Negative expiratory pressure: A new tool for evaluating lung function in children?

The negative expiratory pressure technique (NEP) has been applied in adults with chronic obstructive pulmonary disease (COPD), demonstrating flow limitation in many of these patients. Because this technique does not require patient cooperation, it is of potential interest for application in the pediatric population. This study was performed to test the feasibility of NEP in children, and to further investigate it in children with asthma and cystic fibrosis (CF). We performed NEP (0.3-0.7 kPa) measurements in 14 healthy children (13.3 years, +/- 2.4), in 12 children with asthma (11.7 years, +/- 3.0), and in 17 children with CF (13.3 years, +/- 2.7). NEP-derived flow-volume loops were visually analyzed for flow limitation at tidal breathing. In addition, expiratory flow at 50% of tidal volume (TEF(50)) was measured. In healthy children, the intraclass coefficient of correlation was 77%, and intraindividual short- and long-term variability was 5.8% and 10.8%, respectively. In asthmatics, TEF(50) was lower compared with controls, and increased after inhalation of salbutamol. However, appropriate size-correction has still to be established. Measurement of TEF(50) using NEP is feasible in children. Despite good reproducibility in individual patients, the high intersubject variability may limit its usefulness as a clinical tool. In addition, the lack of flow limitation using NEP even in severely obstructed patients with CF warrants further investigation.     

Phase I clinical trial on adjuvant active immunotherapy of human gliomas with GD2-conjugate

The objective of this study was to determine the feasibility, toxicity, and potential therapeutic benefits of an adjuvant active immunotherapy using a tumour specific ganglioside (GD2) conjugate for the adjuvant treatment of recurrent or progressive gliomas. Seven patients with proven GD2 expression in surgical specimens underwent a vaccination course with GD2-KLH/MPL-A conjugate. The follow-up was performed according to WHO guidelines regarding common toxicity criteria. Antibody titres against the ganglioside and the adjuvants were analysed. All patients developed a local type 4 reaction. Anti-GD2-antibody titres could not be detected, despite high titres against the immunoadjuvants. No tumour regression was observed. The disease remained stable for a median of 21.5 weeks (6-34 weeks). The median survival time after the first immunization was 47 weeks. The medial total survival time was 76 weeks. Adverse effects have not been observed. Active GD2-KLH/MPL-A immunization was technically feasible, but did not elicit anti-GD2 antibody generation.     

Bilateral human fetal striatal transplantation in Huntington's disease

BACKGROUND: Transplanted striatal cells have been demonstrated to survive, grow, establish afferent and efferent connections, and improve behavioral signs in animal models of Huntington's disease (HD). OBJECTIVE: To evaluate feasibility and safety and to provide preliminary information regarding the efficacy of bilateral human fetal striatal transplantation in HD. METHODS: Seven symptomatic patients with genetically confirmed HD underwent bilateral stereotactic transplantation of two to eight fetal striata per side in two staged procedures. Tissue was dissected from the lateral half of the lateral ventricular eminence of donors 8 to 9 weeks postconception. Subjects received cyclosporine for 6 months. RESULTS: Three subjects developed subdural hemorrhages (SDHs) and two required surgical drainage. One subject died 18 months after surgery from probable cardiac arrhythmia secondary to severe atherosclerotic cardiac disease. Autopsy demonstrated clearly demarcated grafts of typical developing striatal morphology, with host-derived dopaminergic fibers extending into the grafts and no evidence of immune rejection. Other adverse events were generally mild and transient. Mean Unified HD Rating Scale (UHDRS) motor scores were 32.9 plus minus 6.2 at baseline and 29.7 plus minus 7.5 12 months after surgery (p = 0.24). Post-hoc analysis, excluding one subject who experienced cognitive and motor deterioration after the development of symptomatic bilateral SDHs, found that UHDRS motor scores were 33.8 plus minus 6.2 at baseline and 27.5 plus minus 5.2 at 12 months (p = 0.03). CONCLUSIONS: Transplantation of human fetal striatal cells is feasible and survival of transplanted cells was demonstrated. Patients with moderately advanced HD are at risk for SDH after transplantation surgery.     

