The Causes of Hypo- and Hyperphosphatemia in Humans.

Phosphate homeostasis involves several major organs that are the skeleton, the intestine, the kidney, and parathyroid glands. Major regulators of phosphate homeostasis are parathormone, fibroblast growth factor 23, 1,25-dihydroxyvitamin D, which respond to variations of serum phosphate levels and act to increase or decrease intestinal absorption and renal tubular reabsorption, through the modulation of expression of transcellular transporters at the intestinal and/or renal tubular level. Any acquired or genetic dysfunction in these major organs or regulators may induce hypo- or hyperphosphatemia. The causes of hypo- and hyperphosphatemia are numerous. This review develops the main causes of acquired and genetic hypo- and hyperphosphatemia.

High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults.

Hereditary tubulopathies are rare diseases with unknown prevalence in adults. Often diagnosed in childhood, hereditary tubulopathies can nevertheless be evoked in adults. Precise diagnosis can be difficult or delayed due to insidious development of symptoms, comorbidities and polypharmacy. Here we evaluated the diagnostic value of a specific panel of known genes implicated in tubulopathies in adult patients and compared to our data obtained in children. To do this we analyzed 1033 non-related adult patients of which 744 had a clinical diagnosis of tubulopathy and 289 had a diagnosis of familial hypercalcemia with hypocalciuria recruited by three European reference centers. Three-quarters of our tubulopathies cohort included individuals with clinical suspicion of Gitelman syndrome, kidney hypophosphatemia and kidney tubular acidosis. We detected pathogenic variants in 26 different genes confirming a genetic diagnosis of tubulopathy in 29% of cases. In 16 cases (2.1%) the genetic testing changed the clinical diagnosis. The diagnosis of familial hypercalcemia with hypocalciuria was confirmed in 12% of cases. Thus, our work demonstrates the genetic origin of tubulopathies in one out of three adult patients, half of the rate observed in children. Hence, establishing a precise diagnosis is crucial for patients, in order to guide care, to survey and prevent chronic complications, and for genetic counselling. At the same time, this work enhances our understanding of complex phenotypes and enriches the database with the causal variants described.

Pre-, post- or no acidification of urine samples for calcium analysis: does it matter?

Background Measuring 24 h-urine calcium concentration is essential to evaluate calcium metabolism and excretion. Manufacturers recommend acidifying the urine before a measurement to ensure calcium solubility, but the literature offers controversial information on this pre-analytical treatment. The objectives of the study were (1) to compare pre-acidification (during urine collection) versus post-acidification (in the laboratory), and (2) to evaluate the impact of acidification on urinary calcium measurements in a large cohort. Methods We evaluated the effects of pre- and post-acidification on 24-h urine samples collected from 10 healthy volunteers. We further studied the impact of acidification on the calcium results for 567 urine samples from routine laboratory practice, including 46 hypercalciuria (≥7.5 mmol/24 h) samples. Results Calciuria values in healthy volunteers ranged from 0.6 to 12.5 mmol/24 h, and no statistical significance was found between non-acidified, pre-acidified and post-acidified conditions. A comparison of the values (ranging from 0.21 to 29.32 mmol/L) for 567 urine samples before and after acidification indicated 25 samples (4.4%) with analytical differences outside limits of acceptance. The bias observed for these deviant values ranged from -3.07 to 1.32 mmol/L; no patient was re-classified as hypercalciuric after acidification, and three patients with hypercalciuria were classified as normocalciuric after acidification. These three deviant patients represent 6.5% of hypercalciuric patients. Conclusions Our results indicate that pre- and post-acidification of urine is not necessary prior to routine calcium analysis.

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing.

Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

Choosing the tool for osteoporosis risk prediction.

PURPOSE OF REVIEW: Predicting fracture risk is a major challenge because it allows the prevention of major osteoporotic fracture in high-risk populations. With the aging of the population, this matter will become of even greater importance. In recent years, novel clinical, biochemical, and imaging tools have been developed to improve the assessment of fracture risk. RECENT FINDINGS: The present review summarizes novel clinical strategies, Dual energy X-ray absorptiometry (DXA)-derived tools, imaging techniques, and biochemical markers that have been developed recently to improve fracture risk prediction. SUMMARY: DXA and clinical fracture risk prediction tools are preferential markers of fracture risk. Clinical fracture risk alone might be used if DXA facilities are unavailable. The fracture risk assessment tool may be used in osteoporosis consultation in many countries. Other tools may be used soon after more studies are performed, particularly trabecular bone score, quantitative ultrasound, bone turnover markers. Specific factors for example falls, hip axis length, vertebral fracture assessment could be used in individual patients. This may significantly improve the clinical decision-making.

