Tissue collection for correlative studies in childhood cancer clinical trials: ethical considerations and special imperatives.

Federal regulations prescribe distinct protections for children participating in research studies. Procedures for collecting tissue specimens from children solely for research purposes must pose no more than a minor increase over minimum risk, thereby limiting the approvable correlative biologic studies to evaluate molecularly targeted agents in children with cancer. Ethical issues arise when approvable correlative studies are a mandatory component of an early-phase pediatric clinical trial of new anticancer agents. The National Cancer Institute Cancer Therapy Evaluation Program sponsored a workshop in 2002 to discuss tissue collection for correlative biologic studies in early-phase childhood cancer clinical studies of molecularly targeted agents. Workshop participants recommended the following: (1) tissue specimens for correlative studies should provide vital clinical and scientific results to qualify for early-phase pediatric study consideration; (2) parents should receive a realistic appraisal of the risks, requirements, and potential for benefit of phase I protocol participation; (3) investigators should clearly distinguish clinically necessary procedures from research procedures of no benefit to the child to improve correlative study informed consent; and (4) participation in correlative research studies included in clinical trials generally should be voluntary. The need to acquire important biologic data regarding new molecular agents will challenge the ingenuity of pediatric cancer researchers, necessitating the application of highly sensitive laboratory assay methods, new imaging procedures, and preclinical models of childhood cancer. Such innovative methods can allow necessary scientific information to be obtained while simultaneously respecting the protections appropriately afforded to children participating in research studies and minimizing the burden of research participation for children with cancer and their families.     

How are health professionals earning their living in Malawi?

Background  

The migration of health professionals from southern Africa to developed nations is negatively affecting the delivery of health care services in the source countries. Oftentimes however, it is the reasons for the out-migration that have been described in the literature. The work and domestic situations of those health professionals continuing to serve in their posts have not been adequately studied.     

Noncortical origins of the spinal motor evoked potential in rats

Motor evoked potentials (MEPs) were recorded from the spinal cord, sciatic nerve, or both during transcortical electrical stimulation in the rat. Four peaks could be consistently identified in the spinal MEP. The latency and amplitude of the peaks varied differentially with intensity and polarity of stimulation. Conduction velocity for Peak 1 of the MEP was 43 m/sec. Bilateral sciatic nerve MEPs were present after unilateral cortical stimulation. The spinal MEP was elicited by stimulation of areas outside the motor cortex, and the response persisted during subcortical stimulation and after motor cortex ablation. We present evidence suggesting that components of the spinal MEP in rats arise from pathways outside the motor cortex.     

Cardiac damage induced by 2-amino-3-methyl-imidazo[4,5-f]quinoline in nonhuman primates.

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus and rhesus monkeys. The finding of high cardiac IQ-DNA adduct levels prompted a histopathological study of perfusion-fixed hearts from 10 tumor-bearing monkeys chronically dosed with IQ at 10 mg/kg or 20 mg/kg 5 days per week for 48-80 months. Two monkeys dosed only with the vehicle for IQ, hydroxypropylcellulose, served as controls. All the monkeys had normal heart weights, and no abnormalities were observed upon gross inspection of the hearts. Microscopically, focal myocardial lesions were observed in 8 of 10 monkeys dosed with IQ. Light microscopic abnormalities included myocyte necrosis with or without chronic inflammatory infiltrates, interstitial fibrosis with myocyte hypertrophy or atrophy, and vasculitis. Electron microscopic findings included disruption of the mitochondrial architecture (i.e., mitochondrial swelling and clearing of matrix densities), myofibrillar loss, disorganization of the normal alignment of sarcomeres, and occasional myocytes showing nuclear hypertrophy or peripheral clumping of the nuclear chromatin. There was some correlation between the cumulative dose of IQ and the extent of the myocardial abnormalities. These findings suggest that chronic exposure to IQ can lead to myocardial damage in monkeys. Although focal and not associated with clinical evidence of heart failure, these abnormalities may represent the initial stages of IQ-induced toxic cardiomyopathy.     

