Mobilization of Endogenous Bone Marrow Derived Endothelial Progenitor Cells and Therapeutic Potential of Parathyroid Hormone after Ischemic Stroke in Mice

PubMed Central

Wang, Li-Li; Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Alaaeddine, Ghina; Li, Jimei; Wei, Ling; Yu, Shan Ping

2014-01-01

Stroke is a major neurovascular disorder threatening human life and health. Very limited clinical treatments are currently available for stroke patients. Stem cell transplantation has shown promising potential as a regenerative treatment after ischemic stroke. The present investigation explores a new concept of mobilizing endogenous stem cells/progenitor cells from the bone marrow using a parathyroid hormone (PTH) therapy after ischemic stroke in adult mice. PTH 1-34 (80 µg/kg, i.p.) was administered 1 hour after focal ischemia and then daily for 6 consecutive days. After 6 days of PTH treatment, there was a significant increase in bone marrow derived CD-34/Fetal liver kinase-1 (Flk-1) positive endothelial progenitor cells (EPCs) in the peripheral blood. PTH treatment significantly increased the expression of trophic/regenerative factors including VEGF, SDF-1, BDNF and Tie-1 in the brain peri-infarct region. Angiogenesis, assessed by co-labeled Glut-1 and BrdU vessels, was significantly increased in PTH-treated ischemic brain compared to vehicle controls. PTH treatment also promoted neuroblast migration from the subventricular zone (SVZ) and increased the number of newly formed neurons in the peri-infarct cortex. PTH-treated mice showed significantly better sensorimotor functional recovery compared to stroke controls. Our data suggests that PTH therapy improves endogenous repair mechanisms after ischemic stroke with functional benefits. Mobilizing endogenous bone marrow-derived stem cells/progenitor cells using PTH and other mobilizers appears an effective and feasible regenerative treatment after ischemic stroke. PMID:24503654

Enhanced visible-light photocatalysis and gas sensor properties of polythiophene supported tin doped titanium nanocomposite

NASA Astrophysics Data System (ADS)

Chandra, M. Ravi; Siva Prasada Reddy, P.; Rao, T. Siva; Pammi, S. V. N.; Siva Kumar, K.; Vijay Babu, K.; Kiran Kumar, Ch.; Hemalatha, K. P. J.

2017-06-01

The polythiophene supported tin doped titanium nanocomposites (PTh/Sn-TiO2) were synthesized by modified sol-gel process through oxidative polymerization of thiophene. The fourier transform infrared spectroscopy (FT-IR) and UV-Vis diffuse reflectance spectroscopy (UV-DRS) analysis confirms the existence of synergetic interaction between metal oxide and polymer along with extension of absorption edge to visible region. The composites are found to be in spherical form with core-shell structure, which is confirmed by scanning electron spectroscopy (SEM) and transmission electron microscopy (TEM) images, the presence of all respective elements of composite are proven by energy-dispersive X-ray spectroscopy (EDX) analysis. The importance of polythiophene on surface of metal oxide has been were studied as a function of photocatalytic activity for degradation of organic pollutant congo red and gas sensor behavior towards liquid petroleum gas (LPG). All the composites are photocatalytically active and the composite with 1.5 wt% thiophene degrades the pollutant congo red within 120 min when compared to remaining catalysts under visible light irradiation. On the other hand, same composite have shown potential gas sensor properties towards LPG at 300 °C. Considering all the results, it can be noted that polythiophene acts as good sensitizer towards LPG and supporter for the tin doped titania that improve the photocatalytic activity under visible light.

Radiofrequency Ablation Followed by Percutaneous Ethanol Ablation Leading to Long-Term Remission of Hyperparathyroidism

PubMed Central

Menon, Arun S.; Nazar, P. K.; Moorthy, Srikanth; Kumar, Harish; Nair, Vasantha; Pavithran, Praveen Valiyaparambil; Bhavani, Nisha; Menon, Vadayath Usha; Abraham, Nithya; Jayakumar, R. Vasukutty

2017-01-01

A 30-year-old male with cerebral palsy and motor impairment presented with right femur fracture. He had gradually worsening mobility and contractures of all extremities for the preceding 5 years. Evaluation showed multiple vertebral and femoral fractures, severe osteoporosis, a large parathyroid adenoma, and parathormone (PTH) exceeding 2500 pg/mL. Because of poor general health and high anesthetic risk, parathyroidectomy was deemed impractical. Ultrasound-guided radiofrequency ablation (RFA) helped achieve 50% size reduction and PTH levels with better control of hypercalcemia. Later, as calcium and PTH remained elevated, percutaneous ethanol ablation was performed with resultant normalization of PTH and substantial symptomatic improvement. Two years later, he still remains normocalcaemic with normal PTH levels. We propose that RFA and percutaneous ethanol ablation be considered as effective short-term options for surgically difficult cases, which could even help achieve long-term remission. Although not previously reported, our case illustrates that both RFA and percutaneous ethanol ablation could be safely performed successively achieving long-term remission. PMID:29264521

Interactions Between Adrenal and Calcium-Regulatory Hormones in Human Health

PubMed Central

Brown, Jenifer M.; Vaidya, Anand

2014-01-01

Purpose of Review To summarize evidence characterizing the interactions between adrenal- and calcium-regulating hormones, and the relevance of these interactions to human cardiovascular and skeletal health. Recent Findings Human studies support the regulation of parathyroid hormone (PTH) by the renin-angiotensin-aldosterone system (RAAS): angiotensin II may stimulate PTH secretion via an acute and direct mechanism, whereas aldosterone may exert a chronic stimulation of PTH secretion. Studies in primary aldosteronism, congestive heart failure, and chronic kidney disease have identified associations between hyperaldosteronism, hyperparathyroidism, and bone loss, which appear to improve when inhibiting the RAAS. Conversely, elevated PTH and insufficient vitamin D status have been associated with adverse cardiovascular outcomes, which may be mediated by the RAAS. Studies of primary hyperparathyroidism implicate PTH-mediated stimulation of the RAAS, and recent evidence shows that the vitamin D-vitamin D receptor (VDR) complex may negatively regulate renin expression and RAAS activity. Ongoing human interventional studies are evaluating the influence of RAAS inhibition on PTH and the influence of VDR agonists on RAAS activity. Summary While previously considered independent endocrine systems, emerging evidence supports a complex web of interactions between adrenal and calcium-regulating hormones, with implications for human cardiovascular and skeletal health. PMID:24694551

Improved adherence with PTH(1–84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis

PubMed Central

Bilezikian, J. P.; Greenspan, S. L.; Wüster, C.; Muñoz-Torres, M.; Bone, H. G.; Rosen, C. J.; Andersen, H. S.; Hanley, D. A.

2016-01-01

Summary The purpose of this study is to examine the effect of PTH(1–84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy. Introduction There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. Methods Seven hundred and eighty-one subjects who received active PTH(1–84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. Results PTH(1–84) treatment over 24 months increased BMD at the lumbar spine by 6.8 % above baseline (p < 0.05). The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with ≥80 % adherence to daily injections of PTH(1–84) (8.3% in adherent vs 4.9 % in poorly adherent patients). Total hip BMD gains were 1.7 % in adherent vs 0.6 % in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1–84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1–84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. Conclusions PTH(1–84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1–84) for up to 24 months is also associated with greater efficacy. PMID:22930240

Synthesis and electrochemical performance of LiV3O8/polythiophene composite as cathode materials for lithium ion batteries

NASA Astrophysics Data System (ADS)

Guo, Haipeng; Liu, Li; Shu, Hongbo; Yang, Xiukang; Yang, Zhenhua; Zhou, Meng; Tan, Jinli; Yan, Zichao; Hu, Hai; Wang, Xianyou

2014-02-01

LiV3O8/polythiophene (LiV3O8/PTh) composite has been chemically synthesized via an in-situ oxidative polymerization method. The structure and morphology of the samples have been characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM). LiV3O8/PTh composite shows a single phase in the XRD pattern, but the existence of PTh has been confirmed by FTIR spectra. HRTEM images show that an uniform PTh layer with a thickness of 3-5 nm covered on the surface of LiV3O8. Electrochemical performance of samples has been characterized by the charge/discharge test, cyclic voltammetry (CV), electrochemical impedance spectroscopic studies (EIS) and galvanostatic intermittent titration technique (GITT). The LiV3O8/PTh composite exhibits much better electrochemical performance than bare LiV3O8. The initial discharge capacities of 15 wt.% LiV3O8/PTh composite are 213.3 and 200.3 mAh g-1 with almost no capacity retention after 50 cycles at current densities of 300 and 900 mA g-1, respectively. PTh could enhance electronic conductivity, decrease the charge transfer resistance, increase the lithium diffusion coefficient, and thus improve cycling performance of LiV3O8. All these results demonstrate that the LiV3O8/PTh composite has a promising application as cathode material for lithium ion batteries.

