Philip R. Fischer

A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children.

BACKGROUND Nutritional rickets remains prevalent in many tropical countries despite the fact that such countries have ample sunlight. Some postulate that a deficiency of dietary calcium, rather than vitamin D, is often responsible for rickets after infancy. METHODS We enrolled 123 Nigerian children (median age, 46 months) with rickets in a randomized, double-blind, controlled trial of 24 weeks of treatment with vitamin D (600,000 U intramuscularly at enrollment and at 12 weeks), calcium (1000 mg daily), or a combination of vitamin D and calcium. We compared the calcium intake of the children at enrollment with that of control children without rickets who were matched for sex, age, and weight. We measured serum calcium and alkaline phosphatase and used a 10-point radiographic score to assess the response to treatment at 24 weeks. RESULTS The daily dietary calcium intake was low in the children with rickets and the control children (median, 203 mg and 196 mg, respectively; P=0.64). Treatment produced a smaller increase in the mean (+/-SD) serum calcium concentration in the vitamin D group (from 7.8+/-0.8 mg per deciliter [2.0+/-0.2 mmol per liter] at base line to 8.3+/-0.7 mg per deciliter [2.1+/-0.2 mmol per liter] at 24 weeks) than in the calcium group (from 7.5+/-0.8 [1.9+/-0.2 mmol per liter] to 9.0+/-0.6 mg per deciliter [2.2+/-0.2 mmol per liter], P<0.001) or the combination-therapy group (from 7.7+/-1.0 [1.9+/-0.25 mmol per liter] to 9.1+/-0.6 mg per deciliter [2.3+/-0.2 mmol per liter], P<0.001). A greater proportion of children in the calcium and combination-therapy groups than in the vitamin D group reached the combined end point of a serum alkaline phosphatase concentration of 350 U per liter or less and radiographic evidence of nearly complete healing of rickets (61 percent, 58 percent, and 19 percent, respectively; P<0.001). CONCLUSIONS Nigerian children with rickets have a low intake of calcium and have a better response to treatment with calcium alone or in combination with vitamin D than to treatment with vitamin D alone.

Nutritional rickets around the world: causes and future directions

Abstract Introduction: Nutritional rickets has been described from at least 59 countries in the last 20 years. Its spectrum of causes differs in different regions of the world. Methods: We conducted a systematic review of articles on nutritional rickets from various geographical regions published in the last 20 years. We extracted information about the prevalence and causes of rickets. Results: Calcium deficiency is the major cause of rickets in Africa and some parts of tropical Asia, but is being recognised increasingly in other parts of the world. A resurgence of vitamin D deficiency has been observed in North America and Europe. Vitamin D-deficiency rickets usually presents in the 1st 18 months of life, whereas calcium deficiency typically presents after weaning and often after the 2nd year. Few studies of rickets in developing countries report values of 25(OH)D to permit distinguishing vitamin D from calcium deficiency. Conclusions: Rickets exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency. Along the spectrum, it is likely that relative deficiencies of calcium and vitamin D interact with genetic and/or environmental factors to stimulate the development of rickets. Vitamin D supplementation alone might not prevent or treat rickets in populations with limited calcium intake.

Bone Structure at the Distal Radius During Adolescent Growth

The incidence of distal forearm fractures peaks during the adolescent growth spurt, but the structural basis for this is unclear. Thus, we studied healthy 6‐ to 21‐yr‐old girls (n = 66) and boys (n = 61) using high‐resolution pQCT (voxel size, 82 μm) at the distal radius. Subjects were classified into five groups by bone‐age: group I (prepuberty, 6–8 yr), group II (early puberty, 9–11 yr), group III (midpuberty, 12–14 yr), group IV (late puberty, 15–17 yr), and group V (postpuberty, 18–21 yr). Compared with group I, trabecular parameters (bone volume fraction, trabecular number, and thickness) did not change in girls but increased in boys from late puberty onward. Cortical thickness and density decreased from pre‐ to midpuberty in girls but were unchanged in boys, before rising to higher levels at the end of puberty in both sexes. Total bone strength, assessed using microfinite element models, increased linearly across bone age groups in both sexes, with boys showing greater bone strength than girls after midpuberty. The proportion of load borne by cortical bone, and the ratio of cortical to trabecular bone volume, decreased transiently during mid‐ to late puberty in both sexes, with apparent cortical porosity peaking during this time. This mirrors the incidence of distal forearm fractures in prior studies. We conclude that regional deficits in cortical bone may underlie the adolescent peak in forearm fractures. Whether these deficits are more severe in children who sustain forearm fractures or persist into later life warrants further study.

