Phase I study of temozolomide and irinotecan for recurrent malignant gliomas in patients receiving enzyme-inducing antiepileptic drugs: a north american brain tumor consortium study.

PURPOSE: To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38. DESIGN: Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m(2)) daily for 5 days from days 1 to 5 every 28 days, and an i.v. infusion of irinotecan on days 1 and 15 of each cycle. The starting dose of irinotecan was 350 mg/m(2), which was escalated to 550 mg/m(2) in 50-mg/m(2) increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1. RESULTS: Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m(2). CONCLUSIONS: The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m(2), administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan.     

Seafood processing in South Africa: a study of working practices, occupational health services and allergic health problems in the industry

The work practices, occupational health services and allergic health problems among workplaces which process seafood in Western Cape province of South Africa were examined. A cross-sectional study was conducted among 68 workplaces that were sent a self-administered postal survey questionnaire. Workplaces reporting a high prevalence of work-related symptoms associated with seafood exposure were also inspected. Forty-one (60%) workplaces responded to the questionnaire. The workforce consisted mainly of women (62%) and 31% were seasonal workers. Common seafoods processed were bony fish (76%) and rock lobster (34%). Major work processes involved freezing (71%), cutting (63%) and degutting (58%). Only 45% of workplaces provided an on-site occupational health service and 58% of workplaces conducted medical surveillance. Positive trends were observed between workplace size and activities such as occupational health service provision (P = 0.002), medical surveillance programmes (P = 0.055) and reporting work-related symptoms (P = 0.016). None of the workplaces had industrial hygiene surveillance programmes to evaluate the effects of exposure to seafood. Common work-related symptoms included skin rashes (78%), asthma (7%) and other non-specific allergies (15%). The annual prevalence of work-related skin symptoms reported per workplace was substantially higher for skin (0-100%) than for asthmatic (0-5%) symptoms. The relatively low prevalence of employer-reported asthmatic symptoms, when compared to epidemiological studies using direct investigator assessment of individual health status, suggests likely under-detection. This can be attributed to under-provision and under-development of occupational health surveillance programmes in workplaces with less than 200 workers. This is compounded further by the lack of specific statutory guidelines for the evaluation and control of bio-aerosols in South African workplaces.     

“Marden-Walker Syndrome”: Neuropathologic Findings in Two Siblings

Neuropathologic examination of two siblings with phenotypic features consistent with Marden-Walker syndrome revealed central nervous system abnormalities which include reduction in the number of spinal anterior horn cells. The occurrence of these changes in a sibling pair provides strong evidence for a genetic etiology. The relationship between the neuropathologic changes and other phenotypic manifestations in this syndrome and in the closely related syndrome of Pena-Shokeir are discussed.     

Assessment of personal and community-level exposures to particulate matter among children with asthma in Detroit, Michigan, as part of Community Action Against Asthma (CAAA)

We report on the research conducted by the Community Action Against Asthma (CAAA) in Detroit, Michigan, to evaluate personal and community-level exposures to particulate matter (PM) among children with asthma living in an urban environment. CAAA is a community-based participatory research collaboration among academia, health agencies, and community-based organizations. CAAA investigates the effects of environmental exposures on the residents of Detroit through a participatory process that engages participants from the affected communities in all aspects of the design and conduct of the research; disseminates the results to all parties involved; and uses the research results to design, in collaboration with all partners, interventions to reduce the identified environmental exposures. The CAAA PM exposure assessment includes four seasonal measurement campaigns each year that are conducted for a 2-week duration each season. In each seasonal measurement period, daily ambient measurements of PM2.5 and PM10 (particulate matter with a mass median aerodynamic diameter less than 2.5 microm and 10 microm, respectively) are collected at two elementary schools in the eastside and southwest communities of Detroit. Concurrently, indoor measurements of PM2.5 and PM10 are made at the schools as well as inside the homes of a subset of 20 children with asthma. Daily personal exposure measurements of PM10 are also collected for these 20 children with asthma. Results from the first five seasonal assessment periods reveal that mean personal PM10 (68.4 39.2 microg/m(3)) and indoor home PM10 (52.2 30.6 microg/m(3)) exposures are significantly greater (p < 0.05) than the outdoor PM10 concentrations (25.8 11.8 microg/m(3)). The same was also found for PM2.5 (indoor PM2.5 = 34.4 21.7 microg/m(3); outdoor PM2.5 = 15.6 8.2 microg/m(3)). In addition, significant differences (p < 0.05) in community-level exposure to both PM10 and PM2.5 are observed between the two Detroit communities (southwest PM10 = 28.9 14.4 microg/m(3)), PM2.5 = 17.0 9.3 microg/m(3); eastside PM10 = 23.8 12.1 microg/m(3), PM2.5 = 15.5 9.0 microg/m(3). The increased levels in the southwest Detroit community are likely due to the proximity to heavy industrial pollutant point sources and interstate motorways. Trace element characterization of filter samples collected over the 2-year period will allow a more complete assessment of the PM components. When combined with other project measures, including concurrent seasonal twice-daily peak expiratory flow and forced expiratory volume at 1 sec and daily asthma symptom and medication dairies for 300 children with asthma living in the two Detroit communities, these data will allow not only investigations into the sources of PM in the Detroit airshed with regard to PM exposure assessment but also the role of air pollutants in exacerbation of childhood asthma.     

