Zinc and multivitamin supplementation have contrasting effects on infant iron status: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND/OBJECTIVES: Zinc (Zn) supplementation adversely affects iron status in animal and adult human studies, but few trials have included young infants. The objective of this study was to determine the effects of Zn and multivitamin (MV) supplementation on infant hematologic and iron status. SUBJECTS/METHODS: In a double-blind RCT, Tanzanian infants were randomized to daily, oral Zn, MV, Zn and MV or placebo treatment arms at the age of 6 weeks of life. Hemoglobin concentration (Hb) and red blood cell indices were measured at baseline and at 6, 12 and 18 months of age. Plasma samples from 589 infants were examined for iron deficiency (ID) at 6 months. RESULTS: In logistic regression models, Zn treatment was associated with greater odds of ID (odds ratio (OR) 1.8 (95% confidence interval (CI) 1.0-3.3)) and MV treatment was associated with lower odds (OR 0.49 (95% CI 0.3-0.9)). In Cox models, MV was associated with a 28% reduction in risk of severe anemia (hazard ratio (HR)=0.72 (95% CI 0.56-0.94)) and a 26% reduction in the risk of severe microcytic anemia (HR=0.74 (0.56-0.96)) through 18 months. No effects of Zn on risk of anemia were seen. Infants treated with MV alone had higher mean Hb (9.9 g/dl (95% CI 9.7-10.1)) than those given placebo (9.6 g/dl (9.4-9.8)) or Zn alone (9.6 g/dl (9.4-9.7)). CONCLUSIONS: MV treatment improved iron status in infancy, whereas Zn worsened iron status but without an associated increase in risk for anemia. Infants in long-term Zn supplementation programs at risk for ID may benefit from screening and/or the addition of a MV supplement.

Waist-to-Height Ratio as an Indicator of High Blood Pressure in Urban Indian School Children.

OBJECTIVE: To examine the utility of waist-to-height ratio to identify risk of high blood pressure when compared to body mass index and waist circumference in South Indian urban school children. DESIGN: Secondary data analysis from a cross-sectional study. SETTING: Urban schools around Bangalore, India. PARTICIPANTS: 1913 children (58.1% males) aged 6-16 years with no prior history of chronic illness (PEACH study). METHODS: Height, weight, waist circumference and of blood pressure were measured. Children with blood pressure ?90th percentile of age-, sex-, and height-adjusted standards were labelled as having high blood pressure. RESULTS: 13.9% had a high waist-to-height ratio, 15.1% were overweight /obese and 21.7% had high waist circumference. High obesity indicators were associated with an increased risk of high blood pressure. The adjusted risk ratios (95% CI) of high systolic blood pressure with waist-to-height ratio, body mass index and waist circumference were 2.48 (1.76, 3.47), 2.59 (1.66, 4.04) and 2.38 (1.74, 3.26), respectively. Similar results were seen with high diastolic blood pressure. CONCLUSION: Obesity indicators, especially waist-to-height ratio due to its ease of measurement, can be useful initial screening tools for risk of high blood pressure in urban Indian school children.

Association of oral iron supplementation with birth outcomes in non-anaemic South Indian pregnant women.

BACKGROUND/OBJECTIVES: Iron in high doses or when given to non-anaemic women may have adverse effects on pregnancy outcomes. This study aimed to estimate the supplemental iron intake in non-anaemic pregnant women attending an urban antenatal care setting in South India and examine the association of supplemental iron intake with birth outcomes. SUBJECTS/METHODS: A cohort of 1196 non-anaemic pregnant women was studied. Daily supplemental iron intake was calculated as total supplemental iron consumed (mg) during pregnancy divided by the total number of days the supplement was recommended. Association of tertiles of supplemental iron intake with term low birth weight (tLBW), preterm delivery and small for gestational age (SGA) was examined using log-binomial regression, adjusting for maternal age, height, body mass index at recruitment, parity, education and type of delivery. RESULTS: Mean haemoglobin in trimester 1 was 12.4 ± 0.9 g/dl and mean supplemental iron intake was 37.7 ± 4.0 mg/day. Women in the highest tertile (>39.2 mg/day) of supplemental iron intake had an increased risk of tLBW as compared with the lowest tertile (⩽ 36.6 mg/day) (adjusted risk ratio: 1.89; 95% confidence interval: 1.26, 2.83). Although supplemental iron intake was negatively correlated with gestational age (r=-0.20, P<0.001) and birth weight (r=-0.07, P=0.011), there was no association between preterm delivery or SGA and supplemental iron intake. CONCLUSIONS: It appears that iron supplementation in non-anaemic pregnant women may not be beneficial, as we have observed the adverse effects with a prescribed dose of 45 mg/day. This may warrant the consideration of an individualized approach for antenatal iron supplementation, especially in non-anaemic women.