Trabecular bone score (TBS) in Cushing's disease: TBS gain after hypercortisolism normalization.

CONTEXT: Hypercortisolism frequently induces trabecular bone loss, more pronounced at the lumbar spine, resulting in osteoporosis, and thus an increase in fracture risk. Several studies have shown bone mass recovery in patients with Cushing's disease (CD) after treatment. OBJECTIVE: To examine treatment effects on TBS (trabecular bone score) in addition to aBMD (areal bone mineral density) in a cohort of patients with CD. DESIGN AND SETTING: Single-center retrospective longitudinal study in patients diagnosed with CD and successfully treated following surgery and/or medical treatment. PATIENTS: We included 31 patients with median age and BMI (body mass index) of 37.7 [28.4;43.3] years old and 27.7 [25.8;30.4] kg/m2, respectively. Median 24 h urinary cortisol before treatment was 213.4 [168.5;478.5] µg/24 h. All subjects were completely biochemically controlled or cured after treatment. MAIN OUTCOME MEASURES: aBMD and TBS were evaluated at AP Spine (L1-L4) with DXA prodigy (GE-Lunar), QDR 4500 (Hologic), and TBS iNsight® (Med-Imaps) before and after treatment. RESULTS: Absolute TBS and aBMD gains following cure of CD were significant (p < 0.0001, and p < 0.001, respectively). aBMD and TBS increased by +3.9 and 8.2 % respectively after cure of CD. aBMD and TBS were not correlated before (p = 0.43) and after treatment (p = 0.53). Linear regression analyses showed that TBS gain was independent of baseline BMI and that low TBS at baseline was predictive of TBS gain after treatment. CONCLUSION: The more significant improvement of microarchitecture assessed by TBS than aBMD and the absence of correlation between TBS and aBMD suggest that TBS may be an adequate marker of bone restoration after cure of CD. To support this conclusion, future studies with larger sample sizes and longer follow-up periods should be carried out.

Implementing Residential Integrated Treatment for Co-occurring Disorders.

Objective: Much is now known about effective treatment for co-occurring substance abuse and psychiatric difficulties and many evidence-based practice recommendations have been disseminated. Implementation of these recommended interventions in daily clinical practice has been more of a struggle. This article describes successful implementation of integrated treatment for co-occurring disorders in a small residential program. Methods: A traditional 28-day addiction service was transformed into a 3-month integrated treatment program and 155 individuals with co-occurring disorders agreed to participate in its evaluation. The transformation entailed a completely new manualized service, training in a number of clinical interventions for all program clinicians, ongoing clinical supervision, and formal measurement of clients' backgrounds, substance abuse, quality of life, mental health symptoms, self-esteem, and satisfaction with the program. We also obtained collateral informants' reports on participants' symptoms, substance use, and quality of life. Fidelity to the treatment model was continuously assessed, as were participants' knowledge and skill acquisition. In addition, impact of the implementation on the program clinicians' morale and attitudes toward evidence-based practices was assessed, as was staff turnover and per diem costs. Results: Despite very problematic clinical and sociodemographic histories, the 86 participants who completed the program showed clinically significant mental health symptom improvement, acquisition of knowledge and skill, and high self-esteem and satisfaction with the program. Program fidelity, clinician morale, commitment to the program, and attitudes toward evidence-based practice were uniformly high. These successes were achieved while maintaining the lowest per-inpatient day cost of all hospital inpatient units. Conclusions: The findings support the contention that evidence-based integrated treatment can be implemented with fidelity in regular clinical practice to the benefit of participants, staff, and the hospital. Our experience was that having a scientist-practitioner working as a staff member on the program to lead the implementation was a key element. Future reports will focus on longer-term follow-up of substance use and quality of life outcomes.

FCH-PET/CT in Primary Hyperparathyroidism With Discordant/Negative MIBI Scintigraphy and Ultrasonography.

