Everything in excess is opposed to nature, even vitamin D: a case report.

SUMMARY: Vitamin D intoxication in children is rare but its incidence is increasing as vitamin D is supplemented more often and in higher doses. Children with cystic fibrosis (CF) are at risk for vitamin D intoxication due to incorrect compounded preparations of liposoluble vitamins. Here, we report a severe vitamin D intoxication in a 4-year-old girl with CF, due to an error in the compounded vitamin A, D, E, and K preparation, presenting clinically with weight loss, constipation, polydipsia, polyuria, and nycturia. The administered compounded preparation contained 10 000-fold the prescribed vitamin D dose. The patient was treated with hyperhydration, loop diuretics, and bisphosphonates. Serum calcium levels normalized after 4 days but serum 25-hydroxyvitamin D levels remained elevated even up to 2 months after treatment. LEARNING POINTS: Vitamin D intoxication should be ruled out when patients with cystic fibrosis (CF) present with acute polyuria, constipation, and weight loss. Prompt treatment is necessary to avert life-threatening complications. Regularly measuring serum calcium and 25-hydroxyvitamin D concentrations in children with CF receiving vitamin A, D, E, and K supplements is important during their follow-up.

[Recommendations for vitamin D supplementation in infants and young children]. / Supplémentation en vitamine D du nourrisson et du jeune enfant.

Vitamin D deficiency occurs rather commonly among healthy pregnant women, newborns and young children, especially in certain risk groups. Since vitamin D plays a role in calcium and phosphor metabolism essential for bone health and in the physiopathology of some autoimmune diseases it seems important to provide recommendations for prevention of vitamin D deficiency. Risk factors include maternal vitamin D deficiency, low intake of fortified food, eg. breastfeeding, low compliance of supplementation, dark skin, inadequate sun exposure, premature birth, overweight, living at high latitude. The aim of this paper is to summarize available data of vitamin D sources, known situations in which deficiency is common and published guidelines on vitamin D supplementation, and translate this information in recommendations for prevention of vitamin D deficiency in healthy paediatric population in Flanders. Infants should receive an oral supplementation of 400 IU/day of vitamin D from birth and this should be continued till the age of 6 years. In cases of dark skin the dose should be 600 IU/day. An healthy life style with outdoor activities and associated sun exposure and intake of fortified nutrition should be advised. The implementation should be promoted by all healthcare professionals working with young children.

Sunlight is an important determinant of vitamin D serum concentrations in cystic fibrosis.

BACKGROUND/OBJECTIVES: The increase of bone disease in adult cystic fibrosis (CF) patients is partly attributed to inadequate serum concentrations of 25-OH cholecalciferol (25 (OH) D) blamed on fat malabsorption. Based on physiological, clinical and biochemical observations this pathogenesis is debatable. The objective was to ascertain the relative importance of different 25 (OH) D sources. SUBJECTS/METHODS: Over 4 consecutive years, 474 annual 25 (OH) D serum concentrations from 141 CF patients of all ages were compared with values of healthy peers and weighed against annual ultraviolet B (UVB) exposure. RESULTS: Ranked per month, 25 (OH) D concentrations depicted a curve strikingly parallel to the amount of UVB exposure in the preceding months. A significant difference exists between 25 (OH) D concentrations in the 'Months with high UVB exposure' (May-October) and the 'Months with low UVB exposure' (November-April) but not with healthy controls in the same period. CONCLUSIONS: 25 (OH) D concentrations clearly respond to the amount of sunshine in preceding months. They are not clearly influenced by daily oral supplements of 800 IU of cholecalciferol. Sun exposure should be encouraged, and the recommended dosage of oral supplements increased.

Lumbar spine bone mineral density in diabetic children with recent onset.

