Monthly Increase in Vitamin D Levels upon Supplementation with 2000 IU/Day in Healthy Volunteers: Result from "Integriamoci", a Pilot Pharmacokinetic Study.

Vitamin D (VD) is a calcium- and phosphate-controlling hormone used to treat bone disorders; yet, several other effects are progressively emerging. VD deficiency is highly prevalent worldwide, with suboptimal exposure to sunlight listed among the leading causes: oral supplementation with either cholecalciferol or calcitriol is used. However, there is a scarcity of clinical studies investigating how quickly VD concentrations can increase after supplementation. In this pilot study, the commercial supplement ImmuD3 (by Erboristeria Magentina®) was chosen as the source of VD and 2000 IU/day was administered for one month to 21 healthy volunteers that had not taken any other VD supplements in the previous 30 days. Plasma VD levels were measured through liquid chromatography coupled to tandem mass spectrometry after 7, 14, and 28 days of supplementation. We found that 95% of the participants had insufficient VD levels at baseline (<30 ng/mL; median 23.72 ng/mL; IQR 18.10-26.15), but after 28 days of supplementation, this percentage dropped to 62% (median 28.35 ng/mL; IQR 25.78-35.20). The median increase in VD level was 3.09 ng/mL (IQR 1.60-5.68) after 7 days and 8.85 ng/mL (IQR 2.85-13.97F) after 28 days. This study suggests the need for continuing VD supplementation and for measuring target level attainment.

Association between vitamin D status and long-term falls-related hospitalization risk in older women.

BACKGROUND: The dose-response relationship of vitamin D status and the risk of serious falls requiring hospitalization in older women is unclear. We examined the association between plasma 25-hydroxyvitamin D (25OHD) with falls-related hospitalizations over 14.5 years in a large cohort of older women. METHODS: In 1348 community-dwelling Australian women aged ≥70 years, plasma 25OHD concentrations were assessed at baseline (1998) using LC-MS/MS. Fall-related hospitalizations were obtained from linked data systems. Baseline grip strength and timed-up-and-go (TUG) were assessed as measures of muscle strength and physical function, respectively. RESULTS: Mean plasma 25OHD was 66.9 ± 28.2 nmol/L. The number of women in the low (LOW; <50 nmol/L), medium (MED; 50 to <75 nmol/L), and higher 25OHD (HIGH; ≥75 nmol/L) categories were 384 (28.5%), 491 (36.4%), and 473 (35.1%), respectively. In the multivariable-adjusted analysis, compared to LOW, women in HIGH had significantly lower hazards for a falls-related hospitalization (HR 0.76 95%CI 0.61-0.95). Restricted cubic spline regression models highlight increasing gradient of risk for a falls-related hospitalization with decreasing 25OHD levels. Generalized additive modeling highlighted higher 25OHD to be associated with better TUG performance. Including TUG into the multivariable-adjusted models did not alter the relationship between 25OHD and injurious falls (HIGH vs. LOW HR 0.76 95%CI 0.60-0.95). CONCLUSIONS: In community-dwelling older Australian women, maintaining plasma 25OHD at 75 nmol/L or above may confer benefits to muscle function and long-term prevention of injurious falls requiring hospitalization. This relationship appears to be independent of better physical function observed in women with higher 25OHD levels.

Magnetic solid phase extraction followed by in-situ derivatization with core-shell structured titanium dioxide coated ferriferrous oxide microspheres for determination of alendronate in plasma.

