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1.  VITamin D supplementation in renAL transplant recipients (VITALE): a prospective, multicentre, double-blind, randomized trial of vitamin D estimating the benefit and safety of vitamin D3 treatment at a dose of 100,000 UI compared with a dose of 12,000 UI in renal transplant recipients: study protocol for a double-blind, randomized, controlled trial 
Trials  2014;15(1):430.
Background
In addition to their effects on bone health, high doses of cholecalciferol may have beneficial non-classic effects including the reduction of incidence of type 2 diabetes mellitus, cardiovascular disease, and cancer. These pleiotropic effects have been documented in observational and experimental studies or in small intervention trials. Vitamin D insufficiency is a frequent finding in renal transplant recipients (RTRs), and this population is at risk of the previously cited complications.
Methods/design
The VITALE study is a prospective, multicentre, double-blind, randomized, controlled trial with two parallel groups that will include a total of 640 RTRs. RTRs with vitamin D insufficiency, defined as circulating 25-hydroxyvitamin D levels of less than 30 ng/ml (or 75 nmol/l), will be randomized between 12 and 48 months after transplantation to blinded groups to receive vitamin D3 (cholecalciferol) either at high or low dose (respectively, 100,000 UI or 12,000 UI every 2 weeks for 2 months then monthly for 22 months) with a follow-up of 2 years. The primary objective of the study is to evaluate the benefit/risk ratio of high-dose versus low-dose cholecalciferol on a composite endpoint consisting of de novo diabetes mellitus; major cardiovascular events; de novo cancer; and patient death. Secondary endpoints will include blood pressure (BP) control; echocardiography findings; the incidences of infection and acute rejection episodes; renal allograft function using estimated glomerular filtration rate; proteinuria; graft survival; bone mineral density; the incidence of fractures; and biological relevant parameters of mineral metabolism.
Discussion
We previously reported that the intensive cholecalciferol treatment (100 000 IU every 2 weeks for 2 months) was safe in RTR. Using a pharmacokinetic approach, we showed that cholecalciferol 100,000 IU monthly should maintain serum 25-hydroxyvitamin D at above 30 ng/ml but below 80 ng/ml after renal transplantation. Taken together, these results are reassuring regarding the safety of the cholecalciferol doses that will be used in the VITALE study. Analysis of data collected during the VITALE study will demonstrate whether high or low-dose cholecalciferol is beneficial in RTRs with vitamin D insufficiency.
Trial registration
ClinicalTrials.gov Identifier: NCT01431430.
doi:10.1186/1745-6215-15-430
PMCID: PMC4233037  PMID: 25376735
Interventional trial; Vitamin D; Renal transplantation; Cancer; Cardiovascular events; Diabetes mellitus
2.  Effects of vitamin D in the elderly population: current status and perspectives 
Archives of Public Health  2014;72(1):32.
Besides its well-known effect on bone metabolism, recent researches suggest that vitamin D may also play a role in the muscular, immune, endocrine, and central nervous systems. Double-blind RCTs support vitamin D supplementation at a dose of 800 IU per day for the prevention of falls and fractures in the senior population. Ecological, case–control and cohort studies have suggested that high vitamin D levels were associated with a reduced risk of autoimmune diseases, type 2 diabetes, cardio-vascular diseases and cancer but large clinical trials are lacking today to provide solid evidence of a vitamin D benefit beyond bone health. At last, the optimal dose, route of administration, dosing interval and duration of vitamin D supplementation at a specific target dose beyond the prevention of vitamin D deficiency need to be further investigated.
doi:10.1186/2049-3258-72-32
PMCID: PMC4181706  PMID: 25279143
3.  Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis 
The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein–Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother’s pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.
doi:10.1177/1756285612473513
PMCID: PMC3582312  PMID: 23483715
Epstein–Barr virus; genetics; multiple sclerosis; smoking; vitamin D
4.  Determination of the best method to estimate glomerular filtration rate from serum creatinine in adult patients with sickle cell disease: a prospective observational cohort study 
BMC Nephrology  2012;13:83.
