Reproductive history of patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

OBJECTIVE: To study the reproductive history of patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) who have a nonfunctioning vitamin D receptor (VDR). DESIGN: Retrospective cohort study. SETTING: Tertiary university-affiliated medical center. PATIENT(S): Sixteen HVDRR patients and six spouses, four female and two male. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The data on age at menarche, time of conception, and number of pregnancies, abortions, and healthy newborns as reported by HVDRR women and partners of HVDRR men were analyzed, as were the results of semen sample analyses from HVDRR men. RESULT(S): All 16 patients had normal puberty. The mean age at menarche was 13.8 ± 0.8 years. Two married HVDRR women reported four normal pregnancies and four healthy newborns. Four married HVDRR men reported 15 pregnancies and nine healthy newborns. The wives of two of these men, who are brothers, gave birth to three healthy newborns and had six natural miscarriages during the second trimester of pregnancy. Time to conceive for all the female study patients was <1 year. Analysis of semen from the four men showed normal parameters. CONCLUSION(S): The VDR is expressed throughout the organs of reproduction, suggesting a role for vitamin D in reproduction. However, the reproductive potential of HVDRR patients with a mutant VDR gene with a nonfunctioning VDR appears to be normal.

Vitamin D Decreases Hepcidin and Inflammatory Markers in Newly Diagnosed Inflammatory Bowel Disease Paediatric Patients: A Prospective Study.

BACKGROUND AND AIMS: The role of hepcidin in inflammatory bowel disease [IBD] in children with anaemia is poorly understood. However, it has been shown that vitamin D suppresses hepcidin expression. We aimed to assess serum hepcidin levels and the effect of vitamin D treatment on those levels in newly diagnosed IBD paediatric patients. METHODS: Eighty-five children were prospectively recruited in the Dana-Dwek Children's Hospital [40 newly diagnosed IBD, 45 healthy controls, 47% female, mean age 13.5 ± 3.4 years]. Blood samples for measurement of interleukin 6 [IL-6], C-reactive protein [CRP], hepcidin, iron parameters and 25-hydroxyvitamin D [25-(OH)-D] levels were obtained at baseline. Patients with mild-to-moderate signs and symptoms of IBD were treated with 4000 units of vitamin D daily for 2 weeks, after which the blood tests were repeated. RESULTS: Basal hepcidin, IL-6, CRP and platelet counts were significantly higher, and haemoglobin, serum iron and transferrin levels were significantly lower in the IBD children compared to controls [p < 0.001]. Eighteen patients completed 2 weeks of treatment with vitamin D. Following treatment, serum 25-(OH)-D concentrations increased by 40% [from 22.5 to 32.5 ng/mL], and serum hepcidin, CRP and ferritin levels decreased by 81%, 81% and 40% [from 33.9 to 6.7 ng/mL, from 23.9 to 4.7 mg/L, and from 27 to 16 ng/mL, respectively] [p ≤ 0.001]. CONCLUSION: Serum hepcidin levels were significantly higher in IBD paediatric patients compared to controls. Following vitamin D treatment, serum hepcidin concentration decreased significantly. These findings suggest a potential role for vitamin D in treating anaemia in IBD children. CLINICALTRIALS.GOV NUMBER: NCT03145896.

The interrelationship between hepcidin, vitamin D, and anemia in children with acute infectious disease.

BACKGROUND: Hepcidin is a master regulator of iron metabolism. Recently, it has been shown that vitamin D suppresses hepcidin expression. Our hypothesis was that hepcidin levels inversely correlate with vitamin D levels in anemic children during acute infection. METHODS: A prospective study was performed on 90 patients (45 females, 45 males, mean age 7.3 ± 5 years) who were admitted to the pediatric ward. Sixty-two patients had infectious disease (32 with coexisting anemia, 30 without anemia), and 28 patients were hospitalized for noninfectious causes. Blood samples for IL-6, hepcidin, iron status parameters, and 25-hydroxyvitamin D (25-OHD) were obtained within 72 h after admission. RESULTS: Serum concentrations of IL-6 and hepcidin were significantly higher and 25-OHD, iron, and transferrin were significantly lower in anemic children with infectious disease compared with controls. Children with a serum 25-OHD level < 20 ng/ml had significantly increased odds of having anemia than those with a level > 20 ng/ml (OR: 6.1, CI: 1.15-32.76). Correlation analyses found positive associations between hepcidin levels and ferritin (R2 = 0.47, P < 0.001) and negative associations between hepcidin and transferrin (R2 = 0.57, P < 0.001). CONCLUSION: Higher IL-6 and lower 25-OHD levels may lead to higher hepcidin levels and subsequently to hypoferremia and anemia in children with acute infection.