PTH prevents the adverse effects of focal radiation on bone architecture in young rats.

PubMed

Chandra, Abhishek; Lan, Shenghui; Zhu, Ji; Lin, Tiao; Zhang, Xianrong; Siclari, Valerie A; Altman, Allison R; Cengel, Keith A; Liu, X Sherry; Qin, Ling

2013-08-01

Radiation therapy is a common treatment regimen for cancer patients. However, its adverse effects on the neighboring bone could lead to fractures with a great impact on quality of life. The underlying mechanism is still elusive and there is no preventive or curative solution for this bone loss. Parathyroid hormone (PTH) is a current therapy for osteoporosis that has potent anabolic effects on bone. In this study, we found that focal radiation from frequent scans of the right tibiae in 1-month-old rats by micro-computed tomography severely decreased trabecular bone mass and deteriorated bone structure. Interestingly, PTH daily injections remarkably improved trabecular bone in the radiated tibiae with increases in trabecular number, thickness, connectivity, structure model index and stiffness, and a decrease in trabecular separation. Histomorphometric analysis revealed that radiation mainly decreased the number of osteoblasts and impaired their mineralization activity but had little effects on osteoclasts. PTH reversed these adverse effects and greatly increased bone formation to a similar level in both radiated and non-radiated bones. Furthermore, PTH protects bone marrow mesenchymal stem cells from radiation-induced damage, including a decrease in number and an increase in adipogenic differentiation. While radiation generated the same amount of free radicals in the bone marrow of vehicle-treated and PTH-treated animals, the percentage of apoptotic bone marrow cells was significantly attenuated in the PTH group. Taken together, our data demonstrate a radioprotective effect of PTH on bone structure and bone marrow and shed new light on a possible clinical application of anabolic treatment in radiotherapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Endogenous PTH deficiency impairs fracture healing and impedes the fracture-healing efficacy of exogenous PTH(1-34).

PubMed

Ren, Yongxin; Liu, Bo; Feng, Yuxu; Shu, Lei; Cao, Xiaojian; Karaplis, Andrew; Goltzman, David; Miao, Dengshun

2011-01-01

Although the capacity of exogenous PTH1-34 to enhance the rate of bone repair is well established in animal models, our understanding of the mechanism(s) whereby PTH induces an anabolic response during skeletal repair remains limited. Furthermore it is unknown whether endogenous PTH is required for fracture healing and how the absence of endogenous PTH would influence the fracture-healing capacity of exogenous PTH. Closed mid-diaphyseal femur fractures were created and stabilized with an intramedullary pin in 8-week-old wild-type and Pth null (Pth(-/-)) mice. Mice received daily injections of vehicle or of PTH1-34 (80 µg/kg) for 1-4 weeks post-fracture, and callus tissue properties were analyzed at 1, 2 and 4 weeks post-fracture. Cartilaginous callus areas were reduced at 1 week post-fracture, but were increased at 2 weeks post-fracture in vehicle-treated and PTH-treated Pth(-/-) mice compared to vehicle-treated and PTH-treated wild-type mice respectively. The mineralized callus areas, bony callus areas, osteoblast number and activity, osteoclast number and surface in callus tissues were all reduced in vehicle-treated and PTH-treated Pth(-/-) mice compared to vehicle-treated and PTH-treated wild-type mice, but were increased in PTH-treated wild-type and Pth(-/-) mice compared to vehicle-treated wild-type and Pth(-/-) mice. Absence of endogenous PTH1-84 impedes bone fracture healing. Exogenous PTH1-34 can act in the absence of endogenous PTH but callus formation, including accelerated endochondral bone formation and callus remodeling as well as mechanical strength of the bone are greater when endogenous PTH is present. Results of this study suggest a complementary role for endogenous PTH1-84 and exogenous PTH1-34 in accelerating fracture healing.

Effects of parathyroid hormone on cortical porosity, non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitus.

PubMed

Campbell, G M; Tiwari, S; Hofbauer, C; Picke, A-K; Rauner, M; Huber, G; Peña, J A; Damm, T; Barkmann, R; Morlock, M M; Hofbauer, L C; Glüer, C-C

2016-01-01

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and the efficacy of bone-forming agents are unclear. We studied diabetes and parathyroid hormone (PTH) treatment effects on cortical porosity (Ct.Po), non-enzymatic glycation (NEG) and bone mechanics in Zucker diabetic fatty (ZDF) rats. Eleven-week old ZDF diabetic (DB) and non-diabetic (ND) rats were given 75μg/kg PTH (1-84) or vehicle 5days per week over 12weeks. The right femora and L4 vertebrae were excised, micro-CT scanned, and tested in 3-point bending and uniaxial compression, respectively. NEG of the samples was determined using fluorescence. Diabetes increased Ct.Po (vertebra (vert): +40.6%, femur (fem): +15.5% vs. ND group, p<0.05) but had no effect on NEG. PTH therapy reduced vertebral NEG in the ND animals only (-73% vs untreated group, p<0.05), and increased femoral NEG in the DB vs. ND groups (+63%, p<0.05). PTH therapy had no effect on Ct.Po. Diabetes negatively affected bone tissue mechanics where reductions in vertebral maximum strain (-22%) and toughness (-42%) were observed in the DB vs. ND group (p<0.05). PTH improved maximum strain in the vertebra of the ND animals (+21%, p<0.05) but did not have an effect in the DB group. PTH increased femoral maximum strain (+21%) and toughness (+28%) in ND and decreased femoral maximum stress (-13%) and toughness (-27%) in the DB animals (treated vs. untreated, p<0.05). Ct.Po correlated negatively with maximum stress (fem: R=-0.35, p<0.05, vert: R=-0.57, p<0.01), maximum strain (fem: R=-0.35, p<0.05, vert: R=-0.43, p<0.05) and toughness (fem: R=-0.34, p<0.05, vert: R=-0.55, p<0.01), and NEG correlated negatively with toughness at the femur (R=-0.34, p<0.05) and maximum strain at the vertebra (R=-0.49, p<0.05). Diabetes increased cortical porosity and reduced bone mechanics, which were not improved with PTH treatment. PTH therapy alone may worsen diabetic bone mechanics through formation of new bone with high AGEs cross-linking. Optimal treatment regimens must address both improvements of bone mass and glycemic control in order to successfully reduce diabetic bone fragility. This article is part of a Special Issue entitled "Bone and diabetes". Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of Concurrent Use of Whole-Body Vibration and Parathyroid Hormone on Bone Structure and Material Properties of Ovariectomized Mice.

PubMed

Matsumoto, Takeshi; Itamochi, Shinya; Hashimoto, Yoshihiro

2016-05-01

This study was designed to determine the effectiveness of whole-body vibration (WBV) and intermittent parathyroid hormone (iPTH) in combination against estrogen deficiency-induced osteoporosis. Female C57BL/6J mice were bilaterally ovariectomized (OVX, n = 40) or sham-operated (sham-OVX, n = 8) at 9 weeks of age. Two weeks later, the OVX mice were randomly divided into four groups (n = 10 each): the control group (c-OVX) and groups treated with iPTH (p-OVX), WBV (w-OVX) and both (pw-OVX). The p-OVX and pw-OVX groups were given human PTH (1-34) at a dose of 30 µg/kg/day. The w-OVX and pw-OVX groups were exposed to WBV at an acceleration of 0.3 g and 45 Hz for 20 min/day. All mice were euthanized after the 18-day treatment, and the left tibiae were harvested. The proximal metaphyseal region was µCT-scanned, and its cortical bone cross-section was analyzed by Fourier transform infrared microspectroscopy and nanoindentation testing. A single application of iPTH or WBV to OVX mice had no effect on bone structure or material properties of cortical bone, which were compromised in comparison to those in sham-OVX mice. The combination of iPTH and WBV improved trabecular bone volume, thickness, and connectivity in OVX mice. Although the combined treatment failed to improve cortical bone structure, its mineral maturity and hardness were restored to the levels observed in sham-OVX mice. There was no evidence of interaction between the two treatments, and the combined effects seemed to be additive. These results suggest combining WBV with iPTH has great potential for treating postmenopausal osteoporosis.

Posttraumatic hydrocephalus: a clinical, neuroradiologic, and neuropsychologic assessment of long-term outcome.

