Search

BackgroundGlobal trends in cardiovascular disease (CVD) exhibit considerable interregional and interethnic differences, which in turn affect long-term CVD risk across diverse populations. An in-depth understanding of the interplay between ethnicity, socioeconomic status, and CVD risk factors and mortality in a contemporaneous population is crucial to informing health policy and resource allocation aimed at mitigating long-term CVD risk. Generating bespoke large-scale and reliable data with sufficient numbers of events is expensive and time-consuming but can be circumvented through utilization and linkage of data routinely collected in electronic health records (EHR). ObjectiveWe aimed to characterize the burden of CVD risk factors across different ethnicities, age groups, and socioeconomic groups, and study CVD incidence and mortality by EHR linkage in London. MethodsThe proposed study will initially be a cross-sectional observational study unfolding into prospective CVD ascertainment through longitudinal follow-up involving linked data. The government-funded National Health System (NHS) Health Check program provides an opportunity for the systematic collation of CVD risk factors on a large scale. NHS Health Check data on approximately 200,000 individuals will be extracted from consenting general practices across London that use the Egton Medical Information Systems (EMIS) EHR software. Data will be analyzed using appropriate statistical techniques to (1) determine the cross-sectional burden of CVD risk factors and their prospective association with CVD outcomes, (2) validate existing prediction tools in diverse populations, and (3) develop bespoke risk prediction tools across diverse ethnic groups. ResultsEnrollment began in January 2019 and is ongoing with initial results to be published mid-2021. ConclusionsThere is an urgent need for more real-life population health studies based on analyses of routine health data available in EHRs. Findings from our study will help quantify, on a large scale, the contemporaneous burden of CVD risk factors by geography and ethnicity in a large multiethnic urban population. Such detailed understanding (especially interethnic and sociodemographic variations) of the burden of CVD risk and its determinants, including heredity, environment, diet, lifestyle, and socioeconomic factors, in a large population sample, will enable the development of tailored and dynamic (continuously learning from new data) risk prediction tools for diverse ethnic groups, and thereby enable the personalized provision of prevention strategies and care. We anticipate that this systematic approach of linking routinely collected data from EHRs to study CVD can be conducted in other settings as EHRs are being implemented worldwide. International Registered Report Identifier (IRRID)PRR1-10.2196/17548

BACKGROUND: Reports of clinical rickets are particularly evident in minority infants and children, but only limited analyses of vitamin D are available in this demographic group. OBJECTIVE: We sought to characterize circulating 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and their determinants, including circulating parathyroid hormone (PTH), total alkaline phosphatase activity (ALP), calcium, and phosphorus, in minority infants and children. DESIGN: We obtained demographic information and blood samples for measurement of PTH, ALP, 25(OH)D, and 1,25(OH)(2)D in >750 6-mo- to 3-y-old children. Dietary intake data were obtained and analyzed. RESULTS: The mean (±SD) 25(OH)D concentration was 66 ± 22 nmol/L (26.3 ± 8.7 ng/dL). A total of 15% of children had 25(OH)D concentrations less than the recommended target threshold of 50 nmol/L. Combined elevations of PTH and ALP occurred in only 2.5% of children. Determinants of 25(OH)D included vitamin D intake, age (decreasing with age), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), formula use (higher intakes), season (greater concentrations in the summer and fall than in the winter and spring), and, inversely, PTH. The mean 1,25(OH)(2)D concentration was 158 ± 58 pmol/L (60.6 ± 22.5 pg/mL), which was consistent with a reference range of 41-274 pmol/L or 15.7-105.5 pg/mL. Determinants for 1,25(OH)(2)D were age (decreasing with age), sex (greater concentrations in girls than in boys), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), and, inversely, serum calcium and phosphorus. CONCLUSIONS: Although 15% of subjects were vitamin D insufficient, only 2.5% of subjects had elevations of both PTH and ALP. The greater 25(OH)D concentrations observed with formula use confirm that dietary vitamin D fortification is effective in this demographic group. Circulating 1,25(OH)(2)D is higher in infants than in older children and adults and, in contrast to 25(OH)D, is not directly correlated with nutrient intakes. Copyright © 2012 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Purpose: O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs DNA damage from alkylating agents by transferring the alkyl adducts from the O(6)-position of guanine in DNA to AGT. The folate analog O(4)-benzylfolic acid (O(4)BF) is an inhibitor of AGT with reported selectivity of the alpha-folate receptor in tumors. We studied plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of O(4)BF in a non-human primate model.Methods: Rhesus monkeys (Macaca mulatta) received O(4)BF (10-50 mg/kg) intravenously, and serial blood and CSF samples were obtained. Analyte concentrations in plasma were measured by HPLC/photo diode array, and an HPLC/MS/MS assay was used for CSF samples.Results: A putative metabolite of O(4)BF was detected in plasma and CSF. O(4)BF and the metabolite inactivated purified AGT with ED(50) of 0.04 mcM. The median clearance of O(4)BF was 8 ml/min/kg and half-life was 1.1 h. The metabolite had a substantially longer half-life (>20 h) and greater AUC than O(4)BF. The AUC of the metabolite increased disproportionately to the dose of O(4)BF, suggesting saturable elimination. CSF penetration of O(4)BF and its metabolite was < 1%. At the 50 mg/kg dose level, the C(max) in CSF for O(4)BF was less than 0.09 mcM and for the metabolite the C(max) ranged from 0.02 to 0.04 mcM (O(4)BF equivalents).Conclusions: Concentrations of O(4)BF and the metabolite in CSF exceeded the ED(50) of AGT; however, recently reported lack of receptor specificity and pharmacokinetic data suggesting saturable elimination of both O(4)BF and its metabolite may limit dose-escalation and future clinical development of this agent. [ABSTRACT FROM AUTHOR]