Vitamin D Status among Israeli Medical Residents.

BACKGROUND: Israel is a country with a sunny climate; however, vitamin D deficiency and insufficiency are common findings in certain populations whose exposure to sunlight is limited. Medical residency is known for long indoor working hours, thus theoretically limiting the opportunities for sun exposure. OBJECTIVES: To evaluate whether the vitamin D status among residents in a single medical center in Tel Aviv is below the normal range. METHODS: Forty-six residents (28 females, 18 males, average age 33.9 ± 2.8 years) in three residency programs (internal medicine, general surgery/obstetrics and gynecology, pediatrics) were recruited. Demographic data, personal lifestyle, physical activity details and sun exposure duration were obtained by a questionnaire. Serum levels for 25(OH)D were analyzed by a radioimmunoassay. RESULTS: The mean serum 25(OH)D concentration was 29.8 ± 5.8 ng/ml. According to Institute of Medicine definitions, none of the residents were vitamin D deficient and only two residents (4%) were vitamin D insufficient (15 ng/ml each). The level of 25(OH)D was similar among the various medical specialties. The 25(OH)D levels correlated with the duration of sun exposure and the number of offspring (regression analysis: R2 = 9.2%, P < 0.04 and R2 = 8.9%, P < 0.04, respectively), but not with nutritional data, blood chemistry, or extent of physical activity. CONCLUSIONS: Most of the residents maintained normal or near normal 25(OH)D levels, indicating that the residency program itself did not pose a significant risk for vitamin D deficiency.

Duodenal Expression of 25 Hydroxyvitamin D3-1α-hydroxylase Is Higher in Adolescents Than in Children and Adults.

CONTEXT: Puberty is associated with increased dietary calcium absorption. However, little is known about the metabolic adaptations that enhance calcium absorption during puberty. OBJECTIVES: To investigate duodenal 25-hydroxy vitamin D-1α-hydroxylase (CYP 27B1) mRNA expression and duodenal 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) production in children, adolescents, and adults. DESIGN AND METHODS: CYP27B1a nd IGF1 mRNA expression and 1,25(OH)2D3 production were determined in duodenal biopsies. CYP27B1 expression was also determined after IGF1R inhibitor treatment of human and mice duodenal explants. mRNA expression was determined by RT-PCR, and CYP27B1 activity was determined by incubating duodenal explants with 25(OH)D3 and measuring 1,25(OH)2D3 production by radioimmunoassay. RESULTS: CYP27B1 mRNA expression was 13.7 and 10.4 times higher in biopsies from adolescents compared to adults and children, respectively. IGF1 mRNA expression was 30% and 45% higher in explants from adolescents and children, respectively, compared to adults. Inhibition of IGF1 receptor activity decreased CYP27B1 expression in explants from both mice (85%) and humans (24%). 1,25(OH)2D3 production reached a maximum velocity of 768 ± 268 pmol/l/mg protein at 748.8 nmol/l of 25(OH)D3 in children and adolescents, whereas the maximum velocity was 86.4 ± 43.2 pmol/l/mg protein in adults. The substrate concentration at which the enzyme shows half of its maximum activity was similar in all groups, ranging between 624 and 837 nmol/L of 25(OH)D3. CONCLUSIONS: Increased CYP27B1 expression and local duodenal 1,25(OH)2D3 production during puberty may be a metabolic adaptation that promotes dietary calcium absorption. IGF1, a major factor in skeletal growth, is also involved in the modulation of CYP27B1 expression in the gut and may increase calcium supply for the growing bone.

Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis.