To detect early abnormalities in bone mineralization, the lumbar spine bone mineral density (BMD) of diabetic children with a diabetes onset of less than 5 years and treated with a similar insulin treatment scheme was measured at the level of the lumbar spine by dual-energy X-ray absorptiometry (DEXA), a most sensitive technique for detecting osteopenia in children. Fifteen male and 8 female children and adolescents (mean age +/- SD: 12.5+/-3.7 years), 1-5 years after the clinical onset of their diabetes, were studied. Measurements of the lumbar spine (L1-L4) BMD, expressed in gHA/cm2 and as a z-score for age, were performed with a commercial DEXA apparatus (Hologic QDR 1000 W, Hologic Inc., Waltham, USA). Calcium-phosphorus metabolism was studied by measuring the circulating levels of calcium, phosphorus, alkaline phosphatase, osteocalcin, 25-OH-vitamin D and parathyroid hormone and the urinary excretion of calcium and phosphorus. The mean BMD of the studied group was 0.75 (0.16) gHA/cm2 giving a mean z-score of -0.31+/-0.95. Only 1 of the patients had a BMD lower than -2 SD. No sex difference in BMD z-score existed. BMD SD was positively correlated with height SD (R = 0.56, p < 0.005), but not with the age of the patients, the duration of the disease, the degree of metabolic control or the studied parameters of the calcium-phosphorus metabolism. In conclusion, diabetic children have a normal lumbar spine BMD during the first years of the disease, when a good metabolic control and no abnormalities in the calcium-phosphorus metabolism are present. As in normal children, areal BMD by DEXA is highly dependent on the body height, necessitating corrections if abnormalities in skeletal growth or pubertal development exist.

Cafeteria diet-induced obese rats have an increased somatostatin protein content and gene expression in the periventricular nucleus.

In human obesity, spontaneous and GRF stimulated growth hormone secretion have been shown to be blunted. We used cafeteria diet fed obese rats as a model to study the central mechanisms involved in growth hormone secretion changes which are observed in obesity. We analysed somatostatin messenger RNA and protein levels in the hypothalamic periventricular nucleus of the rats by non radioactive in situ hybridization and immunocytochemistry respectively. The optical density of somatostatin mRNA, measured by a computerized image system, was significantly higher in cafeteria diet fed rats (1014 +/- 87 vs 444 +/- 45; p < 0.05). The integrated optical density of somatostatin protein was also significantly higher in cafeteria rats compared to the control rats (222 +/- 36 vs 114 +/- 24; p < 0.05). In conclusion, cafeteria diet induced obese rats have a higher somatostatin biosynthesis in the periventricular nucleus. Further studies are needed to establish the possible link of this increased somatostatin gene expression with the decreased GH production.

Pearson marrow pancreas syndrome: a molecular study and clinical management.

Human mitochondrial DNA (mt DNA) lesions can cause a heterogeneous group of mitochondrial degenerative disorders. We report on a 5-year-old patient suffering from the full-blown picture of Pearson syndrome. His symptoms started in the first year of life with failure to thrive, followed by chronic diarrhoea and lactic acidosis at 18 months of age. Analysis of mitochondrial DNA revealed large amounts of mt DNA molecules with a 2.7 kb deletion in all tissues examined. The diagnosis of Pearson syndrome was made initially in the absence of haematological disturbances. In the following months neutropenia, sideroblastic anaemia and hypoparathyroidism developed. Daily administration of dichloroacetate (DCA) and bicarbonate controls the lactic acidosis, while episodic treatments with filgastrim (Neupogen) reverse episodes of severe neutropenia. Calcium and vitamin D supplementation compensate for the hypoparathyroidism. Chronic administration of DCA and supportive treatment for a long period help to stabilize patients with multiorgan dysfunction.

The weight gain and ultimate adiposity in cafeteria diet-induced obesity is unrelated to the central serotoninergic tonus.