Purpose: Temozolomide pharmacokinetics were evaluated in children receiving concurrent O(6)-benzylguanine (O(6)BG), which enhanced the hematological toxicity of temozolomide.Methods: Temozolomide was administered orally, daily for 5 days starting at 28 mg/m(2) per day with escalations to 40, 55, 75 and 100 mg/m(2) per day with O(6)BG intravenously daily for 5 days at doses of 60, 90 or 120 mg/m(2) per day. Plasma samples were drawn over 48 h after the day 5 dose. Temozolomide was quantified with a validated HPLC/tandem mass spectroscopic assay.Results: Temozolomide was rapidly absorbed (mean T (max), 2.1 h). The mean apparent clearance (CL/F) (96 mL/min/m(2)) was similar to the CL/F for temozolomide alone and was not age- or gender-dependent. There was minimal inter-patient variability.Conclusions: The enhanced hematologic toxicity resulting from combining O(6)BG with temozolomide does not appear to be the result of a pharmacokinetic interaction between the agents. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent research suggests that cardiovascular disease (CVD) and bone loss are functionally interwoven. This study examined the concomitant effects of a nutritional treatment of osteopaenia on CVD-risk factors. METHODS: A 1-year placebo-controlled trial was conducted on middle-aged women with normal (group A) or low (groups B and C) bone mineral density. Subjects (n = 20 per group) took daily either a placebo, calcium carbonate alone or combined to a vitamin (C and B(6))-proline capsule, respectively. Urinary pyridoxic acid (used to assess treatment compliance), plasma homocysteine, serum lipids and lipoproteins were measured before and after nutritional intervention. RESULTS: Groups were comparable at baseline in most parameters of interest. No changes occurred in groups A and B. The 4%, 7% and 25% reductions of total cholesterol, LDL and triglycerides, and 14% elevation of HDL were all significant in group C. A trend toward reduction was observed for homocysteine in this group. CONCLUSIONS: Vitamins C (500 mg) and B(6) (75 mg) combined with proline had consistent beneficial effects on CVD-risk factors, whereas calcium alone did not. This study also underlined the importance of considering vitamin B(6) status as a potential CVD risk factor. [ABSTRACT FROM AUTHOR]

Presents information on a study which assessed the link between vitamin D insufficiency to levels of wintertime 25-hydroxyvitamin D among young Canadian women. Study design; Measurements and statistical analysis; Results and discussion.