CONTEXT: The contribution of [18F]F-fluorocholine (FCH)-positron emission tomography (PET)/computed tomography (CT) in normocalcemic primary hyperparathyroidism (nPHPT) remains unknown. OBJECTIVE: To evaluate the sensitivity and specificity of FCH-PET/CT in a cohort of osteoporotic patients with nPHPT and discordant or negative [99mTc]Tc-sestamibi scintigraphy and ultrasonography who all underwent parathyroidectomy (PTX). DESIGN: Longitudinal retrospective cohort study in patients referred for osteoporosis with mild biological primary hyperparathyroidism. SETTING: Tertiary referral center with expertise in bone metabolism and surgical management of hyperparathyroidism. PATIENTS: Among 109 patients with PHPT analyzed, 3 groups were individualized according to total serum calcium (tCa) and ionized calcium (iCa): 32 patients with hypercalcemia (HtCa group), 39 patients with normal tCa and elevated iCa (NtCa group), and 38 patients with both normal tCa and iCa (NiCa). All patients had biochemical follow-up confirming or not the success of PTX. MAIN OUTCOME MEASURES: To evaluate the performance of FCH-PET/CT in terms of sensitivity and specificity, and to compare with first-line imaging procedures in the setting of nPHPT. RESULTS: The sensitivity of FCH-PET/CT was 67% in the hypercalcemic group, 48% in the NtCa group (P = .05 vs HtCa), and 33% in the NiCa group (P = .004 vs HtCa). Specificity ranged from 97% to 99%. FCH-PET/CT was positive in 64.3% of patients with negative conventional imaging, with biochemical resolution after PTX in 77.8% of patients. Triple negative imaging was observed in 20 patients, with PHPT resolution in 85% of these patients. CONCLUSION: This study highlights the contribution of FCH-PET/CT in a well-phenotyped cohort of normocalcemic patients with discordant or negative findings in [99mTc]Tc-sestamibi scintigraphy and ultrasonography. However, negative imaging in nPHPT does not rule out the possibility of surgical cure by an experienced surgeon.

Protein Structure Initiative Material Repository: an open shared public resource of structural genomics plasmids for the biological community.

The Protein Structure Initiative Material Repository (PSI-MR; http://psimr.asu.edu) provides centralized storage and distribution for the protein expression plasmids created by PSI researchers. These plasmids are a resource that allows the research community to dissect the biological function of proteins whose structures have been identified by the PSI. The plasmid annotation, which includes the full length sequence, vector information and associated publications, is stored in a freely available, searchable database called DNASU (http://dnasu.asu.edu). Each PSI plasmid is also linked to a variety of additional resources, which facilitates cross-referencing of a particular plasmid to protein annotations and experimental data. Plasmid samples can be requested directly through the website. We have also developed a novel strategy to avoid the most common concern encountered when distributing plasmids namely, the complexity of material transfer agreement (MTA) processing and the resulting delays this causes. The Expedited Process MTA, in which we created a network of institutions that agree to the terms of transfer in advance of a material request, eliminates these delays. Our hope is that by creating a repository of expression-ready plasmids and expediting the process for receiving these plasmids, we will help accelerate the accessibility and pace of scientific discovery.

Bone and primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a disease caused by excessive and inappropriate secretion of parathyroid hormone resulting in hypercalcemia. It is usually diagnosed incidentally in case of hypercalcemia, osteoporosis or, more rarely, renal involvement such as lithiasis. The clinical presentation reflects hypercalcemia and involves several organs, mainly the cardiovascular system, bone, and kidneys. However, most patients with PHPT are asymptomatic. The diagnosis is biological, obvious when serum calcium and parathyroid hormone levels are high, but difficult when one of these two values is normal. The diagnosis of normocalcemic PHPT is possible only after ruling out all causes of secondary hyperparathyroidism. Parathyroid imaging does not contribute to the positive diagnosis but guides surgery and rules out an associated thyroid abnormality. Parathyroid surgery is the gold standard treatment. Parathyroid surgery is indicated in the presence or risk of complications, and it is the only treatment that prevents fractures. Pharmaceutical treatments have only limited effects on complications and are limited to cases where surgery is contraindicated. After parathyroid surgery, the use of bisphosphonates must be avoided as they seem to interfere with the parathyroidectomy's fracture-preventing effects. In the absence of surgical indication, medical monitoring of patients includes assessment of laboratory values, bone density, and renal function.

18F-fluorocholine PET/CT and conventional imaging in primary hyperparathyroidism.