1,25(OH)2D3, the active form of vitamin D, has an antiproliferative and antifibrotic effect on hepatic stellate cells. Our aim was to investigate the potential of 1,25(OH)2D3 to inhibit the development of liver fibrosis and to ameliorate established fibrosis in vivo. The antifibrotic effect of 1,25(OH)2D3 was investigated in a thioacetamide (TAA) model (as a preventive treatment and as a remedial treatment) and in a bile duct ligation model. In the preventive model, rats received simultaneously intraperitoneum injection of TAA and/or 1,25(OH)2D3 for 10 wk. In the remedial model, rats were treated with TAA for 10 wk and then received 1,25(OH)2D3 or saline for 8 wk. Fibrotic score was determined by Masson staining. Collagen I, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP1), platelet-derived growth factor (PDGF), and transforming growth factor-ß (TGF-ß) expression were measured by Western blot analysis and real-time PCR. Hypercalemia was detected by chemistry measurements. Preventive treatment of 1,25(OH)2D3 significantly suppressed liver fibrosis both macroscopically and microscopically and significantly lowered the fibrotic score of the TAA + 1,25(OH)2D3 group compared with the TAA group. 1,25(OH)2D3 significantly inhibited expression of PDGF and TGF-ß by ∼50% and suppressed the expression of collagen Iα1, TIMP1, and α-SMA by approximately three-, two-, and threefold, respectively. In contrast, 1,25(OH)2D3 was inefficient in amelioration of established liver fibrosis. Administration of 1,25(OH)2D3 to bile duct ligation rats led to a high mortality rate probably caused by hypercalcemia. We conclude that 1,25(OH)2D3 may be considered as a potential preventive treatment in an in vivo model but failed to ameliorate established cirrhosis.

Hypoparathyroidism and central diabetes insipidus: in search of the link.

UNLABELLED: Two siblings (a 15-year-old boy and an 11-year-old girl) who presented with hypocalcemic seizure at the age of 2 years and 2 months (boy) and 2 years and 4 months (girl) were diagnosed with hypoparathyroidism. At the age of 3 years, the girl developed central diabetes insipidus with good response to desmopressin acetate treatment. The family history was unremarkable, and there was no consanguinity between the parents. The father is of Iraqi/Egyptian Jewish origin and the mother is of Iranian/Romanian Jewish origin. Sequence analysis of the candidate genes for isolated hypoparathyroidism encoding calcium-sensing receptor, parathyroid hormone, and glial cells missing homolog B did not reveal any mutations. Whole-exome sequencing identified a homozygous mutation in the autoimmune regulatory gene (AIRE), c.374A>G;p.Y85C, characteristic for Jewish Iranians with autoimmune polyendocrine syndrome type 1 (APS1), which was confirmed by the Sanger sequencing. Antibodies against the adrenal, pancreatic islet cell, ovary, thyroid, pituitary, celiac, and parietal cell were negative in both siblings, while anti-diuretic hormone antibodies were positive only in the girl. No other symptoms or signs of APS1 developed during all the years of follow-up. CONCLUSION: APS1 should be part of the differential diagnosis in children presenting with isolated hypoparathyroidism or hypoparathyroidism with central diabetes insipidus (CDI). These cases show that the AIRE mutation characteristic of Iranian Jews can also be found in non-Iranian Jews.

A mutated vitamin D receptor in hereditary vitamin D-resistant rickets prevents induction of bronchial hyperreactivity and inflammation.

CONTEXT: Previous studies have reported an association between vitamin D deficiency and asthma. Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) patients provide a natural model to assess the role of the vitamin D receptor (VDR) in regulating human lung immune responses and airway hyperreactivity. OBJECTIVES: The aim of the study was to determine the role of the VDR on lung functions, airways, and systemic markers of inflammation and allergy in HVDRR patients. DESIGN AND METHODS: Thirteen HVDRR patients (aged 6-37 y) and 17 normal controls (aged 6-38 y) underwent spirometry, a methacholine challenge test (MCT), blood tests, allergy skin tests, determination of fractional exhaled nitric oxide, and measurement of serum and exhaled breath condensate cytokines, including IL-4, IL-5, IL-10, IL-17, and interferon-γ levels. RESULTS: All HVDRR patients had negative MCT results, whereas six controls (35.3%) had positive MCT results (P < .014). Serum IgE levels, eosinophil counts, and fractional exhaled nitric oxide and allergy skin test results were similar for the HVDRR patients and controls, as were the serum cytokine concentrations. The HVDRR patients had different cytokine levels in their exhaled breath condensate (increased IL-4 and IL-17 and decreased IL-5, IL-10, and interferon-γ levels) compared to the controls (P < .005). CONCLUSIONS: HVDRR patients show diverse exhaled cytokine profiles but seem to be protected against provoked bronchial hyperreactivity and clinical asthma. These findings suggest that an intact VDR has an important role in asthma pathophysiology.

