The mechanism of carcinogenesis by the neutral fraction of cigarette smoke condensate

Sixteen groups, each of 50 Swiss female SPF mice, were treated thrice weekly with various combinations of 3,4-benzopyrene (BP) and/or the neutral fraction of cigarette smoke (NF) in acetone applied to the skin. Some groups received one carcinogen, some the other and some a mixture of the two. Skin tumour incidence rates were found to increase both with the dose of NF and with the dose of BP. With BP alone a threshold dose was found beyond which a very heavy incidence rate of malignant skin tumours occurred. After correction of the results for intercurrent deaths it was found that when NF and BP are applied together as a mixture they do not act independently in the production of malignant skin tumours but interact positively. This suggests that some of the components of NF act as cocarcinogens rather than as complete carcinogens. Treatment with NF appeared to increase the incidence of malignant lymphomas. The data were not suitable for deciding whether the various treatments influenced the rates of incidence of internal tumours of other types, for example, lung tumours.     

Geographies of inequality: child pedestrian injury and walking school buses in Auckland, New Zealand

In the face of mounting concern at traffic congestion in the vicinity of schools and the associated risks of child pedestrian injury, the 'walking school bus' (WSB) idea has been rapidly adopted within metropolitan Auckland. WSBs involve volunteers guiding children to and from school in an orderly manner following established walking routes. This paper reports on a survey of the 34 Auckland primary schools which had adopted the scheme by November 2002. Despite rates of child pedestrian injury being highest in areas of socio-economic deprivation, our survey found WSB developments highly concentrated in low deprivation neighbourhoods. The inequitable socio-spatial distribution of WSBs in Auckland suggests that the ability to respond to road safety issues is closely correlated with socio-economic privilege. While our respondents identified a number of individual and community health benefits accruing from WSBs, we conclude that the initiative has a limited ability to address public health challenges originating within an inequitable and car-dominated urban political system.     

Kinetics and maintenance of acquired resistance in mice to Listeria monocytogenes.

In the mouse system, acquired resistance to Listeria monocytogenes can only be demonstrated after immunization with viable microorganisms. A successful state of immunity cannot be elicited with formalin-killed organisms or bacterial cell-derived products. Viable, serologically cross-reactive organisms (not mouse pathogenic) do not induce a state of immunity as measured by acquired resistance. The duration of immunity, once established, is dose independent, and the absolute interval of its existence is not extended by secondary challenge with large numbers of viable organisms. The decline of immunity in actively immunized animals is not altered by antigenic challenge with formalin-killed cells or cell products. This indicates that the cellular requirements for the development of host resistance are similar for induction as well as maintenance. In vitro measurements of cellular immunity by migration inhibition indicate that formalin-killed organisms as well as cell products were recognized by actively sensitized lymphocytes obtained from immune animals.     

Clinical efficacy and pharmacokinetics of montelukast in dyspeptic children with duodenal eosinophilia

BACKGROUND: Montelukast, a competitive cysteinyl leucotriene-1 receptor antagonist, reduces airway eosinophilia in asthmatics. We evaluated the effect of this drug in children with eosinophilic duodenitis, defined histologically as duodenal mucosa with peak eosinophil count of more than 10 eosinophils/hpf. METHODS: Forty children and adolescents (6-18 yr) with dyspepsia and duodenal eosinophilia were enrolled in a double blind, randomized, placebo-controlled, cross-over study of monteleukast therapy. Subjects were randomized to receive either 10 mg montelukast or an identical placebo once daily and were evaluated on day 14 for symptomatic and biochemical responses. Subjects were also randomized to one of two blood sampling schemes to evaluate montelukast pharmacokinetics. RESULTS: Using a post treatment global pain assessment, a positive clinical response was observed in 62.1% of patients receiving montelukast compared with 32.4% on placebo (p < 0.02). Pain assessment score deteriorated in 45% of montelukast responders (5/11) after cross-over to placebo and improved in 62% (8/13) of placebo non-responders on cross-over to montelukast. In patients with peak duodenal eosinophil counts between 20-29/hpf (n=19), a positive pain assessment response was observed in 84% of patients receiving montelukast compared to 42% receiving placebo (p < 0.01). Response rate did not differ by age, gender or histologic findings at baseline. Pharmacokinetic analysis yielded parameter estimates for absorption rate constant (Ka), apparent volume of distribution (Vd/F) and elimination rate constant (Kel) of 0.42 h, 0.19 L/kg and 0.26 h, respectively. The relative extent of systemic drug exposure was comparable to that observed in previous pediatric investigations with similar weight-adjusted montelukast doses. Neither dose nor calculated drug exposure were associated with the level of post treatment pain assessment or the change in biochemical markers. CONCLUSIONS: These data suggest a beneficial role for montelukast in the treatment of pediatric patients with dyspepsia associated with duodenal eosinophilia.     