Four hundred nine high school students were surveyed to determine the percentage who had experienced suicidal ideation. The sample was then divided into high- and low-suicidal-risk groups. High-risk subjects were found to have significantly poorer quality friendships, lower self-esteem, and had experienced more life stress in the previous year. [ABSTRACT FROM AUTHOR]

Aggressive lymphomas are curable with doxorubicin-based chemotherapy. In patients presenting with elevated serum bilirubin, doxorubicin is commonly dose reduced or delayed based on limited pharmacokinetic data. We evaluated plasma pharmacokinetics of doxorubicin and its metabolite doxorubicinol as well as toxicity in 59 patients with normal bilirubin levels and 10 patients with elevated bilirubin levels. Patients received full-dose EPOCH +/-rituximab. Median (range) age was 51 (18-75) years. Patients with elevated bilirubin levels had higher international prognostic index and poorer performance status. Although median doxorubicin clearance was lower and median plasma doxorubicin and doxorubicinol concentrations were higher in patients with elevated bilirubin levels, values were within the concentration range observed in patients with normal levels. Rates of febrile neutropenia were similar between groups, but there was greater grade 4 neutropenia and thrombocytopenia during the first but not subsequent treatment cycles in patients with elevated bilirubin. More grade 3/4 gastrointestinal and neurotoxicity occurred in patients with elevated bilirubin during the first but not subsequent cycles. Although toxicity was greater on cycle 1, the adverse effects were managed safely. These results show that empiric dose reductions of continuous infusion doxorubicin may not be necessary in patients with elevated bilirubin levels. This trial was registered at www.clinicaltrials.gov as #NCT00001337, #NCT00069238, and #NCT00005780., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

We report that recessive inheritance of a post-GPI attachment to proteins 2 (PGAP2) gene variant results in the hyperphosphatasia with neurologic deficit (HPMRS) phenotype described by Mabry et al., in 1970. HPMRS, or Mabry syndrome, is now known to be one of 21 inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs), or GPI biosynthesis defects (GPIBDs). Bi-allelic mutations in at least six genes result in HPMRS phenotypes. Disruption of four phosphatidylinositol glycan (PIG) biosynthesis genes, PIGV, PIGO, PIGW and PIGY, expressed in the endoplasmic reticulum, result in HPMRS 1, 2, 5 and 6; disruption of the PGAP2 and PGAP3 genes, necessary for stabilizing the association of GPI anchored proteins (AP) with the Golgi membrane, result in HPMRS 3 and 4. We used exome sequencing to identify a novel homozygous missense PGAP2 variant NM&#95;014489.3:c.881C > T, p.Thr294Met in two index patients and targeted sequencing to identify this variant in an unrelated patient. Rescue assays were conducted in two PGAP2 deficient cell lines, PGAP2 KO cells generated by CRISPR/Cas9 and PGAP2 deficient CHO cells, in order to examine the pathogenicity of the PGAP2 variant. First, we used the CHO rescue assay to establish that the wild type PGAP2 isoform 1, translated from transcript 1, is less active than the wild type PGAP2 isoform 8, translated from transcript 12 (alternatively spliced to omit exon 3). As a result, in our variant rescue assays, we used the more active NM&#95;001256240.2:c.698C > T, p.Thr233Met isoform 8 instead of NM&#95;014489.3:c.881C > T, p.Thr294Met isoform 1. Flow cytometric analysis showed that restoration of cell surface CD59 and CD55 with variant PGAP2 isoform 8, driven by the weak (pTA FLAG) promoter, was less efficient than wild type isoform 8. Therefore, we conclude that recessive inheritance of c.881C > T PGAP2, expressed as the hypomorphic PGAP2 c.698C > T, p.Thr233Met isoform 8, results in prototypical Mabry phenotype, HPMRS3 (GPIBD 8 [MIM: 614207]). This study highlights the need for long-term follow up of individuals with rare diseases in order to ensure that they benefit from innovations in diagnosis and treatment., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Repeated use of inhaled β2 agonists is common in asthma or COPD exacerbations. It can lead to hyperlactatemia., Case Reports: We report two asthmatic patients who presented in the emergency department for an asthma exacerbation. The first patient developed hyperlactatemia at 3.9 mmol/L and the second patient developed hyperlactatemia at 5.6 mmol/L after terbutaline treatment. Both patients had a favorable outcome after adjusting the aerosol dose to clinical parameters., Discussion: Lactic acidosis induced by the use of inhaled β2 agonists is not synonymous of clinical deterioration. However, this side effect may be complicated by a tachypnea compensating for metabolic acidosis and should be known to avoid unnecessary therapeutic escalation., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: We aimed to compare the associations of directly measured plasma free 25-hydroxyvitamin D [25(OH)D] and total 25(OH)D concentrations with insulin sensitivity (SI) and β-cell function in nondiabetic Hispanics and African Americans. We hypothesized that directly measured free 25(OH)D would be more strongly associated with these measures of glucose homeostasis and that associations would differ by race., Design: We studied 1189 nondiabetic participants in the Insulin Resistance Atherosclerosis Study Family Study using data from baseline examinations from 2000 to 2002. SI, acute insulin response, and disposition index (DI) were determined from frequently sampled intravenous glucose tolerance tests. Plasma free and total 25(OH)D concentrations were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively., Results: The median concentrations of plasma free 25(OH)D were 3.46 pg/mL for Hispanics and 2.17 pg/mL for African Americans (P < 0.0001), whereas the median concentrations of plasma total 25(OH)D were 16 ng/mL for Hispanics and 10 ng/mL for African Americans (P < 0.0001). Plasma free and total 25(OH)D were both positively associated with SI and DI in generalized estimating equations adjusted for demographic and lifestyle factors. After further adjustment with body mass index, the associations were no longer statistically significant, except for a significant association between plasma free 25(OH)D and SI. There was no effect modification by ethnicity on any of the exposure-outcome associations., Conclusions: Our data showed that plasma free 25(OH)D had a slightly stronger association with SI compared with plasma total 25(OH)D, although the difference was modest and there were no marked differences in the associations between Hispanics and African Americans., (Copyright © 2017 Endocrine Society)