In this study, for the first time, magnetic solid phase extraction (MSPE) was combined with in-situ derivatization to determine alendronate in plasma. TiO2 coated Fe3O4 microspheres (denoted as Fe3O4@TiO2) were synthesized via polydopamine coating, titanium ions immobilizing and calcination steps. The as-prepared microspheres could selectively extract alendronate and be quickly isolated from plasma. The drug-adsorbed Fe3O4@TiO2 microspheres were then directly incubated in derivatization reagent solution to perform novel in-situ derivatization and elution procedure, in which the derivatized alendronate lost its affinity to TiO2 and was spontaneously eluted for further LC-MS/MS detection. Satisfactory results were obtained on the creative attempt to couple dispersive magnetic solid phase extraction with in-situ derivatization. The developed method was validated and demonstrated good linearity (0.05-500 ng mL-1), low detection limit (20 pg mL-1), great accuracy (100.6% to 105.3%) and precision (RSDs<5.27%). Manual operation and analysis time could be greatly reduced compared to other reported methods. The method was successfully applied to a pharmacokinetic study in beagle dogs.

An innovative derivatization-free IC-MS/MS method for the detection of bisphosphonates in horse plasma.

Bisphosphonates are prohibited drugs according to Article 6 of the International Agreement on Breeding, Racing and Wagering of the International Federation of Horseracing Authorities (IFHA) and the International Equestrian Federation (FEI). These compounds are used for the treatment of lameness, navicular and bone diseases in horses and are divided into two groups: non-nitrogen-containing bisphosphonate drugs (e.g. clodronic acid) and nitrogen-containing bisphosphonate drugs (e.g. zoledronic acid). Their hydrophilic properties and the high affinity for the bone matrix make the control of their use quite difficult. Current analytical strategies to detect such compounds often rely on a solid phase extraction (SPE) followed by detection by means of UHPLC-MS/MS after methylation with chemical reagents. To improve the analysis throughput and to eliminate the need for chemical derivatization, an innovative 96-well SPE followed by ion chromatography-mass spectrometry was developed. Analyses are conducted on an ICS-6000 HPIC system coupled to a TSQ Altis™ (Thermo Scientific™). The use of a 96-well SPE allowed 5-fold sample increase and a 6-fold throughput improvement. While preliminary results conducted on horse plasma exhibited similar performances to the method for the detection of non-nitrogen-containing bisphosphonates, the analytical performances of nitrogen-containing bisphosphonates were greatly improved.

Oral Delivery of Teriparatide Using a Nanoemulsion System: Design, in Vitro and in Vivo Evaluation.

PURPOSE: Investigate the possibility of delivering teriparatide orally using nanoemulsion. METHOD: Teriparatide was allowed to interact with chitosan in the presence of HPßCD.The formed polyelectrolyte complex (PEC) was characterized by DSC, FTIR, DLS and for entrapment efficiency. PEC was the incorporated in an oil phase consisting of Oleic Acid, Labrasol and Plurol Oleique to form a nanoemulsion. This preparation was characterized for refractive index, viscosity, pH, conductivity, particle size, and morphology.Bioavailability of the preparation was evaluated using rabbits against SC injection. The efficacy of the formula was tested using ovariectomized rats (an osteoporosis animal model) and mechanical and histological tests were conducted on their bones. The stability of the preparation was evaluated by storing samples at 4o C, 25o C and 40o C for three months. RESULTS: PEC testing demonstrate a complex formation with particle size of 208 nm, zeta potential of +17 mV and entrapment efficiency of 49%. For the nanoemulsion, the results demonstrate the formation of a nano-sized dispersed system (108 nm) with a drug loading of 98% and a percent protection of 90% and 71% in SGF and SIF respectively. Bioavailability results showed a sustained release profile was achieved following the oral formulation administration. Efficacy studies showed improvement in the strength, thickness and connectivity of bones. Short-term stability study demostrated that the nanoemulsion is mostly stable at 4o C. CONCLUSION: These findings demonstrate the ability of delivering Teriparatide orally using oleic acid based dispersion in combination with chitosan PEC.

Renalase in children with chronic kidney disease.