The Practice of Travel Medicine: Guidelines by the Infectious Diseases Society of America

David R. Hill, Charles D. Ericsson, Richard D. Pearson, Jay S. Keystone, David O. Freedman, Phyllis E. Kozarsky, Herbert L. DuPont, Frank J. Bia, Philip R. Fischer, and Edward T. Ryan National Travel Health Network and Centre and Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, England; Department of Medicine, University of Toronto, and Center for Travel and Tropical Medicine, Toronto General Hospital, Toronto, Ontario, Canada; Department of Internal Medicine, Clinical Infectious Diseases, University of Texas Medical School at Houston, Department of Internal Medicine, St. Luke’s Hospital, and Center for Infectious Diseases, University of Texas at Houston School of Public Health, and Department of Medicine, Baylor College of Medicine, Houston, Texas; Departments of Medicine and Pathology, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia; Departments of Medicine and Epidemiology, Division of Geographic Medicine, University of Alabama at Birmingham, Birmingham; Department of Medicine, Infectious Diseases, Emory University School of Medicine, and 16 Division of Global Migration and Quarantine, Centers for Disease Control and Prevention, Atlanta, Georgia; Department of Medicine and Laboratory Medicine, Yale Medical School, New Haven, Connecticut; Department of Pediatrics, Division of General Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, and Mayo Eugenio Litta Children’s Hospital, Mayo Clinic, Rochester, Minnesota; and Department of Medicine, Division of Infectious Diseases, Harvard Medical School, Harvard School of Public Health, and Tropical and Geographic Medicine Center, Massachusetts General Hospital, Boston, Massachusetts

Postural Tachycardia in Children and Adolescents: What is Abnormal?

OBJECTIVES To evaluate whether the use of adult heart rate (HR) criteria is appropriate for diagnosing orthostatic intolerance (OI) and postural tachycardia syndrome (POTS) in children and adolescents, and to establish normative data and diagnostic criteria for pediatric OI and POTS. STUDY DESIGN A total of 106 normal controls aged 8-19 years (mean age, 14.5±3.3 years) underwent standardized autonomic testing, including 5 minutes of 70-degree head-up tilt. The orthostatic HR increment and absolute orthostatic HR were assessed and retrospectively compared with values in 654 pediatric patients of similar age (mean age, 15.5±2.3 years) who were referred to our Clinical Autonomic Laboratory with symptoms of OI. RESULTS The HR increment was mildly higher in patients referred for OI/POTS, but there was considerable overlap between the patient and control groups. Some 42% of the normal controls had an HR increment of ≥30 beats per minute. The 95th percentile for the orthostatic HR increment in the normal controls was 42.9 beats per minute. There was a greater and more consistent difference in absolute orthostatic HR between the 2 groups, although there was still considerable overlap. CONCLUSION The diagnostic criteria for OI and POTS in adults are unsuitable for children and adolescents. Based on our normative data, we propose new criteria for the diagnosis of OI and POTS in children and adolescents.

Postural Orthostatic Tachycardia Syndrome: A Clinical Review

Postural orthostatic tachycardia syndrome was defined in adult patients as an increase >30 beats per minute in heart rate of a symptomatic patient when moving from supine to upright position. Clinical signs may include postural tachycardia, headache, abdominal discomfort, dizziness/presyncope, nausea, and fatigue. The most common adolescent presentation involves teenagers within 1-3 years of their growth spurt who, after a period of inactivity from illness or injury, cannot return to normal activity levels because of symptoms induced by upright posture. Postural orthostatic tachycardia syndrome is complex and likely has numerous, concurrent pathophysiologic etiologies, presenting along a wide spectrum of potential symptoms. Nonpharmacologic treatment includes (1) increasing aerobic exercise, (2) lower-extremity strengthening, (3) increasing fluid/salt intake, (4) psychophysiologic training for management of pain/anxiety, and (5) family education. Pharmacologic treatment is recommended on a case-by-case basis, and can include beta-blocking agents to blunt orthostatic increases in heart rate, alpha-adrenergic agents to increase peripheral vascular resistance, mineralocorticoid agents to increase blood volume, and serotonin reuptake inhibitors. An interdisciplinary research approach may determine mechanistic root causes of symptoms, and is investigating novel management plans for affected patients.