The role of vitamin D receptor in innate and adaptive immunity: a study in hereditary vitamin D-resistant rickets patients.

CONTEXT: Vitamin D has regulatory effects on innate and adaptive immunity. Curiously, hereditary vitamin D-resistant rickets (HVDRR) patients show no increased incidence of infectious or autoimmune diseases. OBJECTIVES: The aim of the study was to investigate the role of vitamin D and the vitamin D receptor (VDR) in innate and adaptive immune responses in monocytes and lymphocytes from HVDRR patients. DESIGN AND METHODS: Fifteen HVDRR patients and 17 controls participated in the investigation. Activated monocytes (lipopolysaccharides) and lymphocytes (anti-CD3, CD28, and α-GalCer) were incubated with and without 25(OH)D3 (100 nM). The mRNA expressions of CYP27B1 and VDR; vitamin D response (TLR2); vitamin D response elements binding protein (hnRNP); antimicrobial peptides cathelicidin and ß-defensin; the transcription factor enhancer binding proteins C/EBPα, C/EBPß, and C/EBPε and enzymes involved in NO generation, Nos2, and Arginase1 were analyzed by RT-PCR. TNF-α, interferon-γ, IL-4, IL-10, and IL-17 concentrations in lymphocyte cultures media were measured by ELISA. RESULTS: Cathelicidin expression was lower in HVDRR monocytes than in control monocytes. 25(OH)D3 increased significantly the expression of cathelicidin in control monocytes (2.3-fold) but only slightly in HVDRR monocytes. 25(OH)D3 increased the expression of VDR (2-fold), C/EBPε (2-fold), C/EBPß (1.7-fold), and hnRNP and suppressed TLR2 only in control monocytes. Unexpectedly, 25(OH)D3 increased the expression of CYP27b1, C/EBPα, Nos2, and Arginase1 in HVDRR monocytes. TNFα and IL-17 concentrations were significantly higher in HVDRR lymphocyte cultures than in controls. 25(OH)D3 suppressed IL-17 only in control lymphocyte. 25(OH)D3 increased IL-4, IL-10, and interferon-γ concentrations in control lymphocyte media but not in HVDRR. CONCLUSIONS: Our results demonstrate impairments in various components of innate immunity in HVDTRR patients' monocytes and a proinflammatory cytokine profile in their lymphocytes. The underlying VDR-independent compensatory mechanisms that protect HVDRR patients from infections and autoimmune diseases remain undetermined.

Calcium absorption, kinetics, bone density, and bone structure in patients with hereditary vitamin D-resistant rickets.

BACKGROUND: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor gene. Children with HVDRR suffer from severe hypocalcemia and rickets that are treatable with extremely high-dose calcium supplements. Surprisingly, spontaneous recovery of calcium metabolism occurs after the end of puberty without the need for further calcium supplementation. OBJECTIVES: To evaluate the role of vitamin D receptor in intestinal calcium absorption and bone, we investigated intestinal fractional calcium absorption (FCA), bone calcium accretion (Vo+), bone mineral density (BMD), and bone structure parameters in HVDRR patients from infancy into adulthood. PATIENTS AND METHODS: Seventeen HVDRR patients aged 1.5-37 yr were investigated. FCA and Vo+ were determined by stable-calcium isotopes. BMD was determined by dual-energy x-ray absorptiometry and bone structure by high-resolution magnetic resonance imaging. RESULTS: FCA in patients aged 1.5-17 yr was 34.9 ± 11.2% compared with 57.3 ± 2.0% in age-matched controls (P < 0.00004), whereas in patients aged 18-26 yr, it was 82.0 ± 7.8 and 53.6 ± 1.2% in controls (P < 0.001). FCA of patients older than 29 yr was comparable to controls. Patients aged 18-26 yr had higher Vo+ than controls (P < 0.02). Patients under 18 and over 29 yr of age had Vo+ comparable to controls. Femoral-neck BMD Z-score was -2.38 ± 0.3 in patients under 18 yr and 0.28 ± 0.87 in postpubertal patients (P < 0.0001). Bone structure by high-resolution magnetic resonance imaging and bone parameters of HVDRR patients and controls were similar. CONCLUSIONS: Evidence from HVDRR patients reveals that calcium absorption is highly vitamin D dependent during infancy until the end of puberty, after which there is a period of about 10 yr in which mechanisms other than vitamin D-dependent ones are substantially involved in calcium absorption.

Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats.

BACKGROUND AND AIM: Hepatic stellate cells (HSCs) are key participants in liver fibrosis development. 1,25(OH)(2)D(3), the active form of vitamin D, has antiproliferative properties and antifibrotic potential, as well as a role in extracellular matrix and matrix metalloproteinase (MMP) regulation in renal and lung fibrosis. Little is known about the role of 1,25(OH)(2)D(3) in liver and its involvement in liver fibrosis. Therefore, we investigated the antiproliferative and antifibrotic effects of 1,25(OH)(2)D(3) in primary cultured HSCs and in a rat model of liver fibrosis induced by thioacetamide (TAA). METHODS: Primary HSCs were isolated from rats' livers and treated with 1,25(OH)(2)D(3). Proliferation was examined by bromodeoxyuridine. Vitamin D receptor (VDR) expression and several fibrotic markers were detected by western blot analysis and real-time PCR. Collagen Iα1 and MMP-9 promoter activity were measured by luciferase assay. MMP-9 enzymatic activity was investigated by zymography. VDR silencing was performed by sh-RNA. An in vivo study was performed on TAA-induced liver fibrosis model in rats treated with or without 1,25(OH)(2)D(3). The fibrotic score and collagen deposition were determined by Masson and by Sirius red staining. RESULTS: While VDR was highly expressed in quiescent HSCs, its expression decreased up to 40% during activation. Addition of 1,25(OH)(2)D(3) to activated HSCs stimulated VDR expression. 1,25(OH)(2)D(3) suppressed HSC proliferation and cyclin D1 expression by ~50% and tissue inhibitor of metalloproteinase 1 (TIMP-1) by 60% and led to a 40% downregulation of collagen Iα1 expression. Moreover, 1,25(OH)(2)D(3) increased MMP-9 activity by 30%. Silencing VDR by sh-RNA demonstrated that suppression of cyclin D1 and collagen Iα1 protein expression was VDR dependent. Treatment with 1,25(OH)(2)D(3) significantly reduced extracellular matrix deposition and lowered the fibrotic score in TAA-induced liver fibrosis. CONCLUSION: 1,25(OH)(2)D(3) has antiproliferative and antifibrotic effects on liver fibrosis in in vitro and in vivo models and may be considered as having potential therapeutic value.

The renin-angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D-resistance rickets (HVDRR).

Vitamin D deficiency has been linked to hypertension and an increased prevalence of cardiovascular risk factors and disease. Studies in vitamin D receptor knockout (VDR KO) mice revealed an overstimulated renin-angiotensin system (RAS) and consequent high blood pressure and cardiac hypertrophy. VDR KO mice correspond phenotypically and metabolically to humans with hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR). There are no data on the cardiovascular system in human HVDRR. To better understand the effects of vitamin D on the human cardiovascular system, the RAS, blood pressure levels, and cardiac structures were examined in HVDRR patients. Seventeen patients (9 males, 8 females, aged 6 to 36 years) with hereditary HVDRR were enrolled. The control group included age- and gender-matched healthy subjects. Serum calcium, phosphorous, creatinine, 25-hydroxyvitamin D [25(OH)D],1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ], parathyroid hormone (PTH), plasma rennin activity (PRA), aldosterone, angiotensin II (AT-II), and angiotensin-converting enzyme (ACE) levels were determined. Ambulatory 24-hour blood pressure measurements and echocardiographic examinations were performed. Serum calcium, phosphorus, and alkaline phosphatase values were normal. Serum 1,25(OH)(2) D(3) and PTH but not PRA and ACE levels were elevated in the HVDRR patients. AT-II levels were higher than normal in the HVDRR patients but not significantly different from those of the controls. Aldosterone levels were normal in all HVDRR patients. No HVDRR patient had hypertension or echocardiographic pathology. These findings reveal that 6- to 36-year-old humans with HVDRR have normal renin and ACE activity, mild but nonsignificant elevation of AT-II, normal aldosterone levels, and no hypertension or gross heart abnormalities.