Background: Renalase is kidney-derived molecule initially considered as catecholamine-inactivating enzyme. However, recent studies suggest that renalase exerts potent cardio- and nephroprotective actions, not related to its enzymatic activity. Purpose: To assess renalase level in children with chronic kidney disease (CKD). Material and methods: Serum renalase, BMI, arterial stiffness, peripheral and central blood pressure, intima-media thickness (IMT), medications, and biochemical parameters were analyzed in 38 children with CKD (12.23 ± 4.19 years) (stage G2-5). Control group consisted of 38 healthy children. Results: In the study group, GFR was 25.74 ± 8.94 mL/min/1.73 m2; 6 children were dialyzed; 26 had arterial hypertension. Renalase level was higher in the study group compared to control group (p < 0.001). In CKD children renalase correlated (p < 0.05) with BMI Z-score (r = -0.36), alfacalcidol dose (r = 0.41), GFR (r = -0.69), hemoglobin (r = -0.48), total cholesterol (r = 0.35), LDL-cholesterol (r = 0.36), triglycerides (r = 0.52), phosphate (r = 0.35), calcium-phosphorus product (r = 0.35), parathormone (r = 0.58), and pulse wave velocity Z-score (r = 0.42). In multivariate analysis GFR (ß = -0.63, p < 0.001), triglycerides (ß = 0.59, p = 0.002), and alfacalcidol dose (ß = -0.49, p = 0.010) were determinants of renalase. Conclusions: In children with CKD there is a strong correlation between renalase level and CKD stage. Furthermore, in these patients renalase does not correlate with blood pressure but may be a marker of arterial stiffness.

Calcifediol (25-hydroxyvitamin D) improvement and calcium-phosphate metabolism of alendronate sodium/vitamin D3 combination in Chinese women with postmenopausal osteoporosis: a post hoc efficacy analysis and safety reappraisal.

BACKGROUND: Vitamin D (VD) insufficiency or deficiency is a frequent comorbidity in Chinese women with postmenopausal osteoporosis (PMO). The present study aimed to investigate 25-hydroxyvitamin D [25(OH) D] improvement and calcium-phosphate metabolism in Chinese PMO patients treated with 70 mg of alendronate sodium and 5600 IU of vitamin D3 (ALN/D5600). METHODS: Chinese PMO women (n = 219) were treated with 12-month ALN/D5600 (n = 111) or calcitriol (n = 108). Changes in 25(OH) D at month 12 were post hoc analyzed by the baseline 25 (OH) D status using the longitudinal analysis. The main safety outcome measures included serum calcium and phosphate and 24-h urine calcium, and the repeated measures mixed model was used to assess the frequencies of the calcium-phosphate metabolic disorders. RESULTS: Absolute change in mean serum 25(OH) D level was the greatest in VD-deficient patients and least in VD-sufficient patients at months six and 12 (both, P < 0.01). Serum calcium level remained significantly lower in the ALN/D5600 treatment group than in the calcitriol treatment group throughout the 12 months. Mean 24-h urine calcium slightly increased in the ALN/D5600 treatment group and significantly increased in the calcitriol treatment group (+ 1.1 and + 0.9 mmol/L at months six and 12; both, P < 0.05). Calcitriol treatment was associated with more frequent hypercalciuria at month six (9.4% vs. 18.5%, P = 0.05), but not at month 12 (12.3% vs. 13.0%). CONCLUSION: Baseline VD status predicted 25(OH) D improvement in PMO patients on 12-month ALN/D5600 treatment. The daily use of 0.25 µg of calcitriol was associated with more frequent hypercalciuria at month six, compared to ALN/5600 treatment, necessitating the safety re-evaluation of calcitriol at a higher dosage.

Chronic vitamin D insufficiency impairs physical performance in C57BL/6J mice.