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy., (Published by Elsevier Inc.)

Primary hyperparathyroidism (PHPT) is associated with hypovitaminosis D as assessed by serum total 25-hydroxyvitamin D (TotalD) levels. The aim of this study is to evaluate whether this is also the case for the calculated bioavailable 25-hydroxyvitamin D (BioD) or free 25-hydroxyvitamin D (FreeD), and whether the vitamin D status is influenced by genetic background. We compared vitamin D status of 88 PHPT patients each with a matched healthy family member sharing genetic background, i.e., first-degree relative (FDR), or not, namely an in-law relative (ILR). We compared TotalD and vitamin D-binding protein (DBP), using the latter to calculate BioD and FreeD. We also genotyped two common DBP polymorphisms (rs7041 and rs4588) likely to affect the affinity for and levels of vitamin D metabolites. TotalD was lower (p < 0.001) in PHPT (12.3 ± 6.6 ng/mL) than either family member group (FDR: 19.4 ± 12.1 and ILR: 23.2 ± 14.1), whether adjusted for DBP or not. DBP levels were also significantly lower (p < 0.001) in PHPT (323 ± 73 mg/L) versus FDR (377 ± 98) or ILR (382 ± 101). The differences between PHPT and control groups for TotalD, BioD, and FreeD were maintained after adjustment for season, gender, and serum creatinine. 25-hydroxyvitamin D, evaluated as total, free, or bioavailable fractions, is decreased in PHPT. No difference was seen between first-degree relative and in-law controls, suggesting that neither genetic nor non-genetic background greatly influences the genesis of the hypovitaminosis D seen in PHPT.

HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5' and 3' UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558-10G>A, that causes an aberrant splice product and a mutation in the 3'UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway., (© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Background: Vincristine sulfate liposome injection (VSLI; Marqibo®) is an encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical trials in adults have demonstrated safety, tolerability, and activity, leading to Food and Drug Administration (FDA) approval for adults with relapsed acute lymphoblastic leukemia (ALL). Pediatric experience with VSLI is limited., Procedure: This single center, phase I dose escalation study examined the safety, toxicity, maximum tolerated dose, and pharmacokinetics of VSLI administered weekly to pediatric patients age <21 years with relapsed or chemotherapy-refractory solid tumors or leukemia., Results: Twenty-one subjects were treated in total. Median age was 13.3 years (range 2-19). Fourteen subjects completed one 28-day cycle of therapy and five subjects completed more than one cycle. No subject experienced dose-limiting toxicity (DLT) at the first dose level (1.75 mg/m(2) /dose, dose range: 2-3.7 mg). At the second dose level (2.25 mg/m(2) /dose, dose range: 1.3-4.5 mg), one subject had transient dose-limiting grade 4 transaminase elevation, and this dose level was expanded with no additional DLT observed. The second dose level then opened to an expansion phase to evaluate activity in ALL. Clinical activity included minimal residual disease negative complete remission in one subject with ALL and stable disease in nine subjects. Clearance of total vincristine was found to be approximately 100-fold lower in comparison to published data using standard vincristine., Conclusions: Children tolerate 2.25 mg/m(2) /dose of weekly VSLI (the adult FDA-approved dose) with evidence for clinical activity without dose-limiting neurotoxicity. Future plans include studying VSLI as substitution for standard vincristine with combination chemotherapy in children with ALL., (© 2016 Wiley Periodicals, Inc.)