Background
Sickle cell disease (SCD) leads to tissue hypoxia resulting in chronic organ dysfunction including SCD associated nephropathy. The goal of our study was to determine the best equation to estimate glomerular filtration rate (GFR) in SCD adult patients.
Methods
We conducted a prospective observational cohort study. Since 2007, all adult SCD patients in steady state, followed in two medical departments, have had their GFR measured using iohexol plasma clearance (gold standard). The Cockcroft-Gault, MDRD-v4, CKP-EPI and finally, MDRD and CKD-EPI equations without adjustment for ethnicity were tested to estimate GFR from serum creatinine. Estimated GFRs were compared to measured GFRs according to the graphical Bland and Altman method.
Results
Sixty-four SCD patients (16 men, median age 27.5 years [range 18.0-67.5], 41 with SS-genotype were studied. They were Sub-Saharan Africa and French West Indies natives and predominantly lean (median body mass index: 22 kg/m2 [16-33]). Hyperfiltration (defined as measured GFR >110 mL/min/1.73 m2) was detected in 53.1% of patients. Urinary albumin/creatinine ratio was higher in patients with hyperfiltration than in patients with normal GFR (4.05 mg/mmol [0.14-60] versus 0.4 mg/mmol [0.7-81], p = 0.01). The CKD-EPI equation without adjustment for ethnicity had both the lowest bias and the greatest precision. Differences between estimated GFRs using the CKP-EPI equation and measured GFRs decreased with increasing GFR values, whereas it increased with the Cockcroft-Gault and MDRD-v4 equations.
Conclusions
We confirm that SCD patients have a high rate of glomerular hyperfiltration, which is frequently associated with microalbuminuria or macroalbuminuria. In non-Afro-American SCD patients, the best method for estimating GFR from serum creatinine is the CKD-EPI equation without adjustment for ethnicity. This equation is particularly accurate to estimate high GFR values, including glomerular hyperfiltration, and thus should be recommended to screen SCD adult patients at high risk for SCD nephropathy.
doi:10.1186/1471-2369-13-83
PMCID: PMC3465224  PMID: 22866669
Sickle cell disease; Glomerular hyperfiltration; Albuminuria; Glomerular filtration rate; CKD-EPI equation; Iohexol plasma clearance; Ethnicity
5.  Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up 
Lupus Science & Medicine  2014;1(1):e000027.
Objectives
Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups.
Methods
Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361).
Results
The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D <10 ng/mL) was observed in 27 (15.9%), insufficiency (10≤25(OH)D<30) in 112 (65.9%) and optimal vitamin D status (25(OH)D≥30) in 31 (18.2%) patients. In multivariate analysis, female gender (p=0.018), absence of defined antiphospholipid syndrome (p=0.002) and higher creatinine clearance (p=0.004) were predictive of lower 25(OH)D levels. In multivariate analysis, lower 25(OH)D levels were associated with high SLE activity (p=0.02). Relapse-free survival rate was not statistically different according to the vitamin D status during the 6-month follow-up (p=0.22).
Conclusions
We found a low vitamin D status in the majority of patients with SLE, and a modest association between lower 25(OH)D levels and high disease activity. There was no association between baseline 25(OH)D levels and relapse-free survival rate.
doi:10.1136/lupus-2014-000027
PMCID: PMC4213833  PMID: 25379192
vitamin D; Systemic Lupus Erythematosus; Autoimmune Diseases; hydroxychloroquine
6.  Diagnosis of growth hormone (GH) deficiency: comparison of pituitary stalk interruption syndrome and transient GH deficiency 
BMC Pediatrics  2009;9:29.
Background
Most patients with childhood non-organic growth hormone (GH) deficiency (GHD) produce a normal GH peak as young adults. Our objectives were to better define this transient GHD and evaluate the factors influencing the growth response of patients with pituitary stalk interruption syndrome (PSIS).