Early detection of subjects with a propensity to obesity might be of great help for setting up preventive intervention studies. In this study we tested whether the development of obesity in Wistar rats, given ad libitum cafeteria foods, could be predicted by a low prolactin (PRL) response to 5-hydroxytryptophan (5HTP), as an index of low hypothalamic serotoninergic tonus. Basal and 5HTP-stimulated (50 mg/kg body weight i.p.) PRL were measured by RIA in 15 young male Wistar rats, whose pelleted diet was afterwards supplemented with cafeteria foods. In the tested animals an increase of PRL between 4 and 56 times the basal value was observed 60 min after the 5HTP injection. After 2 months of feeding, marked inter-individual differences in weight gain between the cafeteria fed animals were observed. After 10 months of feeding, median body fat percentage, assessed by dual X-ray absorptiometry, of the overfed rats was significantly higher than that of control animals: median (range): 41.2% (28.9 - 51.5%) vs 25.1 (18.0 - 32.2%) (p < 0.0001). The PRL response at the start of the experiment was neither correlated with the monthly weight increases, nor with the fat mass percentage at the end of the experiment, suggesting that a pre-existing low hypothalamic serotoninergic tonus is probably not involved in the overeating and ultimate overweight of cafeteria diet fed animals.

High-dose growth hormone treatment of short children born small for gestational age.

The effect of GH administration was evaluated over 2 yr in 50 short, prepubertal, non-GH deficient children born small for gestational age, who had been randomly allocated to a group receiving no treatment or daily sc GH treatment at a dose of 0.2 or 0.3 IU/kg. At the start of the study, mean age was 5.2 yr, bone age was 4.0 yr, height SDS was -3.5, height velocity SDS was -0.8, weight SDS was -2.7, and body mass index SDS was -1.9. Catch-up growth was observed in none of the untreated and all of the treated children. The response to GH treatment included a near doubling of growth velocity and of weight gain and a mean height increment of more than 2 SDS. GH treatment was associated with a distinct acceleration of bone maturation. The differences between the growth responses evoked by the two GH doses were minor. The prepubertal GH-induced catch-up growth was associated with elevated serum concentrations of insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and osteocalcin, whereas insulin-like growth factor-II levels remained unaltered. GH treatment was well tolerated. In conclusion, high-dose GH administration over 2 yr is emerging as a potential therapy to increase the short stature that results from insufficient catch-up growth in young children born small for gestational age. The long-term impact of this approach remains to be delineated.

Bone metabolism and mineralisation after cytotoxic chemotherapy including ifosfamide.

Lumbar spine bone mineral density and bone mineral metabolism were studied in 13 children three months or more after completion of cytotoxic chemotherapy that included ifosfamide given for different malignancies. Blood and urine were analysed for calcium, phosphorus, and magnesium and blood for alkaline phosphatase activity, parathyroid hormone, and 1,25(OH)2 vitamin D3. Bone mineral density (BMD) was measured at the lumbar spine (L1-L4) using a commercial dual x ray absorptiometer. Serum concentrations of calcium, phosphorus, and magnesium and alkaline phosphatase activity, as well as plasma 1,25(OH)2 vitamin D3 concentrations were normal in all children. Slightly raised parathyroid hormone concentrations were seen in two children. An increased urinary excretion of calcium was found in five children. Mean (SD) BMD of the children was -0.88 (1.44). Three children had osteopenia, as defined by a BMD lower than -2 SD for age and sex related standards. No significant relation was found between the BMD and the biochemical parameters. In conclusion, a normal BMD was found in most patients who had received ifosfamide, even in those with persisting hypercalciuria.

Ifosfamide-induced Fanconi's syndrome with growth failure in a 2-year-old child.

Fanconi's syndrome with phosphopenic rickets is described in a 2-year-old girl who had been treated for an embryonal sarcoma with multiagent chemotherapy including high-dose ifosfamide. The radiological and biochemical signs of rickets disappeared after treatment with 25-OH vitamin D3 and phosphorus supplements. Monitoring of tubular function in children during and after treatment with ifosfamide is mandatory.

[Effect of the hypothalamus on membrane permeability to ionic calcium currents]. / Influence de l'hypothalamus sur la perméabilité membranaire aux courants ioniques calciques.