The gene (GC) for the vitamin D binding protein (DBP) shows significant genetic variation. Two missense variants, p.D432E and p.T436K, are common polymorphisms and both may influence vitamin D metabolism. However, less common variants, identified biochemically, have been reported previously. This study aimed to identify the underlying mutations by molecular screening and to characterize the mutant proteins by mass spectrometry. Denaturing high performance liquid chromatography (DHPLC) was used for screening genetic variants in GC exons and exon/intron boundaries of genomic DNA samples. Sanger sequencing identified the specific mutations. An immuno-capture coupled mass spectrometry method was used to characterize protein variants in serum samples. Initial molecular screening identified 10 samples (out of 761) containing an alanine deletion at codon 246 in exon 7 (p.A246del, c.737&#95;739delCTG), and 1 sample (out of 97) containing a cysteine to phenylalanine substitution at codon 311 in exon 8 (p.C311F, c.932G>T). The mutant allele proteins and posttranslational modified products were distinguishable from the wild-type proteins by mass spectrum profiling. Loss of a disulfide bond due to loss of cysteine-311 was accompanied by the appearance of a novel mixed disulfide species, consistent with S-cysteinylation of the remaining unpaired cysteine-299 in the mutant protein. We confirm earlier biochemical studies indicating that there are additional deleterious GC mutations, some of which may be low-frequency variants. The major findings of this study indicate that additional mutant proteins are secreted and can be identified in the circulation. By combining molecular screening and mass spectrometric methods, mutant DBP species can be identified and characterized., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Vincristine sulfate liposomes injection (VSLI, Marqibo®) is an FDA approved encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical pharmacokinetics show VSLI to be a long-circulating, slow release formulation that is confined to plasma, and prior data on cerebrospinal fluid (CSF) pharmacokinetics are lacking. We report our results comparing CSF and plasma pharmacokinetic parameters of intravenous aqueous vincristine to intravenous VSLI using an established non-human primate (NHP) model., Methods: Three adult male rhesus monkeys (Macaca mulatta) were administered 0.1 mg/kg (1.2 mg/m(2) human-equivalent dose) of vincristine or VSLI in a crossover pharmacokinetic study. Serial paired blood and CSF samples were obtained before infusion, at the end of infusion (EOI) and at various time points thereafter., Results: In contrast to standard vincristine, which had a multi-exponential plasma disappearance curve with a median initial (EOI to 30 min post-infusion) half-life (T1/2) of 4.8 min (range, 4.4-5.0 min) and terminal T1/2 of 24.3 h, a near-monoexponential curve with a median T1/2 of 17.9 h (range, 13.9-21.5 h) hours was calculated with VSLI. The ratios Cl VCR:Cl VSLI for the individual NHP were 300, 463 and 477. Vincristine was not detected in any CSF sample after administration of either formulation., Conclusions: In three animals, each serving as their own control, we demonstrate that the pharmacokinetic profile of VSLI shows markedly prolonged clearance (approximately 400-fold lower) of total vincristine in comparison to the standard aqueous formulation, enhancing our understanding of VSLI pharmacokinetics. Several clinical trials incorporating VSLI as substitution for standard vincristine are in progress.

