predicted, the N400 amplitude was found to be significantly higher to the incongruent picture-word pair (i.e. the child knew it was an incorrect pairing) than to the congruent picture-word pair (i.e. the child knew it was a correct pairing). This effect was found for each of the four age groups (5 to 6 years, 7 to 8 years, 9 to 10 years, 11 to 12 years). This task accurately estimated current receptive vocabulary in typically developing children. Although still in the development stage, it may eventually serve as an adjunct to a thorough neurological and neurodevelopmental assessment of some children presenting with moderate to severe cerebral palsy.     

Demograghic and socio-economic determinants of community and hospital services costs for people with HIV/AIDS in London.

We examined the influence of demographic, social and economic background of people with HIV/AIDS in London on total community and hospital services costs. This was a retrospective study of community and hospital service use, needs and costs based on structured questionnaires administered by trained interviewers and costing information obtained from the service purchasers and providers, based on two Genito-urinary Medicine clinics in London: the Jefferiss Wing at St. Mary's Hospital and Patric Clements at the Central Middlesex Hospital, London, England. The subjects were 225 HIV infected patients (105 asymptomatic, 59 symptomatic non-AIDS and 61 AIDS). We found that over and above well established determinants of health care costs for HIV infected people such as disease stage and transmission category, social and economic factors such as employment and support of a living-in partner significantly reduced community services costs. Private health insurance had a similar effect, though only a small proportion of HIV people had such cover. The cost of community services for HIV infected non-European Union nationals, mainly of African origin, was one quarter that for the European Union nationals. Community services costs were highest for heterosexually infected women and lowest for heterosexually infected men after adjusting for other factors. Hospital services costs were significantly higher for HIV infected people lacking educational qualifications and employment. We conclude that access to community care for HIV infected non-EU nationals appears to be very poor as the cost of their community services was one quarter that for the EU nationals after adjusting for the effects of transmission category, disease stage, living with a partner, employment and having a private health insurance. Additional incentives for informal care for HIV infected people could be a cost-effective way to improve their community health service provisions.     

Rizatriptan: a review of its efficacy in the management of migraine.

Rizatriptan is an orally active serotonin 5-HT1 receptor agonist selective for the 5-HT(1B/1D) subtypes. The efficacy of oral rizatriptan (5 or 10 mg) has been demonstrated in large (n = 309 to 1746) well designed comparative trials with placebo and oral sumatriptan. Two hours postdose, rizatriptan 5 or 10 mg was more effective than placebo at producing pain relief or a pain free status, relieving migraine-associated symptoms and normalising functional ability. In general, rizatriptan 10 mg appeared to be more effective than rizatriptan 5 mg. However, recurrence rates with rizatriptan 5 and 10 mg appeared to be similar to those with placebo. Patients were significantly more likely to achieve pain relief within 2 hours after receiving rizatriptan 5 mg than sumatriptan 25 mg and after rizatriptan 10 mg than sumatriptan 50 mg. This was also observed with rizatriptan 10 mg compared with sumatriptan 100 mg according to an age-adjusted and a prespecified per-protocol analysis. In general, rizatriptan was better than sumatriptan at relieving migraine-associated symptoms, particularly nausea, and in normalising functional ability depending on which doses were compared. The incidence of headache recurrence, time to onset of recurrence and the need for escape medication in nonresponders appeared to be similar between rizatriptan and sumatriptan. Over the 24 hours after the dose, rizatriptan 10 mg improved the quality of life of patients with migraine compared with placebo. Rizatriptan 10 mg also significantly improved work function compared with placebo and with sumatriptan 50 mg. Rizatriptan appears to be well tolerated with most adverse events being mild and transient. The most commonly experienced events included general digestive complaints, general neurological complaints, dizziness, somnolence, asthenia/fatigue and pain and pressure sensations. In clinical trials, the overall incidence of adverse events with rizatriptan 5 or 10 mg was similar to that with sumatriptan 25 or 50 mg but lower than that with sumatriptan 100 mg. Chest pain was reported by 1 to 3% of rizatriptan recipients and by 3 to 6% of patients receiving sumatriptan (25, 50 or 100 mg); clinically significant effects on ECG parameters, heart rate or blood pressure were not observed with rizatriptan. Conclusions: Rizatriptan produces pain relief and a pain free status, relieves associated symptoms of migraine, normalises functional ability and improves patient quality of life. Rizatriptan 10 mg appears to be more effective than rizatriptan 5 mg. In comparison with oral sumatriptan, rizatriptan may provide better relief from pain and nausea, with some evidence of a faster onset of action. Thus, rizatriptan 5 or 10 mg is likely to establish a place as an effective and well tolerated agent for the management of acute migraine.     

Sibrafiban

Sibrafiban is the orally administered, nonpeptide, double-prodrug of Ro 44-3888 which is a selective glycoprotein IIb/IIIa receptor antagonist. It is currently undergoing clinical trials for secondary prevention of cardiac events in patients stabilised after acute coronary syndromes. In a phase II dose-finding study (TIMI 12) in patients stabilised after a myocardial infarction (MI) or an episode of unstable angina, there was a dose-dependent inhibition of platelet aggregation which correlated closely with the plasma concentration of the total active drug. An ongoing phase III study (SYMPHONY) compares the effects of sibrafiban on cardiac events with that of aspirin in patients stabilised after a Q wave MI or an episode of unstable angina. This large trial uses twice daily dosage regimens to produce the plasma concentrations which were associated with less bleeding in the earlier dose-ranging trial. A long term (minimum duration 12 months) phase III study (2nd SYMPHONY) is under way to compare the effects of sibrafiban on cardiac events with those of aspirin in patients stabilised after an MI or an episode of unstable angina. The most common adverse events associated with sibrafiban include bleeding, with minor haemorrhages occurring more often than with aspirin.