Household food insecurity and dietary diversity as correlates of maternal and child undernutrition in rural Cambodia.

OBJECTIVES: To assess household food insecurity and dietary diversity as correlates of maternal and child anthropometric status and anemia in rural Cambodia. METHODS: Trained interviewers administered a survey to 900 households in four rural districts of Prey Veng, Cambodia. The Household Food Insecurity Access Scale (HFIAS) and Household Dietary Diversity Score (HDDS) were used to assess household food insecurity and dietary diversity. The height, weight and hemoglobin concentration of the mother and youngest child under 5 years in each household were measured. Multivariate logistic regression models were constructed to assess the association between household food insecurity and dietary diversity, and child stunting and wasting, maternal thinness, maternal and child anemia. RESULTS: The mean (s.d.) HFIAS and HDDS scores were 5.3 (3.9) and 4.7 (1.6), respectively. The respective prevalences of mild, moderate and severe food insecurity were 33, 37 and 12%. Maternal thinness, child stunting and child wasting were present in 14.6, 25.4 and 8.1% of respondents, respectively. The risk of maternal thinness, but not child stunting or wasting, increased as the severity of household food insecurity increased. Household food insecurity was also positively associated with maternal, but not child, anemia. Household dietary diversity status was not significantly associated with any of the outcomes we assessed. CONCLUSIONS: Efforts to improve household food security are important as a means of promoting maternal nutritional status; however, additional research is needed to better understand the role of other factors that are driving the burden of child undernutrition in Cambodia.

Predictors of stunting, wasting and underweight among Tanzanian children born to HIV-infected women.

BACKGROUND/OBJECTIVES: Children born to human immunodeficiency virus (HIV)-infected women are susceptible to undernutrition, but modifiable risk factors and the time course of the development of undernutrition have not been well characterized. The objective of this study was to identify maternal, socioeconomic and child characteristics that are associated with stunting, wasting and underweight among Tanzanian children born to HIV-infected mothers, followed from 6 weeks of age for 24 months. SUBJECTS/METHODS: Maternal and socioeconomic characteristics were recorded during pregnancy, data pertaining to the infant's birth were collected immediately after delivery, morbidity histories and anthropometric measurements were performed monthly. Multivariate Cox proportional hazards methods were used to assess the association between potential predictors and the time to first episode of stunting, wasting and underweight. RESULTS: A total of 2387 infants (54.0% male) were enrolled and followed for a median duration of 21.2 months. The respective prevalence of prematurity (<37 weeks) and low birth weight (<2500 g) was 15.2% and 7.0%; 11.3% of infants were HIV-positive at 6 weeks. Median time to first episode of stunting, wasting and underweight was 8.7, 7.2 and 7.0 months, respectively. Low maternal education, few household possessions, low infant birth weight, child HIV infection and male sex were all independent predictors of stunting, wasting and underweight. In addition, preterm infants were more likely to become wasted and underweight, whereas those with a low Apgar score at birth were more likely to become stunted. CONCLUSIONS: Interventions to improve maternal education and nutritional status, reduce mother-to-child transmission of HIV, and increase birth weight may lower the risk of undernutrition among children born to HIV-infected women.

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy.

OBJECTIVE: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). METHODS: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. RESULTS: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. CONCLUSIONS: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. METHODS: Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. RESULTS: Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003). CONCLUSIONS: Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.

Antioxidant status of young children: response to an antioxidant supplement.