Background: Sub-optimal vitamin D status is common worldwide and the condition may be associated with increased risk for various chronic diseases. In particular, low vitamin D status is highly prevalent in indigenous communities in Canada, although limited data are available on the determinants of serum 25-hydroxyvitamin D (25(OH)D) concentrations in this population. The relationship between traditional food consumption and vitamin D status has not been well documented., Objective: To investigate the determinants of serum 25(OH)D status in a First Nations community in Ontario, Canada, with a focus on the role of traditional food consumption and activities., Methods: A cross-sectional analysis was conducted within the Sandy Lake Health and Diabetes Project (2003-2005). A total of 445 participants (>12 years of age) were assessed for serum 25(OH)D status, anthropometric and lifestyle variables, including traditional and non-traditional dietary practices and activities. Diet patterns were identified using factor analysis, and multivariate linear regression analysis was used to analyse the determinants of 25(OH)D concentrations., Results: Mean serum 25(OH)D concentrations were 22.1 nmol/L (16.9, 29.9 nmol/L) in men and 20.5 nmol/L (16.0, 27.3 nmol/L) in women. Multivariate determinants of higher serum 25(OH)D included higher consumption of traditional and healthier market foods, higher wild fish consumption, male gender, spring/summer season of blood collection and more frequent physical activity. Significant negative determinants included hours of TV/day, higher BMI and higher consumption of unhealthy market foods., Conclusions: Traditional food consumption contributed independently to higher 25(OH)D concentrations in a First Nations community with a high prevalence of sub-optimal vitamin D status., Competing Interests: This work was supported by contributions from the Canadian Institutes of Health Research, the Public Health Agency of Canada and the Dairy Research Cluster Initiative (Dairy Farmers of Canada, Agriculture and Agri-Food Canada, the Canadian Dairy Network and the Canadian Dairy Commission); S. Mansuri was supported through a University of Toronto Department of Medicine Graduate Student Award.

Aims: To investigate the associations of 25-hydroxyvitamin D (25(OH)D) with insulin resistance (IR), beta-cell function and metabolic syndrome (MetS) in a First Nations population., Methods: We conducted a cross-sectional analysis using data from the Sandy Lake Health and Diabetes Project (2003-2005). A total of 390 participants (>12 y) were assessed for 25(OH)D, fasting glucose, insulin, lipids, blood pressure, inflammatory markers, anthropometric and lifestyle variables and a 75-g oral glucose tolerance test was administered. IR was calculated using the Matsuda insulin sensitivity index (ISOGTT) and the computational homeostasis model assessment of IR (HOMA2-IR). Beta-cell function was calculated using the insulinogenic index (IGI) divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2). The 2009 harmonized criteria were used to define MetS., Results: Higher 25(OH)D was associated with a decreased prevalence of dysglycemia (OR = 0.71 95% CI, 0.51-0.97 per SD increase). In addition, there were significant associations of 25(OH)D with measures of insulin action (ISOGTT; beta=0.31; 95% CI, 0.12, 0.49; HOMA2-IR; beta = -29; 95% CI -0.46, -0.11 and beta-cell function (ISSI-2; beta = 0.15; 95% CI, 0.02, 0.28). The prevalence of MetS was 41%. There was a decreased risk (OR=0.73, 95% CI 0.56, 0.94) of MetS per SD increase in baseline 25(OH)D. Finally, there was a significant positive association of 25(OH)D with adiponectin (beta = 0.16; 95% CI = 0.01, 0.31)., Conclusions: These results support a potential role for vitamin D metabolism in the natural history of T2DM among Aboriginal Canadians, although carefully designed randomized trials will be required to establish causality., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Context: The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical features include congenital heart defects, facial dysmorphism, and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS., Case Description: Our patient is a 16-year-old adolescent male with dysmorphic facial features and delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by fluorescence in situ hybridization. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. As a result of symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings., Conclusions: Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.

Purpose: Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways. Several tumor types, including high-grade gliomas and pediatric pontine gliomas, exhibit Akt activation. Perifosine, an orally bioavailable, synthetic alkylphospholipid and potent Akt inhibitor, has demonstrated activity in some preclinical models, but absent activity in a genetically engineered mouse model of pontine glioma. We evaluated the plasma and cerebrospinal fluid pharmacokinetics of orally administered perifosine in a non-human primate model to evaluate CNS penetration., Methods: Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0 mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64 days. Perifosine was quantified with a validated HPLC/tandem mass spectrometry assay. Pharmacokinetic parameters were estimated using non-compartmental methods. CSF penetration was calculated from the areas under the concentration-time curves., Results: Peak plasma concentrations (C max) ranged from 11.7-19.3 µM, and remained >1 µM for >28 days. Time to C max (T max) was 19 h. The median (range) AUCPl was 3148 (2502-4705) µM/h, with a median (range) terminal half-life (t 1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (T max 64-235 h). CSF AUCs and t 1/2 were 6358 (2266-7568) nM/h and 277 (146-350) h, respectively. Perifosine concentrations in the CSF remained over  nM for >35 days. The mean CSF penetration was 0.16 %., Conclusion: CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (>2 months) after a single oral dose.

