Ellen B. Fung

Feeding Dysfunction is Associated with Poor Growth and Health Status in Children with Cerebral Palsy

OBJECTIVE To describe parent-reported feeding dysfunction and its association with health and nutritional status in children with cerebral palsy. DESIGN Anthropometry was measured and z scores calculated. The Child Health Questionnaire was used to assess health status, and a categorical scale (none to severe) was used to classify subjects according to severity of feeding dysfunction. SUBJECTS 230 children (9.7+/-4.6 years; 59% boys) with moderate to severe cerebral palsy were recruited from 6 centers in the United States and Canada. STATISTICAL ANALYSES Descriptive statistics, the Kruskal-Wallis and Pearson chi2 tests. RESULTS Severity of feeding dysfunction was strongly associated with indicators of poor health and nutritional status. The mean weight z scores were -1.7, -2.5, -3.3, and -1.8 among children with none, mild, moderate, or severe (largely tube-fed) feeding dysfunction, respectively (P= .003). Similar results were observed for height z score (P=.008), triceps z score (P=.03), and poor Global Health score (part of the Child Health Questionnaire) (P<.001). Subjects who were tube fed were taller (P=.014) and had greater body fat stores (triceps z score, P=.001) than orally fed subjects with similar motor impairment. For subjects exclusively fed by mouth, a dose-response relationship was observed between feeding dysfunction severity and poor nutritional status. Subjects with only mild feeding dysfunction had reduced triceps z score (-0.9) compared with those with no feeding problems (-0.3). CONCLUSION For children with moderate to severe cerebral palsy, feeding dysfunction is a common problem associated with poor health and nutritional status. Even children with only mild feeding dysfunction, requiring chopped or mashed foods, may be at risk for poor nutritional status. Parental report of feeding dysfunction with a structured questionnaire may be useful in screening children for nutritional risk.

A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

Deferasirox is a once‐daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open‐label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non‐progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose‐dependent LIC reductions were observed with deferasirox and deferoxamine. Once‐daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.

Oxidative stress and inflammation in iron‐overloaded patients with β‐thalassaemia or sickle cell disease

Blood transfusion therapy is life‐saving for patients with β‐thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1·8‐fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0·001) and specific diagnosis (P = 0·019). A significant 2‐fold elevation of non‐transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2·2‐fold elevation of the inflammatory marker interleukin (IL)‐6 relative to controls, and a 3·6‐ and 1·7‐fold increase in IL‐5 and IL‐10 relative to thalassaemia. Although α‐tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, γ‐tocopherol, a nitric oxide‐selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and γ‐tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.

Health status of children with moderate to severe cerebral palsy

The aim of the study was to evaluate the health of children with cerebral palsy (CP) using a global assessment of quality of life, condition-specific measures, and assessments of health care use. A multicenter population-based cross-sectional survey of 235 children, aged 2 to 18 years, with moderate to severe impairment, was carried out using Gross Motor Function Classification System (GMFCS) levels III (n = 56), IV (n = 55), and V (n = 122). This study group scored significantly below the mean on the Child Health Questionnaire (CHQ) for Pain, General Health, Physical Functioning, and Impact on Parents. These children used more medications than children without CP from a national sample. Fifty-nine children used feeding tubes. Children in GMFCS level V who used a feeding tube had the lowest estimate of mental age, required the most health care resources, used the most medications, had the most respiratory problems, and had the lowest Global Health scores. Children with the most severe motor disability who have feeding tubes are an especially frail group who require numerous health-related resources and treatments. Also, there is a relationship among measures of health status such as the CHQ, functional abilities, use of resources, and mental age, but each appears to measure different aspects of health and well-being and should be used in combination to reflect childrens overall health status.