PubMed

Mazzini, Letizia; Campini, Riccardo; Angelino, Elisabetta; Rognone, Felice; Pastore, Ilaria; Oliveri, Giuseppe

2003-11-01

To detect the clinical and radiologic characteristics of posttraumatic hydrocephalus (PTH), to define its prognostic value, and to assess the effects of shunt surgery. Correlational study on a prospective cohort. Brain injury rehabilitation center. One hundred forty patients with severe traumatic brain injury (TBI) referred to an inpatient intensive rehabilitation unit of primary care in a university-based system. Not applicable. The Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS), FIM instrument, and Neurobehavioural Rating Scale (NRS), as well as single-photon emission computed tomography (SPECT) and magnetic resonance imaging. PTH was found in 45% of patients. Risk factors for PTH were as follows: age (P<.04), duration of coma (P<.0001), and decompressive craniectomy (P<.0001). PTH correlated with the degree of hypoperfusion in the temporal lobes (P<.001). Patients who showed clinical deterioration improved after surgery. PTH correlated significantly with GOS, DRS, FIM, and NRS (P<.0001) 1 year after the trauma, and it influenced the appearance of posttraumatic epilepsy (P<.02). PTH concerns about 50% of patients with severe TBI. It influences functional and behavioral outcome and the appearance of posttraumatic epilepsy. The selection of patients for surgery can be defined principally on a clinical basis. SPECT may be helpful for differentiating ventricular enlargement due to cortical atrophy and hydrocephalus.

Hypercalcemic Disorders in Children.

PubMed

Stokes, Victoria J; Nielsen, Morten F; Hannan, Fadil M; Thakker, Rajesh V

2017-11-01

Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Down-regulation of parathyroid hormone (PTH) receptors in cultured bone cells is associated with agonist-specific intracellular processing of PTH-receptor complexes.

PubMed

Teitelbaum, A P; Silve, C M; Nyiredy, K O; Arnaud, C D

1986-02-01

Exposure of cultured embryonic chicken bone cells to the PTH agonists bovine (b) PTH-(1-34) and [8Nle, 18Nle, 34Tyr]bPTH-(1-34)amide [bPTH-(1-34)A] reduces the subsequent cAMP response to the hormone and decreases the specific binding of 125I-labeled PTH to these cultures. To determine whether PTH receptor down-regulation in cultured bone cells is mediated by cellular internalization of PTH-receptor complexes, we measured the uptake of [125I]bPTH-(1-34) into an acid-resistant compartment. Uptake of radioactivity into this compartment was inhibited by incubating cells at 4 C with phenylarsineoxide and unlabeled bPTH-(1-34). Tracer uptake into the acid-resistant compartment at any time was directly proportional to total cell binding at 22 C. Thus, it is likely that PTH-receptor complexes are internalized by bone cells. This mechanism may explain the loss of cell surface receptors after PTH pretreatment. To determine whether internalized PTH-receptor complexes are reinserted into the plasma membrane, we measured PTH binding and PTH stimulation of cAMP production after cells were exposed to monensin, a known inhibitor of receptor recycling. Monensin (25 microM) had no effect on PTH receptor number or affinity and did not alter PTH-stimulated cAMP accumulation. However, monensin (25 microM) incubated with cells pretreated with various concentrations of bPTH-(1-34) for 1 h potentiated the effect of the hormone to reduce subsequent [125I]bPTH-(1-34) binding and PTH-stimulated cAMP accumulation by more than 2 orders of magnitude. Chloroquine also potentiated PTH-induced down-regulation of PTH receptors. By contrast, neither agent influenced PTH binding or PTH-stimulated cAMP production in cells pretreated with the antagonist bPTH-(3-34)A. Thus, monensin potentiated PTH receptor loss only in cells pretreated with PTH agonists, indicating that antagonist-occupied receptors may be processed differently from agonist-occupied receptors in bone cells. The data further suggest that the attenuation of PTH stimulation of cAMP production in treated bone cells may be, at least in part, due to receptor-mediated endocytosis of the hormone.

Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease.

PubMed

Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Rus-Machan, Jutta; Kienreich, Katharina; Verheyen, Nicolas; Gaksch, Martin; Grübler, Martin; Fahrleitner-Pammer, Astrid; Mrak, Peter; Toplak, Hermann; Kraigher-Krainer, Elisabeth; März, Winfried; Pilz, Stefan

2014-01-01

Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon. © 2013.

Intermittent parathyroid hormone administration improves periodontal healing in rats.

PubMed

Vasconcelos, Daniel Fernando Pereira; Marques, Marcelo Rocha; Benatti, Bruno Braga; Barros, Silvana Pereira; Nociti, Francisco Humberto; Novaes, Pedro Duarte

2014-05-01

Intermittent administration of parathyroid hormone (PTH) promotes new bone formation in patients with osteoporosis and bone fractures. It was shown previously that PTH also reduces periodontitis-related bone loss. The aim of this study is to evaluate the effect of treatment with PTH on periodontal healing in rats. Fenestration defects were created at the buccal surface of the distal root of the mandibular first molars, and both periodontal ligament (PDL) and cementum were removed. Animals were then assigned to two groups (eight animals per group): group 1: control, placebo administration; and group 2: test, human PTH (hPTH) 1-34 administration at a concentration of 40 μg/kg. For both groups, the animals were injected every 2 days, and the animals were sacrificed at 14 and 21 days after surgery. Specimens were harvested and processed for routine decalcified histologic sections. The following parameters were assessed: 1) remaining bone defect extension (RBDE); 2) newly formed bone density (NFBD); 3) total callus area (TCA); 4) osteoclast number (ON) in the callus region; and 5) newly formed dental cementum-like tissue (NFC). Birefringence of root PDL reattachment was also evaluated. Birefringence analysis showed root PDL reattachment for both groups 21 days after treatment. Intermittent hPTH 1-34 administration decreased RBDE (P <0.01) and increased NFBD (P <0.01), TCA (P <0.01), area of NFC (P <0.01), and ON in the callus region (P <0.01). Within the limits of the present study, intermittent administration of hPTH 1-34 led to an enhanced periodontal healing process compared with non-treated animals.

PTH 1-34 Ameliorates the Osteopenia and Delayed Healing of Stabilized Tibia Fracture in Mice with Achondroplasia Resulting from Gain-Of-Function Mutation of FGFR3

PubMed Central

Chen, Hangang; Sun, Xianding; Yin, Liangjun; Chen, Shuai; Zhu, Ying; Huang, Junlan; Jiang, Wanling; Chen, Bo; Zhang, Ruobin; Chen, Lin; Nie, Mao; Xie, Yangli; Deng, Zhongliang

2017-01-01

Bone fracture healing is processed through multiple stages including the cartilaginous callus formation and its transition to bony callus. FGFR3 negatively regulates chondrogenesis and enhances osteogenesis during skeleton development. We previously found in mice carrying gain-of-function mutation of FGFR3 that FGFR3 delays the healing of un-stabilized fracture that heals mainly through endochondral ossification. Since fracture is regularly treated in clinics with rigid fixation, and stabilized fracture is healed largely through intramembranous ossification, we asked whether FGFR3, a key regulator of osteogenesis, also affect the regeneration of stabilized fracture. We found that gain-of-function mutation of FGFR3 inhibits the initiation of chondrogenesis and the subsequent bone formation. We further studied whether PTH1-34 can improve the osteopenia and delayed healing of the stabilized tibia fracture in mice with achondroplasia. Fracture healing was evaluated by radiography, micro-CT, biomechanical tests, histology, and real-time polymerase chain reaction (RT-PCR) analysis. We found that PTH 1-34 can alleviate the decreased bone mass and compromised architecture in ACH mice. Histological analysis revealed that administration of PTH1-34 increased the size of both the total callus and cartilaginous callus at 14 days after the surgery in ACH mice. RT-PCR data suggested that systemic PTH1-34 accelerated the initiation of chondrogenesis and chondrocyte maturation (earlier and higher levels of expression of chondrogenesis related markers) and enhanced the osteogenic differentiation in the fracture callus in ACH mice. These results indicate that the PTH1-34 administration resulted in an enhanced callus formation during bone fracture healing in ACH mice, which is at least in part mediated by an increase of cartilaginous callus at early stage and the promotion of bone formation in bony callus. In summary, in this study we revealed that FGFR3 delays the regeneration of stabilized fracture by inhibiting both the chondrogenesis and osteogenesis, and PTH1-34 treatment can improve the dysregulated bone metabolism and delayed bone injury healing resulting from gain-of-function mutation of FGFR3. PMID:29104492

Experience with a third-generation parathyroid hormone assay (BIO-PTH) in the diagnosis of primary hyperparathyroidism in a Brazilian population.