Methods
We studied 72 prepubertal patients with a GH peak < 6.7 ng/ml after 2 stimulation tests, treated with 0.2 mg GH/kg/w for at least 3 years. Group 1 (n = 53, 4.7 ± 4.0 years) had PSIS and Group 2 (n = 19, 9.2 ± 3.0 years) had transient GHD and normal pituitary.
Results
At diagnosis, 64% of Group 1 and one Group 2 were < 5 years old. The growth rate of 59% Group 1 and two Group 2 patients was ≤ -2 SDS. The GH peak of 64% Group 1 patients and no Group 2 patients was < 3 ng/ml. The plasma insulin-like growth factor-1 of all Group 1 and all but one Group 2 patients was ≤ -2 z scores.
During the first year of GH treatment, the growth rate was ≥ 2 SDS in 81% Group 1 and 37% Group 2 patients. In Group 1, it was negatively correlated with the GH peak before treatment (P < 0.03), and with the difference between the target and adult heights (P < 0.01).
The height gain SDSs between diagnosis and adult height were 1.7 ± 1.2 in Group 1 (n = 30) and 1.08 ± 0.8 in Group 2 (n = 12, P = 0.05).
Conclusion
The factors of the growth response to GH treatment should be analysed separately for each population: with and without PSIS or other markers.
doi:10.1186/1471-2431-9-29
PMCID: PMC2684107  PMID: 19419564
7.  Childhood craniopharyngioma: greater hypothalamic involvement before surgery is associated with higher homeostasis model insulin resistance index 
BMC Pediatrics  2009;9:24.
Background
Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA). As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R) and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change.
Methods
27 children with craniopharyngioma were classified as either grade 0 (n = 7, no hypothalamic involvement), grade 1 (n = 8, compression without involvement), or grade 2 (n = 12, severe involvement).
Results
Despite having similar body mass indexes (BMI), the grade 2 patients had higher glucose, insulin and HOMA before surgery than the grade 0 (P = 0.02, <0.05 and 0.02 respectively) and 1 patients (P < 0.02 and <0.03 for both insulin and HOMA). The grade 0 (5.8 ± 4.9) and 1 (7.2 ± 5.3) patients gained significantly less weight (kg) during the year after surgery than did the grade 2 (16.3 ± 7.4) patients. The pre-surgery HOMA was positively correlated with these weight changes (P < 0.03).
The data for the whole population before and 6–18 months after surgery showed increases in BMI (P < 0.0001), insulin (P < 0.005), and leptin (P = 0.0005), and decreases in sOB-R (P < 0.04) and ghrelin (P < 0.03).
Conclusion
The hypothalamic involvement by the craniopharyngioma before surgery seems to determine the degree of insulin resistance, regardless of the BMI. The pre-surgery HOMA values were correlated with the post-surgery weight gain. This suggests that obesity should be prevented by reducing inn secretion in those cases with hypothalamic involvement.
doi:10.1186/1471-2431-9-24
PMCID: PMC2675525  PMID: 19341477
8.  Selecting short-statured children needing growth hormone testing: Derivation and validation of a clinical decision rule 
BMC Pediatrics  2008;8:29.
Background
Numerous short-statured children are evaluated for growth hormone (GH) deficiency (GHD). In most patients, GH provocative tests are normal and are thus in retrospect unnecessary.
Methods
A retrospective cohort study was conducted to identify predictors of growth hormone (GH) deficiency (GHD) in children seen for short stature, and to construct a very sensitive and fairly specific predictive tool to avoid unnecessary GH provocative tests. GHD was defined by the presence of 2 GH concentration peaks < 10 ng/ml. Certain GHD was defined as GHD and viewing pituitary stalk interruption syndrome on magnetic resonance imaging. Independent predictors were identified with uni- and multi-variate analyses and then combined in a decision rule that was validated in another population.