Growth and Health in Children With Moderate-to-Severe Cerebral Palsy

BACKGROUND. Children with cerebral palsy frequently grow poorly. The purpose of this study was to describe observed growth patterns and their relationship to health and social participation in a representative sample of children with moderate-severe cerebral palsy. METHODS. In a 6-site, multicentered, region-based cross-sectional study, multiple sources were used to identify children with moderate or severe cerebral palsy. There were 273 children enrolled, 58% male, 71% white, with Gross Motor Function Classification System levels III (22%), IV (25%), or V (53%). Anthropometric measures included: weight, knee height, upper arm length, midupper arm muscle area, triceps skinfold, and subscapular skinfold. Intraobserver and interobserver reliability was established. Health care use (days in bed, days in hospital, and visits to doctor or emergency department) and social participation (days missed of school or of usual activities for child and family) over the preceding 4 weeks were measured by questionnaire. Growth curves were developed and z scores calculated for each of the 6 measures. Cluster analysis methodology was then used to create 3 distinct groups of subjects based on average z scores across the 6 measures chosen to provide an overview of growth. RESULTS. Gender-specific growth curves with 10th, 25th, 50th, 75th, and 90th percentiles for each of the 6 measurements were created. Cluster analyses identified 3 clusters of subjects based on their average z scores for these measures. The subjects with the best growth had fewest days of health care use and fewest days of social participation missed, and the subjects with the worst growth had the most days of health care use and most days of participation missed. CONCLUSIONS. Growth patterns in children with cerebral palsy were associated with their overall health and social participation. The role of these cerebral palsy-specific growth curves in clinical decision-making will require further study.

Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem

Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X‐ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty‐one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z‐scores < −2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty‐six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.

The effect of vitamins C and E on biomarkers of oxidative stress depends on baseline level

Oxidative stress is elevated in obesity, and may be a major mechanism for obesity-related diseases. Nonsmokers (n=396) were randomized to 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Treatment effect was examined in multiple regression analyses using an intention-to-treat approach. Vitamin C (P=0.001) and vitamin E (P=0.043) reduced plasma F2-isoprostanes. In the overall sample, changes from baseline were +6.8, -10.6, and -3.9% for placebo, vitamin C, and vitamin E groups, respectively. However, a significant interaction with baseline F2-isoprostane was found. When baseline F2-isoprostane was >50 microg/mL, vitamin C reduced F2-isoprostane by 22% (P=0.01). Vitamin E reduced it by 9.8% (P=0.46). Below that cut point, neither treatment produced further reductions. F2-isoprostane>50 microg/mL was strongly associated with obesity, and was present in 42% of the sample. Change in malondialdehyde concentration was minimal. These findings suggest a role for vitamin C in reducing lipid peroxidation. Future research on effects of vitamins C or E on plasma F2-isoprostane should limit participants to those with baseline levels >50 mug/mL. Further studies are needed to establish whether treatment with vitamins C or E in persons with concentrations above that cut point could slow the development of cardiovascular disease.

Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America.

This study aimed to determine differences in the rates of growth, endocrine‐ and calcium‐related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23·2 years (range 6·1–75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = −0·73 ± 1·24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under‐treated. 12·8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

Vitamin C treatment reduces elevated C-reactive protein

Plasma C-reactive protein (CRP) is an inflammatory biomarker that predicts cardiovascular disease. Lowering elevated CRP with statins has reduced the incidence of cardiovascular disease. We investigated whether vitamin C or E could reduce CRP. Healthy nonsmokers (N=396) were randomized to three groups, 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Median baseline CRP was low, 0.85 mg/L. No treatment effect was seen when all participants were included. However, a significant interaction was found, indicating that treatment effect depends on baseline CRP concentration. Among participants with CRP indicative of elevated cardiovascular risk (> or =1.0 mg/L), vitamin C reduced the median CRP by 25.3% vs placebo (p=0.02) (median reduction in the vitamin C group, 0.25 mg/L, 16.7%). These effects are similar to those of statins. The vitamin E effect was not significant. In summary, treatment with vitamin C but not vitamin E significantly reduced CRP among individuals with CRP > or =1.0 mg/L. Among the obese, 75% had CRP > or =1.0 mg/L. Research is needed to determine whether reducing this inflammatory biomarker with vitamin C could reduce diseases associated with obesity. But research on clinical benefits of antioxidants should limit participants to persons with elevations in the target biomarkers.

Bone mineral density in children with sickle cell anemia.

We evaluated bone mineral density (BMD) and risk factors for poor bone mineralization in children with sickle cell anemia (SCA).