Self-image, adolescence, and disability.

The purpose of the present study was to examine the self-image of a group of young persons with cerebral palsy. The respondents (3 girls and 4 boys, ages 12 to 17 years) were interviewed and asked to complete a personality inventory. The results from the personality inventory revealed that the respondents viewed themselves in a very positive manner and rated markedly higher than norm groups. This positive view corresponded well with the findings of the interview. The following conclusions are made: Further studies on self-image and the psychosocial development of adolescents with disabilities should (a) focus on the social interaction outside their immediate families, and (b) continue to use and develop methods where these adolescents can give voice to their own experiences and opinions.     

Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.     

Fetal lung growth in laryngeal atresia and tracheal agenesis

Three cases of airway obstruction in fetuses born at 21, 32 and 40 weeks gestation are reported. The first had laryngeal atresia, cystic dysplastic kidneys, oligohydramnios and immense fluid-filled lungs. The second had upper tracheal agenesis, a tracheo-oesophageal fistula, a cystic dysplastic horseshoe kidney, oligohydramnios and normal-sized lungs. The third had a pin-hole mucosal tract through an otherwise atretic larynx, normal kidneys, no oligohydramnios and normal-sized lungs. Lung weight:body weight ratios, radial alveolar or radial canalicular counts and point-counting of sections of lungs in cases 1 and 2 show that laryngeal or tracheal obstruction may prevent or reduce the pulmonary hypoplasia associated with renal dysplasia, and in cases 2 and 3, that grossly enlarged, hyperplastic lungs may not be seen unless obstruction is complete.     

Functional and structural characteristics of the glycosaminoglycans of the bladder luminal surface

The glycosaminoglycan layer of bladder has been proposed to play a crucial role in protecting the bladder from harmful substances in urine. Rats were partially cystectomized to determine whether bladder glycosaminoglycans are routinely eluted from the bladder surface in detectable quantities. Cystectomy produced no detectable qualitative or quantitative changes in excreted GAG thereby showing that most urinary glycosaminoglycan originates in the kidney and not from the bladder. Damaging the glycosaminoglycan layer by a dilute acid wash, however, leads to a consistent decrease in the output of urinary GAG which recovers to normal at the same rate as the layer regenerates. This suggests that the newly exposed sites tightly bind urinary GAG. We suggest that such binding may be a component of the normal physiological defense mechanism of the bladder. The bladder glycosaminoglycan layer was isolated, dilute acid being used to elute ionically-bound material and brief trypsinization to elute intercalated proteoglycans from the luminal surface. The GAG from the luminal surface, which was present at a density of one chain per 50 nm.2 of bladder surface, was quite different in composition from that isolated from the whole bladder.     

Recombinant erythropoietin improves exercise capacity in anemic hemodialysis patients

The objective of this study was to quantitate the improvement in exercise capacity produced in anemic chronic hemodialysis (HD) patients after correction of their anemia with recombinant human erythropoietin (rHuEPO). The maximal exercise capacity and quadriceps strength of 19 anemic HD patients was tested before and after correction of the anemia with rHuEPO. A progressive work exercise protocol (PWET) on a cycle ergometer was used to compare measurements of maximal oxygen uptake (VO2max), maximal heart rate, and subjective assessment of fatigue during the test. Measurements of quadriceps strength were performed before the cycle ergometer studies. At baseline, all patients had reduced VO2max (15.3 +/- 5.4 mL/kg/min) and maximal exercise heart rates (138.5 +/- 23.9 beats/min). rHuEPO increased the mean hematocrit from 21.2% to 35%, and this was associated with a 17% increase (P less than 0.0005) in the VO2max. At any specified work load, rHuEPO treatment decreased heart rate, minute ventilation, and the subjective perception of fatigue. Both isometric and isokinetic measurements of quadriceps strength were improved following administration of rHuEPO. The maximal exercise heart rate was decreased in comparison to the baseline measurements (P less than 0.04), suggesting that in contrast to normal subjects, HD patients stop exercise before oxygen transport limitations are reached. In this unselected group of chronic HD patients, rHuEPO produced clinically significant improvements in both aerobic exercise capacity and isometric and isokinetic quadriceps strength. The improvement in aerobic capacity was substantially less than would have been expected from the correction of a comparable degree of anemia in non-HD patients. None of the 19 treated patients attained the exercise performance level predicted for a sedentary normal subject.     

A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects.

The erythropoietic response to graded doses of recombinant human erythropoietin (epoetin alfa) was assessed in 24 hemodialysis patients by quantitative ferrokinetic studies, and measurement of the reticulocyte count and plasma levels of transferrin receptor protein. These responses were compared to those of 22 normal subjects. Epoetin alfa was given intravenously at 15, 50 or 150 U/kg every other day for four injections. Three patients with chronic renal failure were restudied after renal function was restored following renal transplantation. The results of these three different measurements of erythroid function showed that the acute response to recombinant human erythropoietin was similar in normal subjects and patients with renal failure. We conclude that chronic uremia does not alter the responsiveness to erythropoietin in vivo.     

Dendrotoxin-sensitive K+ currents contribute to accommodation in murine spiral ganglion neurons

We have previously identified two broad electrophysiological classes of spiral ganglion neuron that differ in their rate of accommodation ( Mo & Davis, 1997 a ). In order to understand the underlying ionic basis of these characteristic firing patterns, we used α-dendrotoxin (α-DTX) to eliminate the contribution of a class of voltage-gated K⁺ channels and assessed its effects on a variety of electrophysiological properties by using the whole-cell configuration of the patch-clamp technique. Exposure to α-DTX caused neurons that initially displayed rapid accommodation to fire continuously during 240 ms depolarizing test pulses within a restricted voltage range. We found a non-monotonic relationship between number of action potentials fired and membrane potential in the presence of α-DTX that peaked at voltages between –40 to –10 mV and declined at more depolarized and hyperpolarized test potentials. The α-DTX-sensitive current had two components that activated in different voltage ranges. Analysis of recordings made from acutely isolated neurons gave estimated half-maximal activation voltages of –63 and 12 mV for the two components. Because α-DTX blocks the Kv1.1, Kv1.2 and Kv1.6 subunits, we examined the action of the Kv1.1-selective blocker dendrotoxin K (DTX-K). We found that this antagonist reproduced the effects of α-DTX on neuronal firing, and that the DTX-K-sensitive current also had two separate components. These data suggest that the transformation from a rapidly adapting to a slowly adapting firing pattern was mediated by the low voltage-activated component of DTX-sensitive current with a potential contribution from the high voltage-activated component at more depolarized potentials. In addition, the effects of DTX-K indicate that Kv1.1 subunits are important constituents of the underlying voltage-gated potassium channels.     

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.