PURPOSE: The purpose of this study was to assess the diagnostic capabilities of preoperative conventional imaging (99mTc-MIBI scintigraphy, cervical ultrasonography [CUS]) and 18F-fluorocholine PET/CT (FCH PET/CT) in the detection of hyperfunctioning parathyroid gland in patients with primary hyperparathyroidism (PHPT) used alone or as a single imaging set. MATERIALS AND METHODS: A total of 51 consecutive patients (6 men, 45 women; mean age, 62 ± 11.6 [SD] years; age range: 28-86 years) with biochemically confirmed PHPT who underwent CUS, single-tracer dual phase 99mTc-MIBI scintigraphy and FCH PET/CT were retrospectively included. 99mTc-MIBI scintigraphy were performed immediately after CUS and interpreted by the same operators. FCH PET/CT examinations were interpreted independently by two nuclear medicine physicians. An additional reading session integrating the three imaging modalities read in consensus as a combined imaging set was performed. RESULTS: At surgery, 74 lesions were removed (32 parathyroid adenomas, 38 parathyroid hyperplasia and 4 subnormal glands). Thirty-six patients (71%) had single-gland disease and 15 patients (29%) had multiglandular disease at histopathological analysis. On a patient basis, sensitivity and accuracy of FCH PET/CT, CUS and 99mTc-MIBI scintigraphy for the detection of abnormal parathyroid glands were 76% (95% CI: 63-87%) and 76% (95% CI: 63-87%), 71% (95% CI: 56-83%) and 71% (95% CI: 56-83%), 33% (95% CI: 21-48%) and 33% (95% CI: 21-48%), respectively. The sensitivity of the combined imaging set was 94% (95% CI: 84-99%) and greater than the sensitivity of each individual imaging technique (P ≤ 0.001 for all). CONCLUSION: Our results suggest that CUS, 99mTc-MIBI scintigraphy and FCH PET/CT interpreted as a single imaging set could be the ideal practice to precisely localize parathyroid lesion in patients with PHPT before surgery.

Osteogenesis Imperfecta: characterization of fractures during pregnancy and post-partum.

BACKGROUND: Pregnancy and breastfeeding are associated with bone density loss. Fracture occurrence during pregnancy and post-partum, and its determinants, remain poorly known in Osteogenesis Imperfecta (OI). The aim of this study was to characterize fractures that occurred during pregnancy and post-partum in OI patients. RESULTS: We conducted a retrospective multicentric study including a total of 50 previously pregnant OI women from 10 Bone Centers in France. Among these patients, 12 (24%) patients experienced fractures during pregnancy or in the 6 months following delivery, and 38 (76%) did not experience any fracture. The most frequent localizations were: proximal femur (25%), spine (25%), distal femur (12.5%), and pelvis (12.5%). Fractures during pregnancy occurred during the third trimester and post-partum fractures occurred with a mean delay of 2 months following delivery. No fractures occurred during childbirth. We next compared the 12 patients with pregnancy or post-partum fractures with the 38 patients without fractures. Mean age at pregnancy was 32.7 ± 3.1 years-old in the fractured group, vs 29.3 ± 5.0 years-old in the non-fractured group (p = 0.002). Breastfeeding was reported in 85.7% of patients in the fractured group, vs 47.1% in the non-fractured group (p = 0.03). All patients with post-partum fractures were breastfeeding. Bone mineral density was significantly lower in patients with pregnancy-related fractures compared with other patients: spine Z-score - 2.9 ± 1.6DS vs - 1.5 ± 1.7DS (p = 0.03), and total hip Z-score - 2.0 ± 0.7DS vs - 0.5 ± 1.4DS (p = 0.04). At least one osteoporosis-inducing risk factor or disease other than OI was identified in 81.8% vs 58.6% of fractured vs non-fractured patients (not significant). Fracture during pregnancy or post-partum was not associated with the severity of OI. Bisphosphonates before pregnancy were reported in 16.7% and 21.1% of patients with pregnancy-related fractures and non-fractured patients, respectively (not significant). CONCLUSIONS: OI management during pregnancy and post-partum should aim for optimal control of modifiable osteoporosis risk factors, particularly in patients with low BMD. Breastfeeding should be avoided.

PSI:Biology-materials repository: a biologist's resource for protein expression plasmids.

The Protein Structure Initiative:Biology-Materials Repository (PSI:Biology-MR; MR; http://psimr.asu.edu ) sequence-verifies, annotates, stores, and distributes the protein expression plasmids and vectors created by the Protein Structure Initiative (PSI). The MR has developed an informatics and sample processing pipeline that manages this process for thousands of samples per month from nearly a dozen PSI centers. DNASU ( http://dnasu.asu.edu ), a freely searchable database, stores the plasmid annotations, which include the full-length sequence, vector information, and associated publications for over 130,000 plasmids created by our laboratory, by the PSI and other consortia, and by individual laboratories for distribution to researchers worldwide. Each plasmid links to external resources, including the PSI Structural Biology Knowledgebase ( http://sbkb.org ), which facilitates cross-referencing of a particular plasmid to additional protein annotations and experimental data. To expedite and simplify plasmid requests, the MR uses an expedited material transfer agreement (EP-MTA) network, where researchers from network institutions can order and receive PSI plasmids without institutional delays. As of March 2011, over 39,000 protein expression plasmids and 78 empty vectors from the PSI are available upon request from DNASU. Overall, the MR's repository of expression-ready plasmids, its automated pipeline, and the rapid process for receiving and distributing these plasmids more effectively allows the research community to dissect the biological function of proteins whose structures have been studied by the PSI.