Otoplasty: an update

Otoplasty is a common cosmetic surgical procedure. Various techniques have been described through the years, many of these addressing only specific aspects of the deformity rather than overall correction of the multiple defects that often occur. To achieve optimal results, an understanding of the embryology of the external ear and an appreciation of the development of otoplasty techniques are useful. Current surgical concepts are emphasized and the authors' graduated approach to otoplasty is presented. Thirty-five cases over a four-year period are reviewed. All achieved a satisfactory cosmetic result; there were 5 complications, 3 being due to Mustarde suture pull-away. Two of these required revision, and revision was also required in another patient who developed a hypertrophic scar. The remaining complication was a minor suture granuloma.     

Of sleep state and postnatal age on arousal responses induced by mild hypoxia in infants

STUDY OBJECTIVES: It has been suggested that mild hypoxia may not be a potent stimulus for arousal during sleep in infants because infants frequently fail to arouse from quiet sleep (QS). Our aim was to characterize arousal responses of sleeping infants in both active sleep (AS) and QS under normoxic and mildly hypoxic (15% O2) conditions over the first 6 months of life. PARTICIPANTS: Five healthy term and 6 healthy preterm infants were each studied at 2 to 5 weeks, 2 to 3 months, and 5 to 6 months postterm. All infants underwent daytime polysomnography during which nasal airflow was monitored using a purpose-built pneumotachograph. All infants were studied under both normoxic (21% O2) and hypoxic (15% O2, balance N2) conditions (presentation order randomized) in each sleep state at each study age. Tests were terminated at arousal, O2 saturation falling below 85%, or 5 minutes (failure to arouse). MEASUREMENTS: Probability of failure to arouse and mean arousal latency were compared between each experimental condition, with each infant serving as its own control. RESULTS: Infants aroused more frequently under hypoxic conditions than under normoxic conditions. Overall, arousal latencies were shorter during hypoxia compared to normoxia in both sleep states at each age. Arousal latencies were longer in QS compared to AS in both hypoxic and normoxic conditions. CONCLUSION: In sleeping infants, mild hypoxia serves as a stimulus for arousal in both AS and QS. Of particular significance is our finding that arousal from AS is readily elicited by mild hypoxia.     

Role of polymorphonuclear leukocytes in silica-induced pulmonary fibrosis.

Silicosis is usually attributed to fibroblast stimulation by secretion of damaged alveolar macrophages (AMs), but the role of polymorphonuclear leukocytes (PMNs) and of continuing cell injury in the pathogenesis has not been fully studied. Mice given intratracheal injections of 2 mg of silica received 3H-thymidine 1 hour before death at intervals to 20 weeks. Cellular populations and lysosomal content of lavage fluids were correlated with morphology, DNA synthesis, and collagen content of the lung. The initial response involved rapid PMN and AM recruitment to the alveoli. Some free particles crossed Type 1 epithelial cells, and silica was found in interstitial macrophages. Focal Type 1 cell damage was rapidly repaired by Type 2 cell proliferation. Although PMN numbers dropped after a few days, they never reached control levels and rose again after 8 weeks; the number of AMs fell to control values from 2 to 8 weeks, then increased again. Glucosaminidase and glucuronidase levels in the lavage fluid were much higher than control levels throughout the study. Increased DNA synthesis by interstitial cells occurred from 2 days to 20 weeks; increased collagen synthesis was found from 4 weeks onward. The continuing inflammatory response of the lung to silica suggests may contribute to fibroblastic stimulation.     

Long-term preservation of cortically dependent visual function in RCS rats by transplantation.

Cell transplantation is one way of limiting the progress of retinal degeneration in animal models of blinding diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Here we transplanted a human retinal pigment epithelial (RPE) cell line into the subretinal space of one such model, the Royal College of Surgeons (RCS) rat, and showed, using head tracking to moving stripes and pattern discrimination in conjunction with single-unit cortical physiology, that cortically mediated vision can be preserved with this treatment.