Vitamin D Receptor Polymorphisms and Nutritional Rickets in Nigerian Children

Nutritional rickets is common in Nigeria where vitamin D deficiency is rare and dietary insufficiency of calcium is common. It occurs more commonly in siblings of affected children than of unaffected children. Postulating that vitamin D receptor (VDR) polymorphisms might relate to the susceptibility of some Nigerian children to develop rickets in the setting of low calcium intake, we compared the VDR genotypes, as determined by the presence or absence of Bsm I, Apa I, Taq I, and Fok I restriction enzyme cleavage sites, between 105 children with active nutritional rickets and 94 subjects representative of the community from which the rachitic children came. In the rickets group, the ff genotype was less common than in the community group, and the FF genotype was relatively increased (f allele frequency, 17% in rachitic children and 26% in the community group, p = 0.03). Neither individual allele frequencies for the other polymorphisms nor combinations of genotypes at different sites were different between the rachitic and community groups. Although it is not clear why a presumed better‐functioning VDR variant (F allele) is associated with an increased risk of developing rickets, this study raises the possibility that VDR alleles might be important in determining an individuals susceptibility to developing rickets when faced with dietary calcium deficiency.

Congenital Malaria: An African Survey

Even in malaria-endemic areas, congenital malaria has been considered to be rare. Some recent reports suggest, however, that up to one fourth of newborns in some areas may be parasitemic. In an effort to determine current prevalence rates of congenital malaria, malaria smears were done on peripheral blood from 100 peripartum mothers and on cord blood from their offspring at each of seven sites spanning sub-Saharan Africa. The prevalence rate of maternal parasitemia was 15% overall and varied from 4% to 30% at the different sites. Congenital malarial infection was found in 7% of newborns, the prevalence rate varying from 0% to 23% at the different sites. There was no apparent relationship between the season of sampling and either the prevalence rates of parasitemia or the penetrance of malaria from mother to offspring. In summary, congenital malarial infection is not rare in sub-Saharan Africa, but the prevalence rate of neonatal parasitemia varies from site to site.

Absence of vitamin D deficiency in young Nigerian children

OBJECTIVE To determine the prevalence of vitamin D deficiency in young Nigerian children residing in an area where nutritional rickets is common. STUDY DESIGN A randomized cluster sample of children aged 6 to 35 months in Jos, Nigeria. RESULTS Of 218 children evaluated, no child in the study had a 25-hydroxyvitamin D (25-OHD) concentration <10 ng/mL (the generally held definition of vitamin D deficiency). Children spent an average of 8.3 hours per day outside of the home. Twenty children (9.2%) had clinical findings of rickets. Children with clinical signs of rickets were more likely to be not currently breast fed and have significantly lower serum calcium concentrations than those without signs of rickets (9.1 vs 9.4 mg/dL, respectively, P =.01). Yet, 25-OHD levels were not significantly different between those children with clinical signs of rickets and those without such clinical signs. CONCLUSION Vitamin D deficiency was not found in this population of young children in whom clinical rickets is common. This is consistent with the hypothesis that dietary calcium insufficiency, without preexisting vitamin D deficiency, accounts for the development of clinical rickets in Nigerian children.

MULTIPLE ORIGINS OF THE MTDNA 9-BP DELETION IN POPULATIONS OF SOUTH INDIA

The origins and genetic affinities of the more than 500 tribal populations living in South Asia are widely disputed. This may reflect differential contributions that continental populations have made to tribal groups in South Asia. We assayed for the presence of the intergenic COII/tRNALys 9-bp deletion in human mtDNA in 646 individuals from 12 caste and 14 tribal populations of South India and compared them to individuals from Africa, Europe, and Asia. The 9-bp deletion is observed in four South Indian tribal populations, the Irula, Yanadi, Siddi, and Maria Gond, and in the Nicobarese. Length polymorphisms of the 9-bp motif are present in the Santal, Khonda Dora, and Jalari, all of whom live in a circumscribed region on the eastern Indian coast. Phylogenetic analyses of mtDNA control region sequence from individuals with the 9-bp deletion indicate that it has arisen independently in some Indian tribal populations. Other 9-bp deletion haplotypes are likely to be of Asian and African origin, implying multiple origins of the 9-bp deletion in South India. These results demonstrate varying genetic affinities of different South Indian tribes to continental populations and underscore the complex histories of the tribal populations living in South Asia.