In this study, we employed a panel of cell lines to determine whether p53-dependent cell death in neuroblastoma (NB) cells is caused by apoptotic cellular function, and we further studied the molecular mechanism of apoptosis induced via the p53-dependent pathway. We obtained evidence that a type of p53-dependent stress, doxorubicin (Doxo) administration, causes accumulation of p53 in the nucleus of NB cells and phosphorylation of several serine residues in both Doxo-sensitive and -resistant cell lines. Upregulation of p53-downstream molecules in cells and upregulation of Noxa in the mitochondrial fraction were observed only in Doxo-sensitive NB cells. Significance of Noxa in the Doxo-induced NB cell death was confirmed by Noxa-knockdown experiments. Mitochondrial dysfunction, including cytochrome-c release and membrane potential disregulation, occurred and resulted in the activation of the intrinsic caspase pathway. However, in the Doxo-resistant cells, the accumulation in the nucleus and phosphorylation of p53 did not induce p53-downstream p21 Cip1/Waf1 expression and the Noxa upregulation, resulting in the retention of the mitochondrial homeostasis. Taken together, these findings indicate that the p53 pathway seems to play a crucial role in NB cell death by Noxa regulation in mitochondria, and inhibition of the induction of p53-downstream effectors may regulate drug resistance of NB cells.

Abstract. Hypoparathyroidism caused by gain-of-function mutations of the calcium-sensing receptor (CaR) in the transmembrane domain is usually severe and difficult to manage. A patient with severe hypoparathyroidism, caused by CaR activating mutation F821L, was treated for 3 days (Day 1 to Day 3) with synthetic human parathyroid hormone 1-34 (teriparatide, PTH). An Ellsworth-Howard test of the patient revealed normal responses of urine phosphate and cyclic AMP excretion, indicating that the patient's renal tubules normally responded to extrinsic PTH. On Day 1 to Day 3, 0.9 µg/kg/day of PTH was administered subcutaneously twice daily at 0800 and 2000. On Day 1, the serum calcium level that was 1.8 mmol/l before PTH administration increased to 2.1 mmol/l at 1200, and gradually decreased to 1.8 mmol/l at 2000. On Days 2 and 3, the maximum calcium levels were 2.5 and 2.4 mmol/l, respectively, at 1200. At 2000, they returned to or below basal levels at 0800. On Day 4 without PTH administration, the calcium levels were maintained at the basal levels at Day 0. The urine calcium/creatinine (Ca/Cr) ratio that was high (>0.4) before PTH injection decreased after PTH administration (0.4>). Changes in the ionized calcium levels were almost parallel with the total calcium levels. The serum inorganic phosphate (IP) level decreased to 2.4 mmol/l at 1000, but gradually increased before the second PTH injection to the level at 0800 on Day 1. The minimum IP level on Days 2 and 3 was 2.1 mmol/l and 2.0 mmol/l, respectively. In contrast to the remarkable changes in the serum calcium level by PTH treatment, the serum magnesium levels showed few changes. These results indicate that PTH therapy could be effective in correcting serum and urine calcium and the phosphate levels in hypoparathyroidism caused by activating mutation of CaR.

Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterised by glucocorticoid insufficiency without mineralocorticoid deficiency. Here, we report a 2 yearold girl with FGD, showing tall stature and skin pigmentation, but no abnormalities of the external genitalia. Serum sodium, potassium and chloride levels were within normal ranges. Endocrinological analysis revealed low serum Cortisol (<5.5 nmol/1), elevated plasma ACTH (875.2 pmol/1) and low 17a-hydroxyprogesterone (<0.303 nmol/1). We suspected the patient of having FGD type 1. Direct and allele-specific sequence analyses of the melanocortin 2 receptor gene (MC2R) revealed compound heterozygous mutations (C21Y and R146H) in the MC2R gene. Her father and mother each had heterozygous C21Y and R146H mutations, respectively, without symptoms of glucocorticoid deficiency. This is the first report of FGD associated with a compound heterozygous mutation of C21Y and R146H in the MC2R gene. KEY WORDSfamilial glucocorticoid deficiency type 1, ACTH, MC2R, compound heterozygous mutations

To describe the characteristics of children with vitamin D deficiency, we reviewed the reports of vitamin D deficiency among Japanese children that were published between 1989 and 2008. We identified 25 patients with vitamin D deficiency in 9 published studies and evaluated their clinical characteristics together with those of 3 patients we recently treated. The patients were distributed in two distinct age groups at diagnosis: < 1 year old and > 1 year old. The main symptom of the < 1 year old age group was hypocalcemic convulsions and that of the > 1 year old age group was bowed legs. Serum calcium, intact PTH, and 1,25(OH)2D levels were significantly lower in the < 1 year age group than in the > 1 year age group. It would be useful to find and make early interventions in cases of children at a high-risk of vitamin D deficiency. KEY WORDSvitamin D deficiency; vitamin D deficient rickets, hypocalcemia

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Diagnosis is usually made when the duplex kidney is recognized. 3 It is more frequent on the right side with female predominance. 1,3,4 However, it can occur atypically, without evidence of duplication of the collecting system or pathognomonic images, 3,4 having characteristics of mass or solid appearance in imaging studies, which can lead to diagnostic uncertainty. Biopsy or resection may be required to obtain a definitive diagnosis. 1 These cases are more common on the left side and they have a male predominance. 3 Renal masses such as hydronephrosis, multicystic nephroma, Wilms tumor, renal cell carcinoma, clear cell sarcoma and mesoblastic nephron should therefore be included in its differential diagnosis, although some are predominantly solid. 1,4 The Lin et al. criteria have been proposed for diagnosis: 3,4 (i) segment of renal parenchyma in imaging test is completely replaced by non-communicating cysts of various sizes without distinguishing renal parenchyma in the lesion, or histological characteristics compatible in the lesion; (ii) renal scintigraphy demonstrate little or no activity of the lesion, and (iii) normal parenchyma seen in the non-affected segment.Other nephro-urological abnormalities have been reported in these patients. [1][2][3][4] Vesicoureteral reflux is the most frequent. [2][3][4] Voiding cystourethrography (VCUG) is recommended in UTIs and anomalies of contralateral upper urinary tract and/or kidney. 2 The ceVUS is an alternative to conventional VCUG. It has comparable or superior sensitivity and it is radiation free. 5 Segmental dysplasias often involute spontaneously, 1,3,4 but follow up is recommended because complications such as hypertension, recurrent UTIs, abdominal pain, or haematuria may require surgical treatment.

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