Vitamin D insufficiency (serum 25-OH vitamin D < 30 ng/ml) affects 70-80% of the general population, yet the long-term impacts on physical performance and the progression of sarcopenia are poorly understood. We therefore followed 6-month-old male C57BL/6J mice (n=6) consuming either sufficient (STD, 1000 IU) or insufficient (LOW, 125 IU) vitamin D3/kg chow for 12 months (equivalent to 20-30 human years). LOW supplemented mice exhibited a rapid decline of serum 25-OH vitamin D levels by two weeks that remained between 11-15 ng/mL for all time points thereafter. After 12 months LOW mice displayed worse grip endurance (34.6 ± 14.1 versus 147.5 ± 50.6 seconds, p=0.001), uphill sprint speed (16.0 ± 1.0 versus 21.8 ± 2.4 meters/min, p=0.0007), and stride length (4.4 ± 0.3 versus 5.1 ± 0.3, p=0.002). LOW mice also showed less lean body mass after 8 months (57.5% ± 5.1% versus 64.5% ± 4.0%, p=0.023), but not after 12 months of supplementation, as well as greater protein expression of atrophy pathway gene atrogin­1. Additionally, microRNA sequencing revealed differential expression of mIR­26a in muscle tissue of LOW mice. These data suggest chronic vitamin D insufficiency may be an important factor contributing to functional decline and sarcopenia.

Extended 3D and 4D cumulative plots for evaluation of unmatched incurred sample reanalysis.

AIM: Incurred sample reanalysis (ISR) helps ensure the reliability of pharmacokinetic studies. An appropriate graph may facilitate the evaluation of an unmatched reanalyses or a failed ISR test. METHODS: We evaluated different ways of visualizing multidimensional ISR data using an extended cumulative ISR plot. RESULTS: 3D and 4D cumulative ISR plots enable comprehensive data analysis using a single plot. We propose to use color for percentage difference classes in bar and XY-scatter plots. For the latter the shape of symbols may represent analyte concentration class, study phase, analyst or subject. CONCLUSION: The extended 3D and 4D cumulative ISR plots facilitate in-study monitoring and post-study inspection of data. It helps find the root cause of unmatched ISR, thus increasing reliability of bioanalytical data.

Poly(methyl vinyl ether-co-maleic acid) for enhancement of solubility, oral bioavailability and anti-osteoporotic effects of raloxifene hydrochloride.

Raloxifene HCl (RH) has poor water solubility and due to its extensive first pass metabolism; its bioavailability is only 2%. The purpose of the present study was to enhance the aqueous solubility, oral bioavailability and anti-osteoporotic effects of RH by electro-sprayed nanoparticles (NPs) in ovariectomized rats. NPs containing RH and different ratio of poly(methyl vinyl ether-co-maleic acid) (PMVEMA) were electrosprayed. The voltage, distance of needle to the collector, flow rate of the solution and polymeric percentage were optimized according to the size of NPs and drug solubility. The optimized formulation was characterized by SEM, XRD, DSC, and FTIR. The pharmacokinetic parameters were studies by oral administration of a single dose of 15mg/kg in Wistar rats. The anti-osteoporotic effects were studied in female ovariectomized rats. Animals were treated with 6mg/kg/day for 2months then serum calcium, phosphorous and alkaline phosphatase levels were measured. RH loaded electrosprayed NPs showed 10-fold enhanced solubility compared to the free drug. Moreover, the XRD and SEM tests displayed an amorphous state of drug in the NPs. FTIR and DSC tests revealed no interaction between the polymer and the drug. Serum calcium, phosphorous and alkaline phosphatase levels were significantly decreased in ovariectomized rats receiving oral RH NPs (P<0.05). No significant difference was detected between RH NPs and estradiol groups (P>0.05). Oral bioavailability of NPs showed 7.5-fold increase compared to the pure drug. The electrosprayed PMVEMA nanoparticles can enhance solubility, bioavailability and antiosteoporotic effects of RH.

Pharmacokinetics of tiludronate in horses: A field population study.