PubMed

Bonanséa, Teresa Cristina P; Ohe, Monique Nakayama; Brandão, Cynthia; Ferrer, Cláudia de Francischi; Santos, Lívia Marcela; Lazaretti-Castro, Marise; Vieira, José Gilberto Henriques

2016-10-01

To evaluate the usefulness of a third-generation PTH assay in the diagnosis of primary hyperparathyroidism (PHPT). Forty-one PHPT patients (4 men and 37 women) with 61.2 ± 10.9 (mean ± SD) years, were studied and had PTH levels measured with two different methods using the same immunochemiluminescent assay plataform (Elecsys 2010 System, Roche). We compared a second-generation assay (I-PTH) with a third-generation PTH assay (Bio-PTH). Two populations of 423 and 120 healthy adults with serum 25OHD levels above 25 ng/mL were used to define normal values in the I-PTH and Bio-PTH assays respectively. Normal PTH values based in the healthy adults population were 24.2-78.0 pg/mL for the I-PTH assay and 19.9-58.5 pg/mL for Bio-PTH assay. In PHPT patients, PTH values ranged from 67 to 553 pg/mL (median: 168 pg/mL) using the I-PTH assay and from 55 to 328 pg/mL (median: 111 pg/mL) using the Bio-PTH assay. Results obtained with the Bio-PTH assay were significantly lower (p < 0.0001, Wilcoxon). In general I-PTH and Bio-PTH showed highly significant correlation (r = 0.952, p < 0.0001). Passing-Bablok analysis gave a regression equation of Bio PTH = 13.44 + 0.59 x intact PTH. PHPT patients had 25OHD levels ranging from 4 to 36 ng/mL (mean 16.2 ng/mL); 35 subjects (85.3%) had values bellow 25 ng/mL. Our results demonstrate that both second and third generation PTH methods are strongly correlated in PHPT patients and control subjects. Lower results with Bio-PTH tests are expected in function of the assay specificity determined by the amino-terminal antibody used.

Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken.

PubMed

Pinheiro, Pedro L C; Cardoso, João C R; Gomes, Ana S; Fuentes, Juan; Power, Deborah M; Canário, Adelino V M

2010-12-01

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) belong to a family of endocrine factors that share a highly conserved N-terminal region (amino acids 1-34) and play key roles in calcium homeostasis, bone formation and skeletal development. Recently, PTH-like peptide (PTH-L) was identified in teleost fish raising questions about the evolution of these proteins. Although PTH and PTHrP have been intensively studied in mammals their function in other vertebrates is poorly documented. Amphibians and birds occupy unique phylogenetic positions, the former at the transition of aquatic to terrestrial life and the latter at the transition to homeothermy. Moreover, both organisms have characteristics indicative of a complex system in calcium regulation. This study investigated PTH family evolution in vertebrates with special emphasis on Xenopus and chicken. The PTH-L gene is present throughout the vertebrates with the exception of placental mammals. Gene structure of PTH and PTH-L seems to be conserved in vertebrates while PTHrP gene structure is divergent and has acquired new exons and alternative promoters. Splice variants of PTHrP and PTH-L are common in Xenopus and chicken and transcripts of the former have a widespread tissue distribution, although PTH-L is more restricted. PTH is widely expressed in fish tissue but from Xenopus to mammals becomes largely restricted to the parathyroid gland. The N-terminal (1-34) region of PTH, PTHrP and PTH-L in Xenopus and chicken share high sequence conservation and the capacity to modify calcium fluxes across epithelia suggesting a conserved role in calcium metabolism possibly via similar receptors. The parathyroid hormone family contains 3 principal members, PTH, PTHrP and the recently identified PTH-L. In teleosts there are 5 genes which encode PTHrP (2), PTH (2) and PTH-L and in tetrapods there are 3 genes (PTHrP, PTH and PTH-L), the exception is placental mammals which have 2 genes and lack PTH-L. It is hypothesized that genes of the PTH family appeared at approximately the same time during the vertebrate radiation and evolved via gene duplication/deletion events. PTH-L was lost from the genome of eutherian mammals and PTH, which has a paracrine distribution in lower vertebrates, became the product of a specific endocrine tissue in Amphibia, the parathyroid gland. The PTHrP gene organisation diverged and became more complex in vertebrates and retained its widespread tissue distribution which is congruent with its paracrine nature.

Changes in Vitamin D and PTH Metabolism in Incident Pediatric Crohn Disease

PubMed Central

Prosnitz, Aaron R.; Leonard, Mary B.; Shults, Justine; Zemel, Babette S.; Hollis, Bruce W.; Denson, Lee A.; Baldassano, Robert N.; Cohen, Aaron B.; Thayu, Meena

2015-01-01

Background and Aims Prior studies of vitamin D metabolism in Crohn disease (CD) did not include controls or examine changes following diagnosis. This study examined associations among 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] and parathyroid hormone (PTH) levels in incident pediatric CD, compared with controls, and following diagnosis. Methods Serum vitamin D and PTH were measured at diagnosis (n = 78), 6, 12, and a median of 43 months (n = 52) later in CD participants, and once in 221 controls. Multivariate regression was used to examine baseline associations, and quasi-least squares regression to assess subsequent changes. Results At diagnosis, 42% of CD participants were 25(OH)D deficient (<20 ng/mL). The odds ratio for deficiency was 2.1 (95% CI 1.1, 3.9; p<0.05) vs. controls, adjusted for age, race, and season. 1,25(OH)2D was lower in CD vs. controls (p<0.05), adjusted for 25(OH)D, tumor necrosis factor–α (TNF-α) and PTH. TNF-α was associated with lower 1,25(OH)2D (p<0.05), and the positive association between PTH and 1,25(OH)2D in controls was absent in CD (interaction p=0.02). Among participants with 25(OH)D <30 ng/mL, CD was associated with lower PTH (p<0.05) vs. controls. Following diagnosis, 25(OH)D and 1,25(OH)2D improved (p<0.001). At the final visit, 3% were 25(OH)D deficient, PTH was no longer low relative to 25(OH)D, and 1,25(OH)2D was significantly elevated (p<0.001), compared with controls. Conclusions Incident CD was associated with 25(OH)D and 1,25(OH)2D deficiency and a relative hypoparathyroidism that resolved following diagnosis. Inflammatory cytokine suppression of PTH and renal 1-α-hyroxylase may contribute to these alterations. PMID:22488969

A decrease in intact parathyroid hormone (iPTH) levels is associated with higher mortality in prevalent hemodialysis patients

PubMed Central

Villa-Bellosta, Ricardo; Rodriguez-Osorio, Laura; Mas, Sebastian; Abadi, Younes; Rubert, Mercedes; de la Piedra, Concepción; Gracia-Iguacel, Carolina; Mahillo, Ignacio; Ortiz, Alberto; Egido, Jesús; González-Parra, Emilio

2017-01-01

Background The mortality of dialysis patients is 10- to 100-fold higher than in the general population. Baseline serum PTH levels, and more recently, changes in serum PTH levels (ΔPTH) over time, have been associated to mortality in dialysis patients. Methods We explored the relationship between ΔPTH over 1 year with mortality over the next year in a prospective cohort of 115 prevalent hemodialysis patients from a single center that had median baseline iPTH levels within guideline recommendations. Results Median baseline iPTH levels were 205 (116.5, 400) pg/ml. ΔiPTH between baseline and 1 year was 85.2 ± 57.1 pg/ml. During the second year of follow-up, 27 patients died. ΔiPTH was significantly higher in patients who survived (+157.30 ± 25.82 pg/ml) than in those who died (+39.03 ± 60.95 pg/ml), while baseline iPTH values were not significantly different. The highest mortality (48%) was observed in patients with a decrease in ΔiPTH (ΔiPTH quartile 1, negative ΔiPTH) and the lowest (12%) mortality in quartile 3 ΔiPTH (ΔiPTH increase 101–300 pg/ml). In a logistic regression model, ΔiPTH was associated with mortality with an odds ratio (OR) of 0.998 (95% CI 0.996–0999, p = 0.038). In multivariable analysis, mortality risk was 73% and 88% lower for patients with ΔiPTH 0–100 pg/ml and 101–300 pg/ml, respectively, than for those with a decrease in ΔiPTH. In patients with a decrease in ΔiPTH, the OR for death was 4.131 (1.515–11.27)(p = 0.006). Conclusions In prevalent hemodialysis patients with median baseline iPTH values within the guideline recommended range, a decrease in ΔiPTH was associated with higher mortality. Further studies are required to understand the mechanisms and therapeutic implications of this observation that challenges current clinical practice. PMID:28339474

Glucocorticoid-induced bone loss can be reversed by the actions of PTH and Risedronate on different pathways for bone formation and mineralization

PubMed Central

Yao, Wei; Cheng, Zhiqiang; Pham, Aaron; Busse, Cheryl; Zimmermann, Elizabeth A.; Ritchie, Robert O.; Lane, Nancy E.