Results
The initial study included 167 patients, 36 (22%) of whom had GHD, including 5 (3%) with certain GHD. Independent predictors of GHD were: growth rate < -1 DS (adjusted odds ratio: 3.2; 95% confidence interval [1.3–7.9]), IGF-I concentration < -2 DS (2.8 [1.1–7.3]) and BMI z-score ≥ 0 (2.8 [1.2–6.5]). A clinical decision rule suggesting that patients be tested only if they had a growth rate < -1 DS and a IGF-I concentration < -2 DS achieved 100% sensitivity [48–100] for certain GHD and 63% [47–79] for GHD, and a specificity of 68% [60–76]. Applying this rule to the validation population (n = 40, including 13 patients with certain GHD), the sensitivity for certain GHD was 92% [76–100] and the specificity 70% [53–88].
Conclusion
We have derived and performed an internal validation of a highly sensitive decision rule that could safely help to avoid more than 2/3 of the unnecessary GH tests. External validation of this rule is needed before any application.
doi:10.1186/1471-2431-8-29
PMCID: PMC2492843  PMID: 18631396
9.  Factors influencing the growth hormone peak and plasma insulin-like growth factor I in young adults with pituitary stalk interruption syndrome 
Background
The diagnostic criteria for growth hormone (GH) deficiency (GHD) in adolescents and young adults are not yet clearly established.
We evaluated the factors influencing the GH peak and plasma insulin-like growth factor (IGF) I in order to determine the cut-off limits for the diagnosis of GHD during the transition period.
Methods
21 patients treated for GHD due to pituitary stalk interruption syndrome at 5.7 ± 4.1 years were reevaluated at 16.0 ± 1.8 years, 0.6 ± 0.6 years after the end of GH treatment. Group 1 had isolated GHD (n = 9) and group 2 had multiple pituitary deficiencies (n = 12), including deficiencies of thyroid stimulating (n = 12), adrenocorticotropin (n = 8) and gonadotropin (n = 9) hormones.
Results
At diagnosis, group 1 had a greater pituitary height (2.8 ± 1.2 vs 1.6 ± 1.1 mm, P = 0.03) and GH peak (3.8 ± 1.9 vs 1.6 ± 1.5 ng/ml, P < 0.02) than did group 2.
At last evaluation, group 1 had greater GH peak (3.9 ± 1.9 vs 0.2 ± 0.4 ng/ml, P = 0.0001) and plasma IGF I (211 ± 88 vs 78 ± 69 ng/ml, P < 0.002) than did group 2. No group 1 and 9 group 2 patients had an undetectable GH peak, while the 3 others had GH peak below 1 ng/ml.
The GH peak decreased between diagnosis and last evaluation only in group 2 (P < 0.008).
Conclusion
The GH peak response to pharmacological stimulation and the plasma IGF I concentration in young adults with GHD of childhood onset depend on the presence of additional pituitary deficiencies, reflecting a more severe defect of the hypothalamic-pituitary axis. The sex steroids cannot increase the IGF I if the GH secretion is zero.
doi:10.1186/1472-6823-8-7
PMCID: PMC2474832  PMID: 18620575
10.  Associations between 25-Hydroxyvitamin D and Immunologic, Metabolic, Inflammatory Markers in Treatment-Naive HIV-Infected Persons: The ANRS CO9 «COPANA» Cohort Study 
PLoS ONE  2013;8(9):e74868.
Objectives
Low 25(OH)D has been associated with dyslipidemia, insulin resistance and inflammation in both general and HIV-infected (mostly treated) populations. We investigated these associations in antiretroviral-naïve HIV-infected persons.
Design
We measured plasma 25(OH)D, metabolic, immunologic and inflammatory markers in 355 persons (204 Whites, 151 Blacks) at enrollment in the ANRS COPANA cohort.
Methods
25(OH)D levels were categorized <10 ng/mL (severe deficiency) and <20 ng/mL (deficiency). Statistical analyses were adjusted for sampling season, ethnicity and the interaction between season and ethnicity.