BACKGROUND: Tiludronate is a bisphosphonate drug marketed to treat different bone conditions in horses. OBJECTIVES: The goal of this study was to measure the plasma concentrations of tiludronate in a population of race and sport horses under field conditions, and using pharmacokinetic population modelling, to estimate detection times for doping control. STUDY DESIGN: Prospective cohort. METHODS: This study was conducted under field conditions on 39 race or sport horses diagnosed with bone conditions based on a lameness examination and treated with tiludronate. Each horse received 1 mg/kg of tiludronate (Tildren® ) intravenously (i.v.). Blood samples (from 1 to 4 per horse with a total of 93 samples) were collected around 10, 20, 30, 40 and 50 days after tiludronate administration. Tiludronate was quantified by HPLC/ESI-MSn . Tiludronate concentrations were analysed using nonlinear mixed-effects modelling (population approach). Monte Carlo simulations were then used to compute a prediction interval to estimate the corresponding quantile of horses predicted to have concentrations below some potential screening limits. RESULTS: This study highlighted pharmacokinetic differences between healthy experimental horses and the population of horses being treated in the field as well as the effect of level of training on plasma tiludronate. Different detection times were computed corresponding to different possible screening limits. MAIN LIMITATIONS: The number of horses in each group was limited, and the specific disease being treated with tiludronate is unknown. CONCLUSIONS: This population pharmacokinetic study on tiludronate will enable racing and other sports authorities to provide a detection time reflecting field conditions for the medication control of tiludronate. More generally, our study design and the data modelling serve as an example of how to generate detection times directly from the target horse population rather than from experimental horses.

Highly sensitive determination of alendronate in human plasma and dialysate using metal-free HPLC-MS/MS.

A highly sensitive method was developed for the analysis of alendronate in human plasma and dialysate using MonoSpin™ SAX® extraction and metal-free high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) following methylation with trimethylsilyldiazomethane. The chromatographic separation of the derivatives for alendronate and alendronate-d6 was achieved on an L-column2 ODS metal-free column (50 mm  ×  2 mm i.d., particle size 3 µm) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.3 ml/min. Quantification was performed by multiple reaction monitoring (MRM) with positive-ion electrospray ionization (ESI). Distinct peaks were observed for alendronate and for the internal standard on each channel within 1 min. The regression equations showed good linearity within the ranges of 2.0-100 ng/0.5 ml for the plasma and 1.0-100 ng/0.5 ml for the dialysate, with the limits of detection at 1.0 ng/0.5 ml for the plasma and 0.5 ng/0.5 ml for the dialysate. Extraction efficiencies for alendronate for the plasma and dialysate were 41.1-51.2% and 63.6-73.4%, respectively. The coefficient of variation (CV) was ≤8.5%. The method was successfully applied to the analyses of real plasma and dialysate samples derived after intravenous administration of alendronate.

Fractures in patients with CKD-diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation.

Mineral and bone disease is omnipresent in patients with chronic kidney disease (CKD) and leads to a diverse range of clinical manifestations, including bone pain and fractures. The accumulation of traditional clinical risk factors, in addition to those related to CKD, enhances the risk of comorbidity and mortality. Despite significant advances in understanding bone disease in CKD, most clinical and biochemical targets used in clinical practice remain controversial, resulting in an undermanagement of bone fragility. Vitamin D supplementation is widely used, but only a few studies have shown beneficial effects and a reduced risk of fracture and mortality. The achievement of serum levels of 25-hydroxyvitamin D is recommended for CKD patients to reduce a high parathyroid hormone level, which is associated with skeletal fractures. Optimal control of parathyroid hormone also improves bone mineralization and lowers circulating bone biomarkers such as alkaline phosphatase and cross-linked collagen type I peptide. The potential value of more recent biomarkers such as sclerostin and fibroblast growth factor 23, as surrogates for bone fragility, is an encouraging new direction in clinical research but is far from being firmly established. This article reviews the literature related to the pathophysiological role of various mineral and biochemical factors involved in renal osteodystrophy. To better understand bone fragility in CKD, new information related to the impact of disturbances of mineral metabolism on bone strength is urgently needed. The combined expertise of clinicians from various medical disciplines appears crucial for the most successful prevention of fractures in these patients.

Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit.

Teriparatide [human parathyroid hormone (1-34)], which exerts an anabolic effect on bone, is used for the treatment of osteoporosis in patients who are at a high risk for fracture. That the once-daily administration of teriparatide causes an increase in cortical porosity in animal models and clinical studies has been a matter of concern. However, it is not well documented that the frequency of administration and/or the total dose of teriparatide affect the cortical porosity. The present study developed 4 teriparatide regimens [20 µg/kg/day (D20), 40 µg/kg/day (D40), 140 µg/kg/week (W140) and 280 µg/kg/week (W280)] in the rabbit as a model animal with a well-developed Haversian system and osteons. The total weekly doses were equivalent in the low-dose groups (D20 and W140) and in the high-dose groups (D40 and W280). After the short-term (1 month) administration of TPDT, micro-CT, histomorphometry and three-dimensional second harmonic generation (3D-SHG) imaging to visualize the bone collagen demonstrated that daily regimens but not weekly regimens were associated with the significant development of cortical porosity and endosteal naïve bone formation by marrow fibrosis. We concomitantly monitored the pharmacokinetics of the plasma teriparatide levels as well as the temporal changes in markers of bone formation and resorption. The analyses in the present study suggested that the daily repeated administration of teriparatide causes more deleterious changes in the cortical microarchitecture than the less frequent administration of higher doses. The findings of the present study may have some implications for use of teriparatide in clinical treatment.

Pharmacokinetics of coadministration of levothyroxine sodium and alendronate sodium new effervescent formulation.

No clinically important pharmacokinetic interference of alendronate occurred between a new effervescent formulation of alendronate and levothyroxine when coadministered. The combination does not materially affect levothyroxine absorption. INTRODUCTION: Concurrent treatment of osteoporosis with alendronate (Aln) and hypothyroidism with levothyroxine (LT4) may be problematic because both drugs are to be taken separately after fasting overnight. The primary objective was to assess pharmacokinetic interactions between a new effervescent formulation of Aln (Aln-NEF) and LT4. METHODS: A randomized, open-label, 3-way crossover study was conducted in 30 healthy adults (15 women). Subjects were dosed 3 times, separated by 35 days, after overnight fasts, with Aln-NEF alone (70 mg), LT4 alone (600 µg), or Aln-NEF and LT4 concurrently. Samples were analyzed for plasma Aln and serum LT4. Pharmacokinetic drug-drug interaction was assessed using 90% confidence intervals (CIs) for the test/reference ratio of the geometric means for area under the concentration-time curve from time zero to last measureable time point (AUC0-t ) and maximum concentration (C max). Results were compared to the default no-effect boundaries of 80 to 125% for the ratio Aln-NEF and LT4 concurrently/Aln-NEF alone and the ratio Aln-NEF and LT4 concurrently/LT4 alone. RESULTS: Geometric mean ratios (Aln-NEF with LT4/Aln-NEF alone) were 0.927 (90% CI 0.795-1.081) for AUC0-8 and 0.912 (90% CI 0.773-1.077) for C max, demonstrating LT4 does not appreciably affect the pharmacokinetics of Aln. Geometric mean ratios (LT4 with Aln-NEF/LT4 alone) were 1.049 (90% CI 0.983-1.119) for AUC0-48 and 1.075 (90% CI 1.006-1.148) for C max, demonstrating LT4 is bioequivalent between the 2 treatments. Coadministration of Aln-NEF and LT4 was well tolerated. CONCLUSIONS: There was no clinically important pharmacokinetic interference between the Aln-NEF formulation and LT4. Aln-NEF does not materially affect LT4 absorption.