2008-01-01

Glucocorticoid (GC) excess decreases bone mineralization and microarchitecture and lead to reduced bone strength. Both anabolic (PTH) and anti-resorptive agents are used to prevent and treat GC-induced bone loss, yet these bone active agents alter bone turnover by very different mechanisms. Our study objective was to determine how PTH and risedronate (Ris) alter bone quality following GC excess. Five-month-old Swiss-Webster male mice were treated with the glucocorticoid (GC) prednisolone (5 mg/kg 60-day slow-release pellet) or placebo (PL)]. At day 28−56, two groups of GC-treated animals had either PTH (5μg/kg, 5x/wk) or Ris (5μg/kg, 5x/wk) intervention. Bone quality and quantity measurements include x-ray tomography microscopy (XTM) for the degree of bone mineralization (DBM), microCT for bone microarchitecture, compression testing for trabecular bone strength, biochemistry and histomorphometry for bone turnover. In addition, real-time PCR and immunohistochemistry were performed to monitor the expression of several key genes regulating Wnt signaling (bone formation) and mineralization. Results Compared to the placebo treated mice, GC treatment decreased trabecular bone volume (BV/TV) and serum osteocalcin, but increased serum CTX and osteoclast surface with a peak at day 28. GC+PTH increased and GC+Ris restored BV/TV to the PL levels after a 28 day treatment period. Average DBM was lowered after GC treatment (−27%), and it was restored to PL level with GC+Ris and GC+PTH. At day 56, RT-PCR revealed that continuous exposure to GC and GC+PTH increased, while GC+Ris decreased the expression of genes that inhibit bone mineralization (Dmp1 and Phex), compared to the PL group. Wnt signaling antagonists Dkk1, Sost and Wif1 were up-regulated by GC treatment but were down-regulated after GC+PTH treatment. Immunohistochemistry of bone sections found GC increased N terminal dmp-1 while PTH treatment increased both N and C terminal dmp-1 staining around osteocytes. Summary GC excess reduced expression of genes that regulate mineralization and increased expression of genes that inhibit Wnt signaling which were associated with reduced bone formation and bone volume over a 60 day treatment period. The addition of both PTH and Ris improved bone mass, DBM and bone strength during concurrent GC treatment, with PTH lowering expression of Wnt inhibitors and increasing bone formation; while Ris lowered the expression of mineralization inhibitors and reversed the deterioration of bone mineralization induced by GC excess. PMID:18975341

A low plasma 1,25(OH)2 vitamin D/PTH (1-84) ratio predicts worsening of renal function in patients with chronic heart failure.

PubMed

Masson, Serge; Barlera, Simona; Colotta, Francesco; Magnoli, Michela; Bonelli, Fabrizio; Moro, Milena; Marchioli, Roberto; Tavazzi, Luigi; Tognoni, Gianni; Latini, Roberto

2016-12-01

Dysregulation of the vitamin D system promotes renal dysfunction and has direct detrimental effects on the heart. Progressive deterioration of renal function is common in patients with chronic heart failure (HF) and is invariably associated with unfavorable outcomes which can be improved by early identification and timely interventions. We examined the relation between two plasma markers of vitamin D metabolism and worsening of renal function (WRF) in a large cohort of patients with chronic HF. Plasma levels of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and parathyroid hormone PTH (1-84) were measured in 1237 patients with clinical evidence of chronic and stable HF enrolled in the multicentre GISSI-HF trial and followed for 3.9years. We examined the relation of 1,25(OH) 2 D, PTH(1-84), and their ratio with WRF, defined as first increase in serum creatinine concentration ≥0.3mg/dL and ≥25% at two consecutive measurements at any time during the study. Lower 1,25(OH) 2 D/PTH(1-84) ratio was associated with a higher baseline serum concentration of creatinine, winter season, female sex and older age; 335 patients (29.6%) experienced an episode of WRF. After adjustment, a lower 1,25(OH) 2 D/PTH(1-84) ratio remained significantly associated with a higher risk of WRF (HR=0.75 [0.62-0.90], p=0.002) and correctly reclassified events. This ratio also independently predicted mortality and admission to hospital for cardiovascular reasons. The plasma 1,25(OH) 2 D/PTH(1-84) ratio is a promising indicator of future risk of deterioration of renal function in patients with chronic HF and mild renal impairment, that may serve to optimize therapies and improve outcomes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Effect of Vibration Treatments Combined with Teriparatide or Strontium Ranelate on Bone Healing and Muscle in Ovariectomized Rats.

PubMed

Komrakova, M; Hoffmann, D B; Nuehnen, V; Stueber, H; Wassmann, M; Wicke, M; Tezval, M; Stuermer, K M; Sehmisch, S

2016-10-01

The aim of the present study was to study the effect of combined therapy of teriparatide (PTH) or strontium ranelate (SR) with whole-body vibration (WBV) on bone healing and muscle properties in an osteopenic rat model. Seventy-two rats (3 months old) were bilaterally ovariectomized (Ovx), and 12 rats were left intact (Non-Ovx). After 8 weeks, bilateral transverse osteotomy was performed at the tibia metaphysis in all rats. Thereafter, Ovx rats were divided into six groups (n = 12): (1) Ovx-no treatment, (2) Ovx + vibration (Vib), (3) SR, (4) SR + Vib, (5) PTH, and (6) PTH + Vib. PTH (40 μg/kg BW sc. 5×/week) and SR (613 mg/kg BW in food daily) were applied on the day of ovariectomy, vibration treatments 5 days later (vertical, 70 Hz, 0.5 mm, 2×/day for 15 min) for up to 6 weeks. In the WBV + SR group, the callus density, trabecular number, and Alp and Oc gene expression were decreased compared to SR alone. In the WBV + PTH group, the cortical and callus widths, biomechanical properties, Opg gene expression, and Opg/Rankl ratio were increased; the cortical and callus densities were decreased compared to PTH alone. A case of non-bridging was found in both vibrated groups. Vibration alone did not change the bone parameters; PTH possessed a stronger effect than SR therapy. In muscles, combined therapies improved the fiber size of Ovx rats. WBV could be applied alone or in combination with anti-osteoporosis drug therapy to improve muscle tissue. However, in patients with fractures, anti-osteoporosis treatments and the application of vibration could have an adverse effect on bone healing.

Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken

PubMed Central

2012-01-01

Background The parathyroid hormone (PTH)-family consists of a group of structurally related factors that regulate calcium and bone homeostasis and are also involved in development of organs such as the heart, mammary gland and immune system. They interact with specific members of family 2 B1 G-protein coupled receptors (GPCRs), which have been characterised in teleosts and mammals. Two PTH/PTHrP receptors, PTH1R and PTH2R exist in mammals and in teleost fish a further receptor PTH3R has also been identified. Recently in chicken, PTH-family members involved in calcium transport were characterized and specific PTHRs are suggested to exist although they have not yet been isolated or functionally characterized. The aim of this study is to further explore the evolution and function of the vertebrate PTH/PTHrP system through the isolation, phylogenetic analysis and functional characterization of the chicken receptors. Results Two PTHRs were isolated in chicken and sequence comparison and phylogenetic analysis indicate that the chicken receptors correspond to PTH1R and PTH3R, which emerged prior to the teleost/tetrapod divergence since they are present in cartilaginous fish. The vertebrate PTH2R receptor and its ligand TIP39 have been lost from bird genomes. Chicken PTH1R and PTH3R have a divergent and widespread tissue expression and are also evident in very early embryonic stages of development. Receptor stimulation studies using HEK293 cells stably expressing the chicken PTH1R and PTH3R and monitoring cAMP production revealed they are activated by chicken 1–34 N-terminal PTH-family peptides in a dose dependent manner. PTH-L and PTHrP were the most effective peptides in activating PTH1R (EC50 = 7.7 nM and EC50 = 22.7 nM, respectively). In contrast, PTH-L (100 nM) produced a small cAMP accumulation on activation of PTH3R but PTHrP and PTH (EC50 = 2.5 nM and EC50 = 22.1 nM, respectively) readily activated the receptor. PTHrP also stimulated intracellular Ca2+ accumulation on activation of PTH1R but not PTH3R. Conclusion Two PTHR homologues of the vertebrate PTH1R and PTH3R were isolated and functionally characterized in chicken. Their distinct pattern of expression during embryo development and in adult tissues, together with their ligand preference, suggests that they have acquired specific functions, which have contributed to their maintenance in the genome. PTH2R and its activating ligand, TIP39, are absent from bird genomes. Nonetheless identification of putative PTH2R and TIP39 in the genome of an ancient agnathan, lamprey, suggests the PTH/PTHrP ligand and receptor family was already present in an early basal paraphyletic group of vertebrates and during the vertebrate radiation diverged via gene/genome duplication and deletion events. Knowledge of the role PTH/PTHrP system in early vertebrates will help to establish evolution of function. PMID:22768871

Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken.