Non-classic unexpected functions of vitamin D.

In the past three decades, our understanding of the physiologic functions of vitamin D1 has extended and includes many unexpected non-classic biological actions. Vitamin D receptors (VDR) and 25-hydroxyvitamin D-1αhydroxylase, the enzyme responsible for the production of 1,25(OH)2D3, the active form of vitamin D, are present in many tissues which are not associated with calcium or bone metabolism. Indeed, 1,25(OH)2D regulates cell proliferation, differentiation and apoptosis in many normal and cancer cells. Epidemiologic studies have shown that vitamin D deficiency increases the risk of cancer, cardiovascular disease and autoimmune disease. However, large scale randomized controlled intervention trials are needed to prove the effects of vitamin D on the prevention and treatment of these diseases. Expression of vitamin D or its metabolites without a subscript refer to both vitamin D2 and vitamin D3 or their metabolites.

Hypoxia induces PTHrP gene transcription in human cancer cells through the HIF-2α.

Parathyroid hormone-related protein (PTHrP) expressed by human cancer cells enhances tumor cell growth and metastasis in vivo and it is considered as the major factor responsible for humoral hypercalcemia of malignancy. Hypoxia is a widespread feature of most solid tumors. Here, we studied the effects of hypoxia on PTHrP expression. We found that PTHrP is transcriptionally induced by prolonged (48 h) hypoxia in multiple human cancer and endothelial cell lines. Pharmacological up or downregulation of hypoxia-inducible factor (HIF) resulted in induction or reduction of PTHrP levels, respectively, implying that PTHrP hypoxic induction is mediated by HIF pathway. Analysis of PTHrP promoter revealed that both HIF-1α and HIF-2α subunits bind to specific hypoxia-responsive elements (HRE) within the P2 promoter of PTHrP. However, only HIF-2α can drive direct transcriptional activation, which can be abolished by mutation in the specific HRE. To the best of our knowledge, these results provide for the first time evidence that PTHrP is regulated by hypoxia in cancer and endothelial cells through the HIF-2 pathway. We suggest that HIF-2 induced by intratumoral hypoxia or by other genetic alterations may contribute to the pathogenesis of hypercalcemia of malignancy and cancer aggressiveness by stimulation of PTHrP expression.

Parathyroid hormone-related protein in preterm human milk.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) has the ability to activate parathyroid hormone receptors and cause hypercalcemia. High concentrations of PTHrP are found in human breastmilk of mothers of term-infants. It is not known whether PTHrP is excreted in preterm human milk. This study tested the hypothesis that PTHrP concentrations in milk obtained from mothers of preterm infants are similar to those found in milk from mothers of term infants. METHODS: We collected samples of expressed human milk obtained from 27 mothers of preterm infants (27-34 weeks' gestation) and from 16 mothers of full-term infants. Samples were collected within the first 72 hours postpartum (colostrum) and again at 1 and 2 weeks postpartum. PTHrP concentrations in these samples were measured by two-site immunoradiometric assay. RESULTS: PTHrP concentrations were significantly higher in samples obtained after 1 week postpartum than in samples obtained during the first 72 hours of life in breastmilk obtained from mothers of both term and preterm infants (P < 0.0001). PTHrP concentrations were similar in colostrum and after 1 week in term and preterm milk. PTHrP concentrations after 2 weeks of lactation were significantly higher in samples obtained from mothers of term infants (P < 0.006). CONCLUSION: Human milk expressed by mothers of preterm infants contains amounts of PTHrP similar to those measured in milk expressed by mothers of term infants.

HsCRP levels: measurement of airway inflammation in asthmatic children.

BACKGROUND: The inflammatory marker, high-sensitivity C-reactive protein (HsCRP), is known to be related to non-allergic asthma, obesity, cardiovascular disease and smoking in adults. The aim of the present study was to determine whether HsCRP is related to respiratory symptoms and pulmonary function test findings in asthmatic children. METHODS: HsCRP was measured in 63 asthmatic children aged 2-12 years. The measurements were performed in 37 children during an episode of acute exacerbation and in 42 children during remission. RESULTS: HsCRP level (14.28 +/- 8.45 mg/L) during exacerbation was significantly higher than the mean level (1.92 +/- 3.16 mg/L) during remission (P < 0.0001), with the decrease being more prominent in children with a low body mass index percentile (P < 0.05). A reciprocal relationship was found between forced expiratory volume in 1 s and high-sensitivity C-reactive protein values (P > 0.049). CONCLUSION: Elevated HsCRP levels were significantly associated with respiratory impairment in children.