The association of the vitamin D status with the persistence of anti-HBs antibody at 20years after primary vaccination with recombinant hepatitis B vaccine in infancy.

BACKGROUND AND OBJECTIVE: Vitamin D has potent immunoregulatory effects due to the expression of its receptor on the majority of immune cells. The aim was to evaluate the association of the vitamin D status with the persistence of anti-HBs antibody and immune response to booster immunization at 20years after primary vaccination with hepatitis B (HB) vaccine. METHODS: Blood samples were collected from 300 adults 20years after completion of the primary HB vaccination in infancy. The serum levels of vitamin D and anti-HBs antibody were measured by ELISA. A single booster dose of a recombinant HB vaccine was administered to a total of 138 subjects, whose anti-HBs titer was<10IU/L. The sera of revaccinated subjects were re-tested for anti-HBs antibody, 4weeks after booster vaccination. RESULTS: At 20years after primary vaccination, the mean vitamin D concentrations were significantly higher in seroprotective subjects as compared to non-seroprotective individuals (P<0.01). The levels of anti-HBs were significantly increased with advanced concentrations of vitamin D (P<0.01). Overall, 125/138 (90.6%) of the revaccinated subjects showed an anamnestic response to booster vaccination. The concentrations of vitamin D were significantly higher in subjects with an anamnestic response to booster vaccination as compared with subjects without this response (P<0.01). CONCLUSION: Vitamin D status may influence the persistence of anti-HBs antibody and durability of protection after primary vaccination with a recombinant HB vaccine in infancy.

Treatment with hydrogen sulfide attenuates sublesional skeletal deterioration following motor complete spinal cord injury in rats.

Treatment with hydrogen sulfide mitigates spinal cord injury-induced sublesional bone loss, possibly through abating oxidative stress, suppressing MMP activity, and activating Wnt/ß-catenin signaling. INTRODUCTION: Spinal cord injury (SCI)-induced sublesional bone loss represents the most severe osteoporosis and is resistant to available treatments to data. The present study was undertaken to explore the therapeutic potential of hydrogen sulfide (H2S) against osteoporosis in a rodent model of motor complete SCI. METHODS: SCI was generated by surgical transaction of the cord at the T3-T4 levels in rats. Treatment with NaHS was initiated through intraperitoneal injection of 0.1 ml/kg/day of 0.28 mol/l NaHS from 12 h following the surgery and over 14 subsequent days. RESULTS: H2S levels in plasma of SCI rats were lower, which was restored by treatment with exogenous H2S. Treatment of SCI rats with exogenous H2S had no significant effect on body mass but increased bone mineral density in femurs and tibiae, increased BV/TV, Tb.Th, and Tb.N and reduced Tb.Sp in proximal tibiae, and increased mineral apposition rate (MAR), bone formation rate (BFR), and osteoblast surface and reduced eroded surface and osteoclast surface in proximal tibiae. More importantly, H2S treatment led to a significant enhancement in ultimate load, stiffness, and energy to max force of femoral diaphysis. Treatment of SCI rats with exogenous H2S reduced malondialdehyde (MDA) levels in serum and femurs, decreased hydroxyproline levels, suppressed activities of matrix metallopeptidase 9 (MMP9), and upregulated Wnt3a, Wnt6, Wnt10, and ctnnb1 expression in femurs. CONCLUSION: Treatment with H2S mitigates SCI-induced sublesional bone loss, possibly through abating oxidative stress, suppressing MMP activity, and activating Wnt/ß-catenin signaling.

[Usefulness of sCD14-ST in the diagnosis of sepsis in patient with renal failure]. / Utilità dell'sCD14-ST per la diagnosi di sepsi nel paziente con insufficienza renale.