OBJECTIVE: To study oxidative stress indicators in healthy young children and their response to a commercially available fruit- and vegetable-based antioxidant supplement. DESIGN: Healthy children were randomly assigned to a placebo and a supplement (commercial antioxidant supplement produced from dried fruit and vegetable extracts and fortified with antioxidants, resembling a gummy-type candy). The placebo and the supplement were taken in 2 doses per day for 21 days. SUBJECTS: Participants were 39 children (26 boys and 13 girls) aged 5 to 10 years. Research was conducted at Primary Children's Medical Center and the University of Utah, Salt Lake City. MAIN OUTCOME MEASURES: Breath and urine samples were collected on days 1 and 21 and assayed for breath pentane and urine 8-hydroxydeoxyguanosine, malondialdehyde, nitrites, and 8-isoprostane as noninvasive indicators of oxidative stress. Urine oxygen radical absorbance capacity was measured at days 1 and 21 as an indirect indicator of the antioxidant capacity of the body. Three-day food records were collected at the beginning and end of the study to measure intake of dietary fruit; vegetable; and antioxidant vitamins A, C, and E. STATISTICAL ANALYSIS: Descriptive statistics, repeated measures analysis of variance, paired t tests, and Pearson r correlations. RESULTS: Markers of oxidative stress were not significantly different between the placebo and supplement groups at day 1 or day 21. The oxidative stress indicators of the healthy children in this study appear to be similar to those of healthy adults and were not changed by antioxidant supplementation. The diet record analyses indicated that mean fruit and vegetable intakes (2.75 servings/day) were similar to the national average intake for children in the United States. APPLICATIONS/CONCLUSIONS: This research presents original information on the subject of oxidative stress in healthy children. The results of this study may be useful as reference baseline markers to use in conjunction with clinical dietary evaluations and for future research with healthy children and with children in disease states who are subject to elevated levels of oxidative stress.

Presynaptic congenital myasthenic syndrome due to quantal release deficiency.

OBJECTIVE: To provide clinical, electrophysiologic, and ultrastructural findings in three patients with a presynaptic congenital myasthenic syndrome (CMS). BACKGROUND: Familial infantile myasthenia and paucity of synaptic vesicles are the only two fully characterized CMS. We are describing here three patients with another form of presynaptic CMS characterized by deficiency of the action potential-dependent release without reduction of the spontaneous release of neurotransmitter from the nerve terminal. METHODS: The authors performed electromyography and anconeus muscle biopsies that included intracellular recordings and electron microscopy of the neuromuscular junction in three patients with presynaptic CMS. They also sequenced part of the P/Q-calcium alpha(1)-subunit gene (CACNA1A) and the acetylcholine receptor subunit (AChR) genes in these patients. RESULTS: In these patients there were additional neurologic findings including nystagmus and ataxia. In all three patients the end-plate potential quantal content (m) was markedly reduced but neither the amplitudes nor the frequencies of miniature end-plate potentials were diminished. Ultrastructurally, postsynaptic end-plate folds, nerve terminal size, and synaptic vesicle number were normal but double-membrane-bound sacs containing synaptic vesicles were present in the nerve terminal of all three patients. The screening of reported pathogenic mutations in the CACNA1A and a mutational analysis of AChR subunit genes were negative. CONCLUSION: This form of CMS appears to result only from a deficiency of the quantal release of neurotransmitter that may be due to an abnormal calcium mechanism or impaired endocytosis and recycling of synaptic vesicles.

Peripheral neuropathies of childhood.

This article has provided a brief overview of the most common inherited and acquired peripheral nerve diseases encountered in childhood. The diagnostic approach of peripheral neuropathies in children often relies on some combination of careful history taking, physical examination findings, a careful determination of family history, electrodiagnostic studies, molecular genetic studies, sural nerve biopsy, and occasionally metabolic laboratory studies. Although pediatric mononeuropathies may have different causes than those observed in adults, the clinical presentations, diagnostic evaluation, and management of mononeuropathies are frequently similar in adults and children. Encouraging progress is being made in the management of acute inflammatory demyelinating polyneuropathy (AIDP), which is the most common acquired neuropathy of childhood. Rapid advances in molecular genetics over the past decade have had a significant impact on our diagnostic approach to hereditary motor sensory neuropathy in particular. In the future it is likely that the sequencing of genes, characterization of protein structure and function, and further elucidation of pathophysiology will have significant impacts on the treatment of many inherited peripheral neuropathies of childhood.

Preserving function in Duchenne dystrophy with long-term pulse prednisone therapy.