Results
25(OH)D insufficiency (<30 ng/mL), deficiency (<20 ng/mL) and severe deficiency (<10 ng/mL) were highly prevalent (93%, 67% and 24% of patients, respectively). Blacks had significantly lower 25(OH)D than Whites (median: 13 vs. 17 ng/mL, P<0.001), with markedly less pronounced seasonal variation. Smoking and drinking alcohol were associated with having a 25 OHD level<10 ng/mL. In patients with 25(OH)D<10 ng/mL, the proportion of persons with a CD4 count<100/mm3 was higher than in patients with 25(OH)D≥10 ng/mL (18.8% vs. 10.7%, P = 0.04). Persons with 25 OHD<10 ng/mL had higher levels of hsCRP (1.60 mg/L [IQR: 0.59–5.76] vs. 1.27 mg/L [0.58–3,39], P = 0.03) and resistin (16.81 ng/L [IQR: 13.82–25.74] vs. 11.56 ng/L [IQR: 8.87–20.46], P = 0.02), and, among Blacks only, sTNFR2 (2.92 ng/mL [2.31–4.13] vs. 2.67 ng/mL, [1.90–3.23], P = 0.04). The strength and significance of the association between CD4<100/mm3 and 25 OHD<10 ng/mL were reduced after adjustment on sTNFR1, sTNFR2, and hsCRP levels. In multivariate analysis, a CD4 count <100/mm3, resistin concentration and smoking were independently associated with 25(OH)D<10 ng/mL.
Conclusions
Severe vitamin D deficiency was associated with low CD4 counts and increased markers of inflammation in ARV-naïve HIV-infected persons.
doi:10.1371/journal.pone.0074868
PMCID: PMC3776742  PMID: 24058636
11.  A Randomised, Double-Blinded, Placebo-Controlled, Parallel Study of Vitamin D3 Supplementation with Different Schemes Based on Multiples of 25,000 IU Doses 
Vitamin D (VTD) treatment is recommended in patients presenting different causes of diseases. To treat these patients, physicians rely on the different available pharmaceutical forms present in their country. Unfortunately, even in a given country, there is no consensus on the best way to treat the patients. In Belgium, VTD is mostly prescribed as ampoules containing 25,000 IU of VTD. In this randomised controlled study, we evaluated whether four therapeutic schemes using multiples of 25,000 IU of VTD according to basal vitamin D concentration were able to increase or maintain the 25(OH)D serum level above 30 ng/mL. We randomized 175 subjects who received the drug (n = 140) or placebo (n = 35). Total duration of the study was 12 weeks. Doses ranged from 4167 to 1667 IU/day. Blood sampling was performed at baseline and each 4 visits. In the treated (placebo) subjects, mean 25(OH)D serum concentration was 18.7 (19.1) ng/mL at baseline and 31.5 (20.7) ng/mL at w-12. At the end of the study, 57.1% of the subjects treated with VTD presented 25(OH)D serum concentration ≥30 ng/mL, whereas 94.3% were ≥20 ng/mL. In conclusion, the doses administered were safe and increased or maintained the 25(OH)D concentration ≥20 ng/mL. However, concentrations ≥30 ng/mL were only achieved in 57.1% of the subjects.
doi:10.1155/2013/327265
PMCID: PMC3568854  PMID: 23431293
12.  Pituitary Stalk Interruption Syndrome in 53 Postpubertal Patients: Factors Influencing the Heterogeneity of Its Presentation 
PLoS ONE  2013;8(1):e53189.
Background
Pituitary stalk interruption syndrome (PSIS) may induce an isolated growth hormone (GH) deficiency or multiple hypothalamic-pituitary (HP) deficiencies. Patients with multiple HP deficiencies, primarily those with adrenocorticotropin (ACTH) deficiency, are at increased risk of morbidity and mortality. Our objective was to identify the factors influencing each symptom and the MRI features of the syndrome to enhance its diagnosis and genetic analysis.