Vitamin D levels and potential impact in systemic sclerosis.

Vitamin D is essential not only for calcium and bone metabolism, but it also may exert other biological activities, including immunomodulation through the expression of vitamin D receptor in antigen-presenting cells and activated T cells. Evidence from animal models and human prospective studies of rheumatoid arthritis, multiple sclerosis, type I diabetes, and systemic lupus erythematosus, indeed suggested an important role for vitamin D as a modifiable environmental factor in autoimmune diseases. In systemic sclerosis (SSc), this role has not been completely dissected, although recent studies clearly evidenced a high prevalence of vitamin D deficiency. Moreover, some degree of association between vitamin D deficiency and disease activity or phenotype characteristics has also been observed. Vitamin D deficiency in SSc may be related to several factors: insufficient sun exposure due to disability and skin fibrosis, insufficient intake because of gut involvement and malabsorption. Although it is advisable to regularly check vitamin D status in these patients, there is no consensus about which vitamin D supplementation regimen might be sufficient to modulate immunological homeostasis, and possibly reduce disease activity or severity, thus further prospective studies are needed. Moreover, novel vitamin D analogues with more pronounced immune modulatory effect and lower activity on calcium metabolism are in the pipeline, and might represent a great innovative opportunity for the treatment of vitamin D deficiency in such autoimmune disorders.

Inadequate response to treatment reveals persistent osteoclast bone resorption in osteoporotic patients.

Several drugs are able to reduce fracture risk in osteoporotic patients. Incident fractures occur despite good adherence to treatment. Inadequate response has been found related to high serum bone biomarkers of bone turnover. We here aimed to analyze bone microarchitecture and cellular profiles of inadequate responders. We retrospectively analyzed bone biopsies from patients with major fractures despite long-term treatment (inadequate responder [IR] n = 31) in comparison to patients with untreated osteoporosis (U-OP, n = 31) and controls without osteoporosis (Ctrl, n = 16). Bone samples were analyzed by histomorphometry and micro-computed tomography. Clinical and bone turnover markers and bone mineral density were assessed. As compared with U-OP patients, IRs were older (mean age 69.7 ± 8.8 vs 63.3 ± 9.3 years, p = 0.007) and had lower mean hip bone mineral density (0.685 ± 0.116 vs 0.786 ± 0.093 g/cm2), p = 0.019 and T-score (-2.3 ± 0.769 vs -1.6 ± 0.900, p = 0.032). BV/TV was lower for IRs than U-OP patients and Ctrls (13.9 ± 3.8% vs 15.2 ± 5.1 and 17.6 ± 5.2%, p = 0.044) as was trabecular thickness (145.6 ± 23.1 vs 160.5 ± 22.7 and 153.7 ± 21.4 µm, p = 0.033). Mean structure model index was lower for IRs than U-OP patients (1.9 ± 0.806 vs 2.4 ± 0.687, p = 0.042) and osteoclast number was higher for IRs than U-OP patients and Ctrls (0.721 ± 0.611 vs 0.394 ± 0.393 and 0.199 ± 0.071 mm-2, p < 0.001). The mean Obl.S/BS was lower for IRs than U-OP patients and Ctrls (1.2 ± 1.3 vs 1.9 ± 1.4 and 3.0 ± 0.638 mm-2, p < 0.0001), and the mean number of labelled surfaces was lower for IRs than U-OP patients (51.6% vs 87%, p = 0.002). Cortical parameters did not significantly differ. We show an imbalance of bone remodeling in favor of bone resorption in IRs. The persistence of high bone resorption suggests insufficient inhibition of bone resorption that could explain the incident fractures with anti-osteoporotic drug use. Adaptation to treatment should be considered to inhibit bone resorption and prevent further fractures.

Smarcc1/Baf155 couples self-renewal gene repression with changes in chromatin structure in mouse embryonic stem cells.