PubMed

Pinheiro, Pedro L C; Cardoso, João C R; Power, Deborah M; Canário, Adelino V M

2012-07-06

The parathyroid hormone (PTH)-family consists of a group of structurally related factors that regulate calcium and bone homeostasis and are also involved in development of organs such as the heart, mammary gland and immune system. They interact with specific members of family 2 B1 G-protein coupled receptors (GPCRs), which have been characterised in teleosts and mammals. Two PTH/PTHrP receptors, PTH1R and PTH2R exist in mammals and in teleost fish a further receptor PTH3R has also been identified. Recently in chicken, PTH-family members involved in calcium transport were characterized and specific PTHRs are suggested to exist although they have not yet been isolated or functionally characterized. The aim of this study is to further explore the evolution and function of the vertebrate PTH/PTHrP system through the isolation, phylogenetic analysis and functional characterization of the chicken receptors. Two PTHRs were isolated in chicken and sequence comparison and phylogenetic analysis indicate that the chicken receptors correspond to PTH1R and PTH3R, which emerged prior to the teleost/tetrapod divergence since they are present in cartilaginous fish. The vertebrate PTH2R receptor and its ligand TIP39 have been lost from bird genomes. Chicken PTH1R and PTH3R have a divergent and widespread tissue expression and are also evident in very early embryonic stages of development. Receptor stimulation studies using HEK293 cells stably expressing the chicken PTH1R and PTH3R and monitoring cAMP production revealed they are activated by chicken 1-34 N-terminal PTH-family peptides in a dose dependent manner. PTH-L and PTHrP were the most effective peptides in activating PTH1R (EC(50) = 7.7 nM and EC(50) = 22.7 nM, respectively). In contrast, PTH-L (100 nM) produced a small cAMP accumulation on activation of PTH3R but PTHrP and PTH (EC(50) = 2.5 nM and EC(50) = 22.1 nM, respectively) readily activated the receptor. PTHrP also stimulated intracellular Ca(2+) accumulation on activation of PTH1R but not PTH3R. Two PTHR homologues of the vertebrate PTH1R and PTH3R were isolated and functionally characterized in chicken. Their distinct pattern of expression during embryo development and in adult tissues, together with their ligand preference, suggests that they have acquired specific functions, which have contributed to their maintenance in the genome. PTH2R and its activating ligand, TIP39, are absent from bird genomes. Nonetheless identification of putative PTH2R and TIP39 in the genome of an ancient agnathan, lamprey, suggests the PTH/PTHrP ligand and receptor family was already present in an early basal paraphyletic group of vertebrates and during the vertebrate radiation diverged via gene/genome duplication and deletion events. Knowledge of the role PTH/PTHrP system in early vertebrates will help to establish evolution of function.

Comparison of parathyroid hormone and G-CSF treatment after myocardial infarction on perfusion and stem cell homing.

PubMed

Huber, Bruno C; Fischer, Rebekka; Brunner, Stefan; Groebner, Michael; Rischpler, Christoph; Segeth, Alexander; Zaruba, Marc M; Wollenweber, Tim; Hacker, Marcus; Franz, Wolfgang-Michael

2010-05-01

Mobilization of stem cells by granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI); however, clinical trials failed to be effective. In search for alternative cytokines, parathyroid hormone (PTH) was recently shown to promote cardiac repair by enhanced neovascularization and cell survival. To compare the impact of the two cytokines G-CSF and PTH on myocardial perfusion, mice were noninvasively and repetitively investigated by pinhole single-photon emission computed tomography (SPECT) after MI. Mobilization and homing of bone marrow-derived stem cells (BMCs) was analyzed by fluorescence-activated cell sorter (FACS) analysis. Mice (C57BL/6J) were infarcted by left anterior descending artery ligation. PTH (80 mug/kg) and G-CSF (100 mug/kg) were injected for 5 days. Perfusion defects were determined by (99m)Tc-sestamibi SPECT at days 6 and 30 after MI. The number of BMCs characterized by Lin(-)/Sca-1(+)/c-kit(+) cells in peripheral blood and heart was analyzed by FACS. Both G-CSF and PTH treatment resulted in an augmented mobilization of BMCs in the peripheral blood. Contrary to G-CSF and controls, PTH and the combination showed significant migration of BMCs in ischemic myocardium associated with a significant reduction of perfusion defects from day 6 to day 30. A combination of both cytokines had no additional effects on migration and perfusion. In our preclinical model, SPECT analyses revealed the functional potential of PTH reducing size of infarction together with an enhanced homing of BMCs to the myocardium in contrast to G-CSF. A combination of both cytokines did not improve the functional outcome, suggesting clinical applications of PTH in ischemic heart diseases.

PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer.

PubMed

Kir, Serkan; Komaba, Hirotaka; Garcia, Ana P; Economopoulos, Konstantinos P; Liu, Wei; Lanske, Beate; Hodin, Richard A; Spiegelman, Bruce M

2016-02-09

Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia. Copyright © 2016 Elsevier Inc. All rights reserved.

Parathyroid hormone (PTH) blood test

MedlinePlus

... PTH) intact molecule; Intact PTH; Hyperparathyroidism - PTH blood test; Hypoparathyroidism - PTH blood test ... drinking for some period of time before the test. Most often, you will not need to fast ...

Combination therapy of Nigella sativa and human parathyroid hormone on bone mass, biomechanical behavior and structure in streptozotocin-induced diabetic rats.

PubMed

Altan, Mehmet Fatih; Kanter, Mehmet; Donmez, Senayi; Kartal, Murat Emre; Buyukbas, Sadik

2007-01-01

Extracts of the seeds of Nigella sativa (NS), an annual herbaceous plant of the Ranunculaceae family, have been used for many years for therapeutic purposes, including their potential anti-diabetic properties. The aim of the present study was to test the hypothesis that combined treatment with NS and human parathyroid hormone (hPTH) is more effective than treatment with NS or hPTH alone in improving bone mass, connectivity, biomechanical behaviour and strength in insulin-dependent diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) at a single dose of 50mg/kg. The diabetic rats received NS (2ml/kg/day, i.p.), hPTH (6microg/kg/day, i.p.) or NS and hPTH combined for 4 weeks, starting 8 weeks after STZ injection. The beta-cells of the pancreatic islets of Langerhans were examined by immunohistochemical methods. In addition, bone sections of femora were processed for histomorphometry and biomechanical analysis. In diabetic rats, the beta-cells were essentially negative for insulin-immunoreactivity. NS treatment (alone or in combination with hPTH) significantly increased the area of insulin immunoreactive beta-cells in diabetic rats; however, hPTH treatment alone only led to a slightly increase in the insulin-immunoreactivity. These results suggest that NS might be used in a similar manner to insulin as a safe and effective therapy for diabetes and might be useful in the treatment of diabetic osteopenia.

Improvement of adynamic bone disease after renal transplantation.

PubMed

Abdallah, K A; Jorgetti, V; Pereira, R C; Reis, L M dos; Pereira, L M; Corrêa, P H S; Borelli, A; Ianhez, L E; Moysés, R M A; David-Neto, E

2006-01-01

Low bone remodeling and relatively low serum parathyroid hormone (PTH) levels characterize adynamic bone disease (ABD). The impact of renal transplantation (RT) on the course of ABD is unknown. We studied prospectively 13 patients with biopsy-proven ABD after RT. Bone histomorphometry and bone mineral density (BMD) measurements were performed in the 1st and 12th months after RT. Serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and osteocalcin were measured regularly throughout the study. Serum PTH levels were slightly elevated at transplantation, normalized at the end of the third month and remained stable thereafter. Bone biopsies performed in the first month after RT revealed low bone turnover in all patients, with positive bone aluminum staining in 5. In the 12th month, second biopsies were performed on 12 patients. Bone histomorphometric dynamic parameters improved in 9 and were completely normalized in 6, whereas no bone mineralization was detected in 3 of these 12 patients. At 12 months post-RT, no bone aluminum was detected in any patient. We also found a decrease in lumbar BMD and an increase in femoral BMD. Patients suffering from ABD, even those with a reduction in PTH levels, may present partial or complete recovery of bone turnover after successful renal transplantation. However, it is not possible to positively identify the mechanisms responsible for the improvement. Identifying these mechanisms should lead to a better understanding of the physiopathology of ABD and to the development of more effective treatments.

Role of etelcalcetide in the management of secondary hyperparathyroidism in hemodialysis patients: a review on current data and place in therapy.