Methods
This study was a retrospective, single-center, case-cohort study of 53 patients with PSIS who had reached pubertal age.
Results
Patients were classified as having an isolated GH deficiency (n = 24, Group 1) or HP deficiencies (n = 29, Group 2); of these, 19 had complete HP deficiency, and 10 had GH deficiency associated with TSH (n = 4), TSH and ACTH (n = 3), TSH and gonadotropin (n = 1) deficiencies or amenorrhea (n = 2). The following features were less frequent in Group 1 than in Group 2: breech presentation (4% vs 35%, P = 0.008), hypoglycemia (0% vs 59%, P<0.00001), micropenis (13% vs 69%, P<0.003), hypothalamic origin (0% vs 52%, P<0.000001), ophthalmic malformation (8% vs 38%, P<0.02) and psychomotor delay (0% vs 31%, P<0.004). The frequencies of all other malformations were similar in both groups (37% vs 59%). A visible pituitary stalk was characteristic of patients belonging to Group 1 (P<0.0002). The GH peak was greater in Group 1 than in Group 2 (P<0.0003), as was the anterior pituitary height (P = 0.01).
Conclusion
The factors that best discriminate patients with multiple HP deficiencies from those with an isolated GH deficiency are breech presentation, hypoglycemia, and micropenis. No patient with an isolated GH deficiency had psychomotor delay, but associated malformations and/or syndromes, with the exception of ophthalmic disorders, occurred with similar frequencies in both groups. We have also shown that each of the above characteristics is associated with a given HP deficiency and/or malformation/syndrome in the majority of cases.
doi:10.1371/journal.pone.0053189
PMCID: PMC3538767  PMID: 23308160
13.  Higher Cord C-Peptide Concentrations Are Associated With Slower Growth Rate in the 1st Year of Life in Girls but Not in Boys 
Diabetes  2011;60(8):2152-2159.
OBJECTIVE
To understand the relationships between maternal glycemia during pregnancy and prenatal and early postnatal growth by evaluating cord C-peptide and IGF-I as mediating biomarkers in boys and girls separately.
RESEARCH DESIGN AND METHODS
We evaluated 342 neonates within the EDEN mother-child cohort study born to mothers without diabetes diagnosis before pregnancy. We measured maternal glycemia at 24–28 weeks of gestation and neonates’ cord blood C-peptide (used as a proxy for fetal insulin) and IGF-I at birth. Reported maternal prepregnancy BMI and all measured infant weights and lengths in the 1st year were recorded. Growth modeling was used to obtain an individual growth curve for each infant in the 1st year. Path models, a type of structural equation modeling, were used for statistical analysis. Path analysis is a multivariate method associated with a graphical display that allows evaluation of mediating factors and distinguishes direct, indirect, and total effects.
RESULTS
Cord C-peptide at birth was positively correlated with maternal prepregnancy BMI and maternal glycemia and was higher in girls. In a path model that represented prenatal growth, there was no significant direct effect of maternal glycemia on birth weight, but the effect of maternal glycemia on birth weight was mediated by fetal insulin and IGF-I in both girls and boys. However, in girls only, higher concentrations of cord C-peptide (but not cord IGF-I or maternal glucose) were associated with slower weight growth in the first 3 months of life.
CONCLUSIONS
Our study underlines the role of the fetal insulin–IGF-I axis in the relationship between maternal glycemia during pregnancy and birth weight. We also show for the first time that high insulin concentration in female fetuses is associated with slower early postnatal growth. This slow, early growth pattern may be programmed by fetal hyperinsulinemia, and girls may be more susceptible than boys to its consequences.
doi:10.2337/db10-1189
PMCID: PMC3142086  PMID: 21700880
14.  Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation 
Background:
Vitamin D could play a protective role in multiple sclerosis.