We report a case of a patient with Duchenne muscular dystrophy who was treated with intermittent pulse prednisone for severe asthma from age 3 to 17 yr and had remarkable preservation of skeletal muscle function. He had a maternal uncle with Duchenne muscular dystrophy who had the identical familial deletion mutation and died at age 19 of respiratory failure. Compared with his untreated uncle, our patient remains partially ambulatory at age 20. This case provides interesting, albeit anecdotal, evidence of considerable clinical benefit from pulse prednisone used on a much longer term basis than has been previously studied and promotes the need for further investigation on this type of therapy in Duchenne muscular dystrophy.

Magnetic resonance imaging of denervated muscle: comparison to electromyography.

The purpose of the study is to further assess the usefulness of short TI (time to inversion) recovery (STIR) magnetic resonance imaging (MRI) in detecting denervation of skeletal muscle compared to needle electromyography (EMG). Ninety subjects with clinical evidence of peripheral nerve injury or radiculopathy underwent STIR MRI and EMG of the affected limb. In 74 (82%) of these subjects, a positive correlation was found between STIR MRI and EMG (P < 0.009). STIR MRI has a relative sensitivity of 84% and specificity of 100% for detecting denervation. A subset of 28 subjects underwent quantitative assessments of signal intensity ratio (SIR) from the STIR MRI. The rank order correlation coefficient between the SIR and abnormal spontaneous activity on EMG was 0.70 (P < 0.001). Increased signal intensity on STIR MRI corresponds closely with spontaneous activity on EMG in denervated muscle. Although less sensitive than EMG in detecting muscle denervation, STIR MRI may be a useful adjunctive diagnostic tool in this setting.

Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies.

The early growth response 2 gene (EGR2) is part of a multigene family encoding Cys2His2 type zinc-finger proteins and may play a role in the regulation of cellular proliferation. Egr2, (also known as Krox20) is the mouse orthologue of human EGR2 and was first identified as an immediate-early response gene, encoding a protein that binds DNA in a sequence-specific manner and acts as a transcription factor. Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS). Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage. We hypothesized that Egr2 may be a transcription factor affecting late myelin genes and that human myelinopathies of the PNS may result from mutations in EGR2. In support of this hypothesis, we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1).

Clinical approach to the diagnostic evaluation of progressive neuromuscular diseases.

This article has reviewed the clinical approach to the diagnostic evaluation of progressive neuromuscular diseases with an emphasis on relevant neuromuscular history, family history, clinical examination findings, laboratory studies, and a brief discussion of the role of muscle biopsy. Molecular genetic and immunocytochemistry studies of muscle have been major advances in the diagnostic evaluation of the neuromuscular disease patient; however, all diagnostic information must be interpreted within the context of relevant clinical information. In some instances, a precise diagnosis is not medically possible; however, the accurate characterization of an individual patient within the most appropriate NMD clinical syndrome often allows the clinician to provide the patient and family with accurate prognostic information and anticipatory guidance for the future. After synthesizing all available clinical and diagnostic information, the physiatrist or neurologist may at times determine that an NMD patient has an inappropriate diagnosis warranting further diagnostic evaluation. This issue focuses on the rehabilitation of progressive neuromuscular diseases with an emphasis on optimization of health, prevention or minimization of complications, and enhancement of quality of life. Appropriate rehabilitation approaches require an accurate diagnosis. In addition, patient quality of life in NMD depends on access to current and accurate information. The first step in providing accurate information and appropriate treatment is constantly ensuring that NMD patients have appropriate diagnoses based on a through evaluation of clinical information and appropriate application of current medical science and available diagnostic technology.

Limb contractures in progressive neuromuscular disease and the role of stretching, orthotics, and surgery.

Contractures are exceedingly common impairments in selected progressive NMD conditions, particularly those with excessive fibrosis and fatty infiltration into muscle (i.e., dystrophic myopathies) and more severe NMD conditions, resulting in significant weakness and wheel-chair reliance, such as SMA. Less than antigravity strength produces an inability to achieve full active range of motion. Static positioning of limbs (generally in flexion) and lack of weight bearing results in fixed contractures. This article has reviewed the prevalence and distribution of contractures in specific NMD conditions. Aggressive rehabilitation strategies, including stretching, positioning, splinting, upright weight bearing, and orthopaedic surgical management may help minimize the degree of disability in NMD patients with contractures.

Spinal deformity in progressive neuromuscular disease. Natural history and management.