25 hydroxy-vitamin D(3)-1alpha hydroxylase expression and activity in cultured human osteoblasts and their modulation by parathyroid hormone, estrogenic compounds and dihydrotestosterone.

Human osteoblasts (hOB) produce and respond to 1,25(OH)(2)D(3) (1,25D), suggesting an autocrine/paracrine system. We therefore examined hormonal modulation of the expression and activity of 25 hydroxy-vitamin D(3)-1alpha hydroxylase (1-Ohase) in hOB. Cells from pre- and post-menopausal women or men, were treated with estrogenic compounds and 1-OHase expression and activity were measured. 1-OHase mRNA expression was highest in pre-menopausal women hOB and was increased by all hormones tested. In post-menopausal hOB all hormones except biochainin A (BA) and genistein (G) increased 1-OHase mRNA expressions to less extent. In male-derived hOB only dihydrotestosterone (DHT) and carboxy BA (cBA) increased 1-OHase mRNA expression. 1,25D production from 25(OH)D(3) had a K(m) of approximately 769-400 ng/ml (1.92-1.07 microM) and V(max) of 31.3-17.4 ng/ml (0.078-0.044 microM/60 min/5 x 10(6)cells) respectively, and was increased by all hormones except raloxifene (Ral) with higher stimulation in pre- than in post-menopausal cells. Only BA was almost five times more potent in pre- rather than post-menopausal hOBs. In male hOB only DHT and cBA increased 1,25D production whereas estradiol-17beta (E(2)) had no effect and BA decreased it. These results provide evidence for the expression of 1-OHase mRNA and production of 1,25D in hOBs, which are age and sex dependent and are hormonally modulated. The role of this local autocrine/paracrine 1,25D system in bone physiology deserves further investigation.

1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells.

In vitro and in vivo studies have shown that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits angiogenesis in cancer. We now examined whether the antiangiogenic effects of 1,25(OH)(2)D(3) are mediated by the hypoxia-inducible factor (HIF)-1 pathway. Our results showed that 1,25(OH)(2)D(3) reduces the protein expression of both the regulated HIF-1alpha subunit and the vascular endothelial growth factor (VEGF) in various human cancer cells. 1,25(OH)(2)D(3) also inhibited HIF-1 transcriptional activity (measured by reporter gene assay) as well as HIF-1 target genes, including VEGF, ET-1, and Glut-1. We also showed that 1,25(OH)(2)D(3) inhibits cell proliferation under hypoxia. Using HIF-1alpha knockout colon cancer cells, we show that the inhibition of the hypoxia-induced VEGF by 1,25(OH)(2)D(3) is mediated through a HIF-dependent pathway. Because HIF-1 is a major positive contributor in human tumorigenesis and angiogenesis, we believe that its inhibition by 1,25(OH)(2)D(3) strengthens the rationale to use vitamin D and its low-calcemic analogues in cancer chemoprevention and therapy.

Is there a role for a random measurement of 24-hour urine calcium excretion in the determination of calcium supplementation in osteoporotic postmenopausal women using alendronate?

The article addresses the clinical query whether a casual determination of 24-hour urinary calcium excretion by the end of first-year treatment with alendronate in osteoporotic postmenopausal women correlates with the change in bone mineral density achieved during that year. The study included 2 arms: a prospective arm (n = 31) with women on long-term hormone replacement therapy were followed for 1 year after addition of alendronate (10 mg/daily); a retrospective arm (n = 33) with women using alendronate for 1 year. Bone mineral density and urine deoxypyridinoline were measured at baseline and 1 year, 24-hour urine calcium was obtained at 1 year. All patients used supplemental calcium, but the exact intake values were not determined. The results demonstrated no correlation between the annual increase in both spine and femur bone density and urinary calcium. Assuming that urinary calcium correlates with calcium intake and absorption, a casual measurement of urinary calcium excretion seems irrelevant for the titration of optimal calcium supplementation in this clinical setup.