Methods:
In an observational, uncontrolled study, vitamin D3 supplementation (3010 IU/day on average) was given to 156 consecutive patients with relapsing–remitting multiple sclerosis, under first-line immunomodulatory therapy and with initial 25-OH-D serum level lower than 100 nmol/l (40 ng/ml). Relapses were determined for 29.1 ± 8.4 months during vitamin D and 29.8 ± 10.1 months before supplementation. The 25-OH-D level was measured before supplementation and several times during supplementation. The incidence rate of relapses before and during supplementation was estimated using negative binomial regression models with follow-up durations as offset terms. The incidence rate and incidence rate ratio of relapses at various 25-OH-D levels were also calculated using negative binomial regression models.
Results:
In 76 patients, immunomodulatory therapy preceded vitamin D supplementation (by 4.2 ± 2.7 years) and in 80 patients both treatments were started simultaneously. Under supplementation, the 25-OH-D level increased from 49 ± 22 nmol/l to 110 ± 26 nmol/l on average. Pooling data collected before and during supplementation, we found a significant strong inverse relationship between the relapse incidence rate and the 25-OH-D level (p < 0.0001), suggesting that vitamin D did indeed influence the relapse rate. Results of univariate, bivariate and multivariate analyses were analogous: in the multivariate model adjusted for age, disease duration and previous use of immunomodulatory therapy, every 10 nmol increase in 25-OH-D level was associated with a reduction in the relapse incidence rate of 13.7%. Dividing iteratively the population made up of pooled periods into two subgroups according to the 25-OH-D levels, the relapse incidence rate ratio decreased as the 25-OH-D level increased up to 110 nmol/l, but a plateau effect was observed beyond this limit.
Conclusion:
Further studies are warranted for accurate quantification of the vitamin D effect.
doi:10.1177/1756285612447090
PMCID: PMC3388527  PMID: 22783368
multiple sclerosis; relapse rate; vitamin D; vitamin D supplementation
15.  Non-Truncated Amino-Terminal PTH Overproduction in Two Patients with Parathyroid Carcinoma: A Possible Link to HRPT2 Gene Inactivation 
Clinical endocrinology  2011;74(6):694-698.
Summary
Objective
Some patients with parathyroid carcinoma present with an over-production of non-truncated amino-terminal (NT-N) PTH, a post-transcriptionally modified form of PTH(1-84). This is usually picked up on an elevated Whole (W) PTH (3rd generation) / Total (T) (2nd generation) PTH assay ratio (N > 0.8).
Patients and Design
Two parathyroid cancer patients with several episodes of hypercalcemia and multiple surgeries are described. In both, W-PTH, T-PTH and circulating PTH molecular forms separated by HPLC were measured with the same assays. qPCR was used to study HRPT2 gene mutation.
Results
The first patient had total calcium of 3.8 and 3.22 mmol/L before the 4th and 5th surgeries, and 3rd/2nd generation PTH ratios of 2.95 and 3.6, respectively. After the 4th surgery, the ratio remained normal for one year and increased progressively to 3.6 over 15 months. This preceded hypercalcemia by 6 months. The ratio became normal after the 5th surgery. HPLC analysis disclosed an over-expression of NT-N PTH to 82.2% (N < 10%) relative to hPTH(1-84) before the 5th surgery. A deletion of all the tested exons of the HRPT2 gene was identified. In the second patient, W-PTH/T-PTH ratio was 0.89 when serum calcium was 3.3 mmol/L. NT-N PTH was also over-expressed at 51.9%. An inactivating mutation of the HRPT2 gene was also identified.
Conclusions
This may suggest that a progressive rise in 3rd/2nd generation ratio may have possible clinical utility to monitor parathyroid cancer recurrence. A possible association between NT-N PTH overproduction and HRPT2 gene inactivation is also suggested.
doi:10.1111/j.1365-2265.2011.04021.x
PMCID: PMC3089698  PMID: 21521290
Hypercalcemia; hyperparathyroidism; parathyroid carcinoma; PTH assays; HRPT2 gene

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