The hypothalamus contains two distinct zones which affect the activity of myocardial and vascular muscle. The median ventricular nucleus stimulates the liberation of peripheral catecholamines and, by so stimulating the adrenoreceptors, opens up the slow calcium canals. The resulting stimulation of the myocardial and vascular muscle cells causes tachycardia, and an increase in myocardial contraction and in peripheral resistance. The paraventricular nucleus antagonises these effects by inhibiting peripheral catecholamine secretion so blocking or slowing the passage of Ca++ through the slow calcium canals. The study of effective, active concentration of D 600, a powerful calcium antagonist, shows that the paraventricular nucleus is not a direct calcium antagonist like D 600 whose effects are not potentiated, and confirms that it acts indirectly by inhibiting peripheral noradrenaline secretion.

[Effect of stimulation of the hypothalamic paraventricular nucleus on the electrical and contractile characteristics of the myocardium in dogs]. / Influence de l'excitation du noyau paraventriculaire hypothalamique sur les caractéristiques électriques et contractiles du myocarde chez le chien.

Electrical stimulation of the hypothalamic paraventricular nucleus results in bradycardia and hypotension. A direct transtemporal approach was used to implant an insulated electrode in the site of the third ventricle. The bradycardia and hypotension have been studied previously and have been shown to be due to inhibition of the alpha and beta vascular and myocardiac adrenergic receptors. The effects of this inhibition on the electrical appearances and the mechanical and phonocardiographic parameters of myocardial contractility were observed in this present study. The force and velocity of LV isometric contraction were reduced as shown by reduction in dP/dT, the delay in its peak and the reduction of the angle between the upstroke of ventricular contraction with the base line. The onset of left ventricular ejection was delayed. The high frequency (60 and 140 Hz) components of the first heart sound disappeared, confirming their contribution to the intensity of this sound. The ECG rapid QRS phase and AV conduction time were unchanged, but the slow phase of the T wave became more negative as the depressant effect on the myocardium increased.

[Electrocardiographic changes during stimulation of the hypothalamus in the dog]. / Modifications électrocardiographiques au cours de l'excitation hypothalamique: étude expérimentale sur le chien.

Electrical stimulation in the area around the ventro-median nuclei of the hypothalamus of the dog produced changes suggestive of ischaemia in the standard bipolar and epicardial leads, principally over the apical, lateral and diaphragmatic walls of the left ventricle. It is suggested that these changes may be the central expression of orthosympathetic stimulation by released catecholamines on the permeability and membrane potentials of the myocardial cells with respect to ions, especially Ca++.

Influence of some hypotensive drugs on the effects of hypothalamic stimulation.

Clonidine, L-alpha-methyldopa, propranolol as well as noradrenaline, when injected directly into the hypothalamic paraventricular (PV) nucleus area, enhance the activity of this center. Lidoflazine appears to be inactive. Since the electrical, chemical and pharmacological stimulation of the PV area elicits the same depressor cardiovascular reactions, a specific differentiation of this nucleus as a depressor center is proposed. The above-mentioned drugs, when introduced into the ventromedial nucleus area, enhance the pressor effects produced by stimulation of this nucleus. Thus, the hypothalamic depressor activity is not linked with an inhibition of the ventromedial pressor activity.

Arterial and venous responses to hypothalamic stimulation in the dog.

Stimulation of the ventro-medial nucleus of the hypothalamus induces active constriction of both pre- and post-capillary vessels in the dog's hindlimb. Alpha-adrenolytic agents reduce these responses, indicating that they are mediated by the sympathetic nervous system. Stimulation of the paraventricular nucleus dilates both resistance and capacitance vessels. The present study demonstrates that hypothalamic neurones can control venomotor tone.

New approach of the cardio-vascular depressive mechanism during lateral hypothalamic stimulation.

Paraventricular nucleus stimulation acts directly on the alpha- and beta-adrenoreceptors in heart and arterioles, eliciting arterial hypotension and cardiac chronotropism and inotropism decrease. Efferent pathways follow sympathetic nervous fibres through the medulla and the thoraco-lumbar ganglionic chain. The role of the alpha- and beta-adrenoreceptors in these depressive reactions is discussed.