PubMed

Friedl, Claudia; Zitt, Emanuel

2018-01-01

Secondary hyperparathyroidism (sHPT) is a frequently occurring severe complication of advanced kidney disease. Its clinical consequences include extraskeletal vascular and valvular calcifications, changes in bone metabolism resulting in renal osteodystrophy, and an increased risk of cardiovascular morbidity and mortality. Calcimimetics are a cornerstone of parathyroid hormone (PTH)-lowering therapy, as confirmed by the recently updated 2017 Kidney Disease: Improving Global Outcomes chronic kidney disease - mineral and bone disorder clinical practice guidelines. Contrary to calcitriol or other vitamin D-receptor activators, calcimimetics reduce PTH without increasing serum-calcium, phosphorus, or FGF23 levels. Etelcalcetide is a new second-generation calcimimetic that has been approved for the treatment of sHPT in adult hemodialysis patients. Whereas the first-generation calcimimetic cinacalcet is taken orally once daily, etelcalcetide is given intravenously thrice weekly at the end of the hemodialysis session. Apart from improving drug adherence, etelcalcetide has proven to be more effective in lowering PTH when compared to cinacalcet, with an acceptable and comparable safety profile. The hope for better gastrointestinal tolerance with intravenous administration did not come true, as etelcalcetide did not significantly mitigate the adverse gastrointestinal effects associated with cinacalcet. Enhanced adherence and strong reductions in PTH, phosphorus, and FGF23 could set the stage for a future large randomized controlled trial to demonstrate that improved biochemical control of mineral metabolism with etelcalcetide in hemodialysis patients translates into cardiovascular and survival benefits and better health-related quality of life.

PTH Reloaded: A New Evolutionary Perspective

PubMed Central

Suarez-Bregua, Paula; Cal, Laura; Cañestro, Cristian; Rotllant, Josep

2017-01-01

The parathyroid hormone (PTH) family is a group of structurally-related secreted peptides involved in bone mineral homeostasis and multitude of developmental processes in vertebrates. These peptides mediate actions through PTH receptors (PTHRs), which belong to the transmembrane G protein-coupled receptor group. To date, genes encoding for PTH and PTHR have only been identified in chordates, suggesting that this signaling pathway may be an evolutionary innovation of our phylum. In vertebrates, we found up to six PTH and three PTHR different paralogs, varying in number between mammals and teleost fishes due to the different rounds of whole-genome duplication and specific gene losses suffered between the two groups of animals. The diversification of the PTH gene family has been accompanied by both functional divergence and convergence, making sometimes difficult the comparison between PTH peptides of teleosts and mammals. Here, we review the roles of all Pth peptides in fishes, and based on the evolutionary history of PTH paralogs, we propose a new and simple nomenclature from PTH1 to PTH4. Moreover, the recent characterization of the Pth4 in zebrafish allows us to consider the prominent role of the brain-to-bone signaling pathway in the regulation of bone development and homeostasis. Finally, comparison between PTH peptides of fish and mammals allows us to discuss an evolutionary model for PTH functions related to bone mineral balance during the vertebrate transition from an aquatic to a terrestrial environment. PMID:29062283

Cognitive changes after parathyroidectomy in patients with secondary hyperparathyroidism.

PubMed

Chou, Fong-Fu; Chen, Jin-Bor; Hsieh, Kun-Chou; Liou, Chia-Wei

2008-04-01

Cognitive impairment was frequently reported in uremic patients with dialysis, but improvements of cognition after parathyroidectomy for symptomatic secondary hyperparathyroidism have never been reported before. Thirty-nine patients, who were successfully operated on with total parathyroidectomy plus autotransplantation were enrolled. Twenty-three dialysis patients, age >50 years, who had a serum level of intact parathyroid hormone (iPTH) greater than 650 pg/ml, and who did not undergo parathyroidectomy were selected as the control group. The mini-mental state examination (MMSE) and the clinical dementia rating (CDR) test were administered to all patients. Before the operation, educational level, symptoms of bone pain, skin itching, general weakness and insomnia were recorded and serum levels of calcium, phosphorus, alkaline phosphatase (Alk-ptase), iPTH, aluminum, and hemoglobin were measured in the study and control groups. At 12-week postoperatively, serum levels of calcium, phosphorus, Alk-ptase, iPTH, and aluminum were measured again and at 16-week postoperatively, the MMSE and the CDR test were administered again. In the control group, both MMSE and CDR test were administered again after the period or 16-week. Serum calcium level was only significant difference (p = 0.002), whereas clinical symptoms, gender, etiologies of secondary hyperparathyroidism, duration of dialysis, educational level, age, and serum levels of phosphorus, Alk-ptase, iPTH, aluminum, and hemoglobin were not significantly different between the two groups. The educational level was the only factor affecting MMSE scores (p = 0.003). In the study group, at 12-week postoperatively, symptoms improved significantly, serum levels of calcium, phosphorus, Alk-ptase, iPTH, and aluminum decreased significantly, and at 16-week postoperatively, MMSE scores increased from 25 +/- 5 (mean +/- SD) to 26 +/- 5 (p < 0.001) and CDR scales decreased significantly (p < 0.001). Neither MMSE scores nor CDR scales of the control group changed significantly after the 16-week period. Parathyroidectomy for symptomatic secondary hyperparathyroidism can improve cognition.

Modifications in Bone Matrix of Estrogen-Deficient Rats Treated with Intermittent PTH

PubMed Central

Campos, Jenifer Freitas; Katchburian, Eduardo; de Medeiros, Valquíria Pereira; Nader, Helena Bonciani; Nonaka, Keico Okino; Plotkin, Lilian Irene; Reginato, Rejane Daniele

2015-01-01

Bone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH), a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34) change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 µg/kg/day (PTH03) or 5 µg/kg/day (PTH5); or 3 times per week at 0.25 µg/kg/day (PTH025). After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD). Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass. PMID:25695082

Intact parathyroid hormone and whole parathyroid hormone assay results disagree in hemodialysis patients under cinacalcet hydrochloride therapy.

PubMed

Koda, Ryo; Kazama, Junichiro James; Matsuo, Koji; Kawamura, Kazuko; Yamamoto, Suguru; Wakasugi, Minako; Takeda, Tetsuro; Narita, Ichiei

2015-08-01

The parathyroid gland secretes 1-84 and 7-84 parathyroid hormone (PTH) fragments, and its regulation is dependent on stimulation of the extracellular calcium-sensing receptor. While the intact PTH system detects both PTH fragments, the whole PTH system detects the 1-84PTH but not the 7-84PTH. Cinacalcet hydrochloride (CH) binds to calcium-sensing receptor as a calcimimetic. Here we investigated the role of CH treatment in the assessment of parathyroid gland function. Stable adult dialysis patients for whom CH therapy was planned were included. Patients for whom CH therapy was not planned were simultaneously included as the control group. The CH group (n = 44) showed significantly higher circulating levels of Ca, intact PTH, and whole PTH, before the CH treatment than the control group (n = 112). The Ca, intact PTH, and whole PTH levels decreased along with the CH therapy, and the Ca levels became comparable in the 8th week of treatment and thereafter. The CH group in the 8th week and thereafter showed significantly lower whole/intact PTH ratios than the control group, while the whole/intact PTH ratio was not significantly different between before and during the CH therapy. A multiple regression analysis revealed that the whole/intact PTH ratio was almost constant, but both the serum Ca level and a CH therapy could potentially modify the fixed number. When the whole PTH levels were estimated by intact PTH levels using the relationship between them in the control group, the levels were clearly overestimated in the CH group. Although the direct effect of CH on the whole/intact PTH ratio is masked by its hypocalcemic action, we could successfully demonstrate that the ratio in CH users is lower than that in the non-users with comparable levels of serum Ca. Evaluating parathyroid function with intact PTH according to the clinical practice guidelines in patients being treated with CH may lead to significant overestimation and subsequent overtreatment.

A lower proportion of circulating active parathyroid hormone in peritoneal dialysis does not allow the pth inter-method adjustment proposed for haemodialysis.

PubMed

González-Casaus, M Luisa; González-Parra, Emilio; Sánchez-González, Carmen; Albalate, Marta; de la Piedra-Gordo, Concepción; Fernández, Elvira; Torregrosa, Vicente; Rodríguez, Mariano; Lorenzo, Víctor

2014-05-21

Parathyroid hormone (PTH) shows a strong correlation with histomorphometric and biochemical parameters of bone turnover, however its measurement presents limitations due to inter-method variability. Circulating PTH is a mixture of peptides, but only on its whole form (1-84 PTH) is responsible of PTH biological activity. Carboxyl-terminal fragments exhibit antagonist actions and their proportion differs at each stage of chronic kidney disease, as consequence of differences on their renal clearance. The aim of this study is to evaluate possible differences in the proportion of these fragments according to dialysis type: haemodialysis (HD) or peritoneal dialysis (PD). Serum total (Ca) and ionized calcium (iCa), phosphate (P), carboxyl-terminal telopeptides of collagen type I (BCTx) were measured in 73 patients on PD (46 men and 27 women with an age between 22 and 82 years). PTH was quantified by six second generation assays (one isotopic and five chemiluminescence assays) and by one third generation PTH method. Mean serum levels of Ca, iCa, P and BCTx were 9.03, 4.76, 4.73 mg/dl and 1181 pmol/l, respectively. Significant differences were observed in PTH values according to the method used. Adjustment of PTH results to PTH Allegro (Nichols) range of 150-300 nmol/l in PD patients showed higher values than those assessed previously for HD population. The percentage of biologically active 1-84 PTH as the 1-84 PTH/ 7-84 PTH ratio in PD were significantly lower than in HD patients, reflecting the higher proportion of 7-84 PTH circulating fragments for a given intact PTH result in PD. PD patients have a higher proportion of 7-84 PTH circulating fragments. Consequently, the inter-method adjustment algorithms proposed for HD patients are not useful for PD patients. This study proposes alternative algorithms for PTH inter-method adjustment to be applied in PD.