Antitumor polycyclic acridines. Part 12. Physical and biological properties of 8,13-diethyl-6-methylquino[4,3,2-kl]acridinium iodide: a lead compound in anticancer drug design

The biophysical and biological characterization of 8,13-diethyl-6-methylquino[4,3,2-k]lacridinium iodide (6) is reported. The compound binds to DNA, as measured by UV, fluorescence, and circular dichroism studies, and stabilizes the double helix and higher order DNA structures (DNA triplexes and quadruplexes) against thermal denaturation. Unlike many DNA ligands, (6) shows no specificity for binding to specific base pair combinations and does not inhibit topoisomerase I (topo I) or topo II activity. Furthermore, the biological fingerprint elicited by (6) in in vitro evaluations does not compare with clinical agents of the topo II inhibition class. The compound provokes cell cycle arrest in response to DNA damage and the biological sequelae are dependent on the p53 status of the cell line. DNA damage by (6) upregulates p53 and p21(CIP/WAF1) proteins. The unusual structure of (6) and its ease of synthesis in a "one-pot" reaction are features that are being exploited in the design and development of a new series of G-quadruplex stabilizing telomerase inhibitors. However, although the second-generation compounds that resulted from (6) present strong telomerase inhibition, (6) in itself presents yet a different mode of action, with a strong preference for triplex DNA, sequences often found in a number of genes.     

Treatment of lipid disorders after stroke

The efficacy of lipid disorder therapy for the primary and secondary prevention of coronary heart disease is established. There are, however, no completed studies specifically directed at reducing the risk of stroke with lipid therapy. Although observational cohort studies have failed to demonstrate an association between lipid disorders and stroke incidence, recently completed trials of subjects at risk for coronary heart disease have shown that statins and fibric acid derivatives reduce not only the risk of myocardial infarction and death, but also that of brain infarction and transient ischemic attacks. Lipid drugs are well tolerated and treatment complications are relatively low. It seems prudent to conclude that the stroke patient with an undesirable lipid profile who has a history of coronary heart disease should receive specific treatment for the lipid disorder. Recommendations are more problematic for stroke patients with lipid disorders but no history of coronary heart disease; most should receive therapy for primary prevention of heart disease. Lipid treatment trials focused on stroke risk reduction are urgently needed.     

Anesthetic management of acquired tracheoesophageal fistula: a brief report

IMPLICATIONS: Tracheoesophageal fistula may be either a congenital lesion or an acquired condition, most often resulting from foreign body ingestion. Location of the lesion has implications for anesthetic management and single lung ventilation may be required to facilitate surgical repair. In pediatric patients, intentional mainstem intubation may be required.     

Caudal epidural blood patch for treating intractable vomiting in a child after placement of a permanent intrathecal catheter

Postdural puncture cerebral spinal fluid (CSF) leak most often manifests as a postdural puncture headache (PDPH). The reported frequency in young children varies (1-4). Persistent CSF leak may also be present without PDPH. We present a case of postoperative nausea and vomiting resulting from a presumed lumbar CSF leak in a nonverbal child after surgical placement of a permanent intrathecal catheter. Treatment with an epidural blood patch (EBP) via the caudal approach resulted in complete relief of symptoms.