Severe spinal deformity in progressive neuromuscular disease (NMD) leads to multiple problems, including poor sitting balance, difficulty with upright seating and positioning, pain, difficulty in attendant care, and potential exacerbation of underlying restrictive respiratory compromise. Severe scoliosis and pelvic obliquity can in some instances completely preclude upright sitting in a wheelchair. This article reviews the prevalence, natural history, and management of scoliosis in neuromuscular diseases at greatest risk for progressive spinal deformity.

Profiles of functional recovery in fifty traumatically brain-injured patients after acute rehabilitation.

Research to demonstrate the efficacy of head injury rehabilitation is important at a time when cost-containment efforts are intensifying. A useful tool that would predict the functional improvement during hospitalization and length of stay (LOS) of persons with traumatic brain injury would be of benefit to patients and their families, insurance carriers, and rehabilitation specialists. This study examines functional improvements made by 50 traumatic brain-injured patients admitted to the rehabilitation unit at the University of California, Davis, Medical Center (UCDMC) as measured by the UCDMC Davis Functional Status Measure (DFSM), which was adapted from the Functional Independence Measure (FIM). The DFSM incorporates additional items to provide a more thorough measure of skills to be rehabilitated. The purpose of this study was to compare scores and profiles on the DFSM items obtained by patients with LOS greater than and less than and equal to the median rehabilitation LOS (23 days). Relationships were explored among admission DFSM scores, LOS for rehabilitation, discharge destination, and functional outcome. Results indicate that patients admitted to the rehabilitation unit attained a similar profile or level of function by discharge, regardless of admission Glasgow Coma Scale scores or admission DFSM scores. There were no significant differences in admission Glasgow Coma Scale score, age, acute LOS, or discharge disposition between the LOS groups. There was a significant difference in median admission DFSM score in 26 of 31 categories between the LOS groups. There was a significant difference in median DFSM change (admission to discharge) in 24 of 31 categories between the LOS groups. The admission DFSM total score was inversely proportional to the length of stay, with a correlation coefficient of 0.78. DFSM change and admission to discharge was linearly correlated with LOS (R = 0.66). The DFSM documents functional outcome and measures gains during inpatient rehabilitation. The DFSM profile is helpful in predicting the LOS needed to achieve those gains.

Urodynamic findings in the tethered spinal cord syndrome: does surgical release improve bladder function?

PURPOSE: We retrospectively reviewed 39 patients with a tethered spinal cord to evaluate whether surgical release positively influenced urological symptoms or urodynamic findings. MATERIALS AND METHODS: The patients were divided into 2 groups: group 1-11 with occult spinal dysraphism and group 2-28 with secondary spinal cord tethering after previous closure of a myelomeningocele or resection of a lipomyelomeningocele. Diagnosis was confirmed in all cases by magnetic resonance imaging or spinal ultrasound. A comprehensive urodynamic evaluation was done immediately preoperatively and 2 to 21 months (mean 7) postoperatively. RESULTS: In group 1 the most common preoperative urodynamic finding was hyperreflexia, which improved or resolved after untethering in 62.5% of the patients. Four adults also reported improved bladder sensation or decreased urgency. In group 2 the most common urodynamic finding was impaired compliance, followed closely by detrusor hyperreflexia. Urodynamic patterns of detrusor hyperreflexia or compliance improved in only 30% of the patients, while 48% had worsened patterns. Only 14% of group 2 had improved symptoms of urinary control but 28% had improved lower extremity function. CONCLUSIONS: Urological symptoms and urodynamic patterns may be improved by early surgical intervention in patients with occult spinal dysraphism. However, untethering did not consistently benefit patients with secondary spinal cord tethering.

Focal posterior interosseous neuropathy in the presence of hereditary motor and sensory neuropathy, type I.

A 30-year-old male with hereditary motor and sensory neuropathy, type I (HMSN I), presented with asymmetric weakness of finger extension and radial deviation with left wrist extension, previously felt to be a manifestation of the peripheral neuropathy. Nerve conduction studies confirmed HMSN I; however, needle EMG revealed marked, ongoing axonal loss in muscles innervated by the left posterior interosseous nerve (PIN) only. At surgery there was focal fusiform swelling in the PIN at exit from the supinator muscle, compatible with localized hypertrophic neuropathy, which has not been reported before in HMSN I. A concomitant focal mononeuropathy should be considered in cases of hereditary neuropathy with marked asymmetry of weakness.