Since many years, researchers have focused their studies to find out early sepsis biomarkers for the purpose of gaining time in the application of early goal-directed therapy protocol. Procalcitonin (PCT) is a reliable biomarker for sepsis, although it has a low specificity and prognostic value. Other recently proposed sepsis biomarkers such as interleukins, C-reactive protein (CRP), myeloid cells expressing triggering receptor-1 (TREM-1) and soluble urokinase-type plasminogen activator receptor (suPAR) still have a controversial and uncertain clinical value. In 2004 a new biomarker, soluble CD14 SubType (sCD14-ST, Presepsin), with a good performance in the diagnosis and prognostic evaluation of sepsis has been proposed. First studies highlighted that Presepsin is highly sensitive and specific at the same time. However, further studies on the clinical value of Presepsin are needed, particularly in order to explain the relationship between Presepsin and kidney failure. Indeed, Presepsin is a 13 KDa molecule theoretically totally filtered by glomerulus and reabsorbed and metabolized by proximal convoluted tubules. Therefore, the Presepsin plasmatic level could be highly influenced by an acute kidney injury in the course of sepsis or by a pre-existing chronic kidney disease. In this article we reviewed the latest evidences about the diagnostic and prognostic performances of Presepsin as a sepsis biomarker. We evaluated the usefulness of Presepsin in the context of acute and chronic kidney dysfunction. The great number of articles have been collected and the thorough revision of data from the nephrologists perspective let us consider this work exhaustive and scientifically reliable, although concise: a good starting point for the physician who wants to make use of Presepsin.

Severe hypocalcaemia and hypophosphataemia following intravenous iron and denosumab: a novel drug interaction.

We present the case of a 59-year-old woman with chronic kidney disease who suffered severe hypocalcaemia and hypophosphataemia after receiving denosumab and intravenous iron. This potentially life-threatening adverse drug interaction has never been reported before. We propose a mechanism to explain it with reference to the physiological derangements caused by both agents on calcium and phosphate homeostasis.

Effect of isolated vitamin D supplementation on the rate of falls and postural balance in postmenopausal women fallers: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the effect of isolated vitamin D supplementation (VITD) on the rate of falls and postural balance in postmenopausal women fallers. METHODS: In this double-blind, placebo-controlled trial, 160 Brazilian younger postmenopausal women were randomized into two groups: VITD group, vitamin D3 supplementation 1,000 IU/day/orally (n = 80) and placebo group (n = 80). Women with amenorrhea at least 12 months, age 50 to 65 years, and a history of falls (previous 12 months) were included. Those with neurological or musculoskeletal disorders, vestibulopathies, drugs use that could affect balance and osteoporosis were excluded. The intervention time was 9 months. Postural balance was assessed by stabilometry (computerized force platform) and investigation on the occurrence/recurrence of falls was performed by interviews. The plasma concentration of 25-hydroxyvitamin D [25(OH)D] was measured by high-performance liquid chromatography. Statistical analysis was achieved by intention-to-treat, using analysis of variance, Student's t test, Tukey test, chi-square, and logistic regression. RESULTS: After 9 months, mean values of 25(OH)D increased from 15.0 ±â€Š7.5 ng/mL to 27.5 ±â€Š10.4 ng/mL (+45.4%) in the VITD group, and decreased from 16.9 ±â€Š6.7 ng/mL to 13.8 ±â€Š6.0 ng/mL (-18.5%) in the placebo group (P < 0.001). The occurrence of falls was higher in the placebo group (+46.3%) with an adjusted risk of 1.95 (95% confidence interval [CI] 1.23-3.08) times more likely to fall and 2.80 (95% CI 1.43-5.50) times higher for recurrent falls compared to the VITD group (P < 0.001). There was reduction in body sway by stabilometry, with lower amplitude of antero-posterior (-35.5%) and latero-lateral (-37.0%) oscillation, only in the VITD group (P < 0.001). CONCLUSIONS: In Brazilian postmenopausal women fallers, isolated vitamin D supplementation for 9 months resulted in a lower incidence of falls and improvement in postural balance.