Parathyroid Hormone, Cognitive Function and Dementia: A Systematic Review

PubMed Central

Lourida, Ilianna; Thompson-Coon, Jo; Dickens, Chris M.; Soni, Maya; Kuźma, Elżbieta; Kos, Katarina; Llewellyn, David J.

2015-01-01

Background Metabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer’s disease and dementia. Abnormal parathyroid hormone (PTH) levels play a role in neuronal calcium dysregulation, hypoperfusion and disrupted neuronal signaling. Some studies support a significant link between PTH levels and dementia whereas others do not. Methods We conducted a systematic review through January 2014 to evaluate the association between PTH and parathyroid conditions, cognitive function and dementia. Eleven electronic databases and citation indexes were searched including Medline, Embase and the Cochrane Library. Hand searches of selected journals, reference lists of primary studies and reviews were also conducted along with websites of key organizations. Two reviewers independently screened titles and abstracts of identified studies. Data extraction and study quality were performed by one and checked by a second reviewer using predefined criteria. A narrative synthesis was performed due to the heterogeneity of included studies. Results The twenty-seven studies identified were of low and moderate quality, and challenging to synthesize due to inadequate reporting. Findings from six observational studies were mixed but suggest a link between higher serum PTH levels and increased odds of poor cognition or dementia. Two case-control studies of hypoparathyroidism provide limited evidence for a link with poorer cognitive function. Thirteen pre-post surgery studies for primary hyperparathyroidism show mixed evidence for improvements in memory though limited agreement in other cognitive domains. There was some degree of cognitive impairment and improvement postoperatively in observational studies of secondary hyperparathyroidism but no evident pattern of associations with specific cognitive domains. Conclusions Mixed evidence offers weak support for a link between PTH, cognition and dementia due to the paucity of high quality research in this area. PMID:26010883

Treatment outcomes of chronic post-traumatic headaches after mild head trauma in US soldiers: an observational study.

PubMed

Erickson, Jay C

2011-06-01

he effectiveness of medical therapies for chronic post-traumatic headaches (PTHs) attributable to mild head trauma in military troops has not been established. To determine the treatment outcomes of acute and prophylactic medical therapies prescribed for chronic PTHs after mild head trauma in US Army soldiers. A retrospective cohort study was conducted with 100 soldiers undergoing treatment for chronic PTH at a single US Army neurology clinic. Headache frequency and Migraine Disability Assessment (MIDAS) scores were determined at the initial clinic visit and then again by phone 3 months after starting headache prophylactic medication. Response rates of headache abortive medications were also determined. Treatment outcomes were compared between subjects with blast-related PTH and non-blast PTH. Ninety-nine of 100 subjects were male. Seventy-seven of 100 subjects had blast PTH and 23/100 subjects had non-blast PTH. Headache characteristics were similar for blast PTH and non-blast PTH with 96% and 95%, respectively, resembling migraine. Headache frequency among all PTH subjects decreased from 17.1 days/month at baseline to 14.5 days/month at follow-up (P = .009). Headache frequency decreased by 41% among non-blast PTH compared to 9% among blast PTH. Fifty-seven percent of non-blast PTH subjects had a 50% or greater decline in headache frequency compared to 29% of blast PTH subjects (P =.023). A significant decline in headache frequency occurred in subjects treated with topiramate (n = 29, -23%, P = .02) but not among those treated with a low-dose tricyclic antidepressant (n = 48, -12%, P = .23). Seventy percent of PTH subjects who used a triptan class medication experienced reliable headache relief within 2 hours compared to 42% of subjects using other headache abortive medications (P = .01). Triptan medications were effective for both blast PTH and non-blast PTH (66% response rate vs 86% response rate, respectively; P = .20). Headache-related disability, as measured by mean MIDAS scores, declined by 57% among all PTH subjects with no significant difference between blast PTH (-56%) and non-blast PTH (-61%). Triptan class medications are usually effective for aborting headaches in military troops with chronic PTH attributed to a concussion from a blast injury or non-blast injury. Topiramate appears to be an effective headache prophylactic therapy in military troops with chronic PTH, whereas low doses of tricyclic antidepressants appear to have little efficacy. Chronic PTH triggered by a blast injury may be less responsive to commonly prescribed headache prophylactic medications compared to non-blast PTH. These conclusions require validation by prospective, controlled clinical trials. © 2011 American Headache Society.

Comparison of Intact PTH and Bio-Intact PTH Assays Among Non-Dialysis Dependent Chronic Kidney Disease Patients.

PubMed

Einbinder, Yael; Benchetrit, Sydney; Golan, Eliezer; Zitman-Gal, Tali

2017-09-01

The third-generation bio-intact parathyroid hormone (PTH) (1-84) assay was designed to overcome problems associated with the detection of C-terminal fragments by the second-generation intact PTH assay. The two assays have been compared primarily among dialysis populations. The present study evaluated the correlations and differences between these two PTH assays among patients with chronic kidney disease (CKD) stages 3 to 5 not yet on dialysis. Blood samples were collected from 98 patients with CKD stages 3 to 5. PTH concentrations were measured simultaneously by using the second-generation - PTH intact-STAT and third-generation bio-intact 1-84 PTH assays. Other serum biomarkers of bone mineral disorders were also assessed. CKD stage was calculated by using the CKD-Epidemiology Collaboration (EPI) formula. Serum bio-intact PTH concentrations were strongly correlated but significantly lower than the intact PTH concentrations (r=0.963, P<0.0001). This finding was consistent among CKD stages 3 to 5. PTH concentrations by both assays (intact and bio-intact PTH) positively correlated with urea (r=0.523, r=0.504; P=0.002, respectively), phosphorus (r=0.532, r=0.521; P<0.0001, respectively) and negatively correlated with blood calcium (r=-0.435, r=-0.476; P<0.0001, respectively), 25(OH) vitamin D, (r=-0.319, r=-0.353; respectively, P<0.0001) and the estimated glomerular filtration rate (r=-0.717, r=-0.688; P<0.0001, respectively). Among patients with CKD stages 3 to 5 not on dialysis, the bio-intact PTH assay detected significantly lower PTH concentrations compared with intact PTH assay. Additional studies that correlate the diagnosis and management of CKD mineral and bone disorders with bone histomorphometric findings are needed to determine whether bio-intact PTH assay results are better surrogate markers in these early stages of CKD. © The Korean Society for Laboratory Medicine

All five host-range variants of Xanthomonas citri carry one pthA homolog with 17.5 repeats that determines pathogenicity on citrus, but none determine host-range variation.

PubMed

Al-Saadi, Abdulwahid; Reddy, Joseph D; Duan, Yong P; Brunings, Asha M; Yuan, Qiaoping; Gabriel, Dean W

2007-08-01

Citrus canker disease is caused by five groups of Xanthomonas citri strains that are distinguished primarily by host range: three from Asia (A, A*, and A(w)) and two that form a phylogenetically distinct clade and originated in South America (B and C). Every X. citri strain carries multiple DNA fragments that hybridize with pthA, which is essential for the pathogenicity of wide-host-range X. citri group A strain 3213. DNA fragments that hybridized with pthA were cloned from a representative strain from all five groups. Each strain carried one and only one pthA homolog that functionally complemented a knockout mutation of pthA in 3213. Every complementing homolog was of identical size to pthA and carried 17.5 nearly identical, direct tandem repeats, including three new genes from narrow-host-range groups C (pthC), A(w) (pthAW), and A* (pthA*). Every noncomplementing paralog was of a different size; one of these was sequenced from group A* (pthA*-2) and was found to have an intact promoter and full-length reading frame but with 15.5 repeats. None of the complementing homologs nor any of the noncomplementing paralogs conferred avirulence to 3213 on grapefruit or suppressed avirulence of a group A* strain on grapefruit. A knockout mutation of pthC in a group C strain resulted in loss of pathogenicity on lime, but the strain was unaffected in ability to elicit an HR on grapefruit. This pthC- mutant was fully complemented by pthA, pthB, or pthC. Analysis of the predicted amino-acid sequences of all functional pthA homologs and nonfunctional paralogs indicated that the specific sequence of the 17th repeat may be essential for pathogenicity of X. citri on citrus.