Little is known about the molecular mechanism(s) governing differentiation decisions in embryonic stem cells (ESCs). To identify factors critical for ESC lineage formation, we carried out a functional genetic screen for factors affecting Nanog promoter activity during mESC differentiation. We report that members of the PBAF chromatin remodeling complex, including Smarca4/Brg1, Smarcb1/Baf47, Smarcc1/Baf155, and Smarce1/Baf57, are required for the repression of Nanog and other self-renewal gene expression upon mouse ESC (mESC) differentiation. Knockdown of Smarcc1 or Smarce1 suppressed loss of Nanog expression in multiple forms of differentiation. This effect occurred in the absence of self-renewal factors normally required for Nanog expression (e.g., Oct4), possibly indicating that changes in chromatin structure, rather than loss of self-renewal gene transcription per se, trigger differentiation. Consistent with this notion, mechanistic studies demonstrated that expression of Smarcc1 is necessary for heterochromatin formation and chromatin compaction during differentiation. Collectively, our data reveal that Smarcc1 plays important roles in facilitating mESCs differentiation by coupling gene repression with global and local changes in chromatin structure.

Vitamin D Supplementation in France in patients with or at risk for osteoporosis: Recent data and new practices.

With intermittent vitamin D supplementation, serum 25-hydroxyvitamin D (25OHD) levels may remain stable only if the dosing interval is shorter than 3 months, the ideal perhaps being about 1 month. Recent data support moderate daily vitamin D doses instead of high intermittent doses, notably in elderly patients prone to falls. The level of evidence is low, however, with no head-to-head comparisons of clinical outcomes such as fractures and falls in groups given identical dosages daily versus intermittently. A challenge to daily vitamin D supplementation in France is the absence of a suitable pharmaceutical formulation. In addition, daily dosing carries a high risk of poor adherence. Until suitable vitamin D3 formulations such as tablets or soft capsules each containing 1000 or 1500 IU become available, we suggest intermittent supplementation according to 2011 GRIO guidelines. Among the available dosages, the lowest should be preferred, with the shortest possible interval, e.g., 50,000 IU monthly rather than 100,000 every two months.

High third generation/second generation PTH ratio in a patient with parathyroid carcinoma: clinical utility of third generation/second generation PTH ratio in patients with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHP) is caused by parathyroid adenomas or hyperplasia, and occasionally by parathyroid carcinoma. Recently a high third generation/second generation PTH ratio has been observed in some patients with parathyroid carcinoma. PATIENTS AND METHODS: We report the case of a 60-year old woman who was presented a fourth episode of PTH-related hypercalcaemia due to a parathyroid carcinoma. Serum PTH levels were measured using a second generation assay and a third generation assay before, 4 and 7 months after the fourth surgery. Then, PTH levels were measured in 294 osteoporotic normocalcaemic patients as well as in 30 consecutive PHP patients. RESULTS: Before surgery of the patient with parathyroid carcinoma, second generation PTH was 229 pg/ml, third generation PTH was 675 pg/ml and third generation/second generation PTH ratio was 2.95. Four and 7 months after surgery the third generation/second generation PTH ratio was 0.70 and 0.66, respectively. All osteoporotic patients had a normal third generation/second generation PTH ratio (0.585 +/- 0.118) whereas only one patient (3.3%) with PHP had a third generation/second generation PTH ratio > 1 (1.54). CONCLUSION: A high third generation/second generation PTH ratio could be observed in patients with parathyroid carcinoma, is uncommon in benign PHP and is absent in osteoporotic patients without PHP. Therefore, PTH level can be measured using second and third generation assays in some PHP patients, and a specific surgical protocol for possible parathyroid carcinoma could be discussed in patients with a high third generation/second generation PTH ratio.

Health literacy knowledge and experiences of senior baccalaureate nursing students.

This study assessed the health literacy knowledge and experiences of senior baccalaureate nursing students enrolled at state universities in Louisiana. A total of 361 nursing students at eight institutions completed the Health Literacy Knowledge and Experience Survey. Results indicated participants were able to identify low socioeconomic groups at high risk for low health literacy, were aware of the consequences associated with low health literacy, and could identify effective interventions used to evaluate patients' understanding of health care teaching. However, knowledge gaps were evident in the following areas: identifying older adults as a high-risk group, screening for health literacy, and assessing guidelines for written health care information. Responses to the Health Literacy Experience scale suggest participants' health literacy experiences were limited regarding conducting health literacy screenings and assessing the reading level, illustrations, and cultural appropriateness of written materials.