Developmental pharmacokinetics and pharmacodynamics of nizatidine

OBJECTIVES: To characterize the impact of development on the pharmacokinetics and pharmacodynamics of nizatidine. METHODS: Children (age range, 5 days-18 years) and adults (age range, 18-50 years) were enrolled in four open-label trials. Nizatidine formulation and dose were determined by age: infants received 2 or 4 mg/kg i.v., children 2.5 or 5 mg/kg in one of three oral liquid formulations, and adolescents and adults received a fixed 150-mg capsule. Nizatidine and N-desmethylnizatidine concentrations were measured in serial post-dose plasma samples by a high-performance liquid chromatographic assay with mass spectrometric detection. Intragastric pH was recorded during a 24-hour post-dose interval. RESULTS: Data on 93 subjects were combined with previous values from 36 individuals to cover an age group not adequately captured and to control for formulation effects. Dose-normalized exposure estimates revealed no apparent age dependence; however, maximum plasma concentration (298.5 +/- 100.7 v 552.8 +/- 152.4 ng/mL per mg/kg dose) and AUC0-infinity (954.4 +/- 379.8 v 1,573.0 +/- 347.4 ng*hour/mL per mg/kg dose) were reduced in extemporaneous formulations in apple juice. The apparent modest age dependence observed for total body clearance (Cl/F) (r = 0.365) and Vss/F (r = 0.221) reflected a formulation-dependent decrease in bioavailability rather than a true age effect. The age-associated changes in lambda z observed for nizatidine and its metabolite were predictable and consistent with developmental acquisition of renal function. Mean and median pH, as well as fraction of time that the dosing interval remained above target pH values, were significantly greater with administration of the drug than without. CONCLUSIONS: The biodisposition of nizatidine in children and adults is similar; however, response after a comparable weight-based dose is equal and potentially greater in children.     

Patients' understanding of cardiac risk factors: a point-prevalence study

A 1-day point-prevalence study was conducted in our 141-bed tertiary cardiac care hospital in order to determine our patients' and their significant others' level of understanding of cardiac risk factors in general and of the patients' personal cardiac risk factors. There were 3 parts to the study: patient interviews, significant other (SO) interviews, and an audit of the participating patients' charts. Of the 87 patients who were able to participate, 71 completed the interviews as did 53 significant others. From recall, only 14 patients and 11 significant others were able to define what a cardiac risk factor was ("Habits or factors that contribute to heart disease") and they were unable to identify many general risk factors. However, when given a recognition task where cardiac risk factors were interspersed with sham factors, the overall mean general knowledge score was 13.6 for patients and 13.9 for significant others out of 16. The correlation between the patients' understanding of their cardiac risk factors and the significant others' understanding of them was reasonably good (r = 0.58, P < .0001), as was the correlation between the SOs' understanding and the charts (r = 0.58, P < .0001). There was less agreement between the patients' understanding and the chart documentation of cardiac risk factors (r = 0.36, P < .01). The findings of this study have implications for patient teaching as well as for documentation of cardiac risk factors.     

Oral vitamin C reduces the injury to skeletal muscle caused by compartment syndrome

Compartment syndrome is a unique form of ischaemia of skeletal muscle which occurs despite patency of the large vessels. Decompression allows the influx of activated leucocytes which cause further injury. Vitamin C is a powerful antioxidant which concentrates preferentially in leucocytes and attenuates reperfusion-induced muscle injury. We have evaluated the use of pretreatment with oral vitamin C in the prevention of injury caused by compartment syndrome in a rat cremasteric muscle model. Acute and delayed effects of pretreatment with vitamin C were assessed at one and 24 hours after decompression of compartment syndrome. Muscle function was assessed electrophysiologically. Vascular, cellular and tissue inflammation was assessed by staining of intercellular adhesion molecule-1 (ICAM-1) and by determination of the activity of myeloperoxidase (MPO) in neutrophils and tissue oedema. Compartment syndrome impaired skeletal muscle function and increased the expression of ICAM-1, activity of MPO and muscle weight increased significantly. Pretreatment with vitamin C preserved muscle function and reduced the expression of ICAM-1, infiltration of the neutrophils and oedema.