Aims: Two single-nucleotide polymorphisms (SNPs) at the calcium-sensing receptor (CASR) gene were previously associated with kidney stones in patients with primary hyperparathyroidism (PHPT): rs1501899, likely associated with a decrease in CASR expression, and Arg990Gly, causing a gain of CASR function. To evaluate the interaction of these two SNPs in the stone risk, we tested the association of stones with the genotype at both SNPs in PHPT patients and the association of rs1501899 with CASR expression as messenger RNA (mRNA) in human kidney samples., Methods and Results: Two hundred and ninety-six PHPT patients were genotyped at the rs1501899 and Arg990Gly SNPs. Minor allele frequency at tested SNPs was higher in PHPT stone formers relative to non-stone forming patients. PHPT patients carrying one or two copies of the minor allele at both rs1501899 and Arg990Gly (n = 16) had the maximal risk of stones (odds ratio, OR 8.3) and higher serum ionized calcium compared with homozygous patients for the wild-type allele at both SNPs. CASR expression as mRNA was measured by real time polymerase chain reaction (PCR) in normal kidney medulla samples from 109 subjects. CASR mRNA was significantly lower in medulla samples from homozygotes for the minor allele at rs1501899 than in subjects with other genotypes., Conclusions: We conclude that the simultaneous presence of the minor allele at rs1501899 and Arg990Gly may amplify the kidney stone risk in PHPT patients, despite their apparently opposite effects on CASR function in the kidney.

An autosomal recessive syndrome of hyperphosphatasia (elevated circulating alkaline phosphatase (AP), seizures and neurologic deficits) was first described by Mabry and colleagues in 1970. Over the ensuing four decades, few cases were reported. In 2010, however, new families were identified and the syndromic nature of the disorder confirmed. Shortly thereafter, next generation sequencing was used to characterize causative defects in the glycosyl phosphatidylinositol (GPI) biosynthetic pathway, based partly on our understanding of how AP is anchored by GPI to the plasma membrane. Whether the seizures and cognitive defects seen in Mabry syndrome patients are attributable in part to the constant hyperphosphatasia is not known, as there are more than 250 other proteins dependent on GPI for their anchoring to the plasma membrane. However, Mabry syndrome may provide a new window on AP function in growth and development.

Context: Glial cells missing-2 (GCM2) is key for parathyroid gland organogenesis. Its persistent expression in the adult parathyroid raises the possibility that overactive forms play a role in the evolution of parathyroid hyperactivity or tumorigenesis. A GCM2 c.844T → G; p.Y282D missense variant has been described within a transactivation inhibitory domain (amino acids 263-352)., Objective: The aims of the study were to 1) assess the frequency of Y282D in Italian primary hyperparathyroidism (PHPT) and control (C) populations, 2) test for association of 282D with PHPT and its phenotypic features, and 3) compare the transactivation potency of GCM2 282D relative to wild-type Y282., Subjects and Methods: Subjects included a large southern Italian cohort (310 PHPT and 433 C) and 2 replication cohorts from northern Italy. Association of 282D with PHPT was tested in all cohorts and with phenotypic features in the larger PHPT cohort. An in vitro GCM promoter-luciferase reporter assay was conducted in HEK293 cells., Results: 282D was significantly increased in the PHPT group, with a minor allele frequency of 0.066 compared with 0.029 in the C group (P = .0008), in the discovery cohort and was more prevalent in the replication cohorts. Combined analysis (510 PHPT and 665 C) yielded a likelihood ratio of 2.27 (95% confidence interval = 1.50-3.42; P < .0001). The 282D variant was not associated with serum calcium, phosphate, creatinine, or PTH levels or with bone mineral density, fractures, or renal stones in the PHPT group. The 282D variant had significantly greater transcriptional activity than the wild-type Y282 (17× basal vs 12× basal; P < 0.05)., Conclusion: The higher frequency of GCM2 282D in PHPT and enhanced transcriptional activity of this variant supports the notion that it could contribute causally to parathyroid tumorigenesis.