Proton MR spectroscopic and diffusion tensor brain MR imaging in X-linked adrenoleukodystrophy: initial experience

PURPOSE: To compare conventional magnetic resonance (MR) imaging, proton MR spectroscopic imaging, and diffusion tensor (DT) MR imaging findings in patients with X chromosome-linked adrenoleukodystrophy (X-ALD). MATERIALS AND METHODS: Multisection proton MR spectroscopy and DT imaging were performed in 11 patients with X-ALD and in 11 healthy control subjects. Quantitative measures of N-acetylaspartate (NAA), choline, and creatine values and of isotropic apparent diffusion coefficient (IADC) and fractional anisotropy (FA) were obtained from coregistered regions of interest. DT imaging and metabolic parameters were compared by using regression analysis. In addition, differences in DT imaging and metabolite measurements between normal- and abnormal-appearing white matter on conventional MR images were evaluated by using a nonparametric (Mann-Whitney) test. RESULTS: A strong logarithmic relationship between NAA value and FA (r = 0.64, P <.001) and an inverse logarithmic relationship were found between NAA value and IADC (r = -0.69, P <.001). Creatine and choline values correlated poorly with IADC and FA. In the normal-appearing white matter of asymptomatic patients, the NAA value was 17% lower than that in the healthy control subjects (P =.016), whereas no significant difference in DT imaging measures was seen in these regions. CONCLUSION: In patients with X-ALD, MR spectroscopic imaging can depict abnormalities in white matter that have a normal appearance on both conventional MR and DT images; this finding suggests that it may be the most sensitive technique for detecting early abnormalities of demyelination or axonal loss in patients with X-ALD.     

Severe head trauma in children: cranial computer tomography and clinical consequences

BACKGROUND: We investigated the prognostic and therapeutic implications of cranial computerized tomography (CCT) examinations after severe head trauma in children. MATERIALS AND METHODS: The CCT scans from 248 children (aged 0.1-14 years) during the course of treatment after severe head trauma were assessed. The initial CCT findings, the frequency of CCT examinations and the schedule as well as duration of treatment were registered. The neurological outcome was examined both 1 month and 1 year after the trauma. RESULTS: Approximately one-third (29%) of the children who suffered from severe head trauma showed no changes in the CCT. Furthermore, 40.3% of the children showed a singular finding in the CCT, whereas 30.6% of all children had a combined injury pattern. One year after trauma, we found no impairment of consciousness in children without pathological CCT findings, as well as in cases with isolated epidural and subdural haemorrhage. Children with massive generalized brain oedema had the poorest prognosis (37% died, 25% had impairment of consciousness). The outcome of children with parenchymal and ventricular bleeding was also unfavourable (23.1% and 33.3% neurological findings). Patients with focal oedema likewise had impairment of consciousness. An average number of 3.0 CCT per child was performed but numbers in single cases varied greatly (1-13 scans per individual). CONCLUSIONS: The initial CCT was of importance regarding further therapy, especially for children in need of surgical treatment. In the other cases, there was no direct impact from CCT findings on treatment procedures in the paediatric intensive care unit. The initial CCT was related to the prognosis, which can be poor even if there are only minimal changes in CCT, such as focal oedema or isolated ventricular bleeding.     

Single and combination toxic metal exposures induce apoptosis in cultured murine podocytes exclusively via the extrinsic caspase 8 pathway.

Arsenite, cadmium, and mercury are among the most abundant toxic metals (TM) in the environment. Although the most common renal manifestation of TM toxicity is proximal tubular dysfunction, significant glomerular injury can also occur. We hypothesized that glomerular injury following TM exposure results from TM-induced apoptosis of podocytes. To test this hypothesis we examined the extent of apoptosis and the apoptotic pathways induced in cultured murine podocytes incubated for three days with arsenite, cadmium, or mercury, and with equimolar combinations of all three metals. Apoptosis was detected by DNA laddering, and the number of apoptotic nuclei determined by Tunel assay. Treatment for three days with each TM resulted in DNA laddering and induced a dose-dependent increase in apoptotic nuclei. In contrast, treatment with equimolar combinations of TM induced significantly fewer apoptotic nuclei than individual TM treatments. Apoptosis induced by each TM was associated with a significant (approximately 400%) increase in caspase 8 activity, but no change in caspase 9 activity, and Western analyses revealed a marked up-regulation of Fas (approximately 500%) and FADD (approximately 300%) with no change in expression of Bax, Bcl-2, or Bcl-xL. Similar to the apoptotic response, combinations of TM induced less caspase 8 activity and Fas/FADD expression than individual TM treatments. Collectively, these results demonstrate that (1) TM induced apoptosis in cultured murine podocytes via the extrinsic Fas-FADD caspase 8 pathway, rather than the mitochondrial apoptotic pathway, and (2) combination TM exposure induced less apoptosis than individual TM, indicating an antagonistic rather than an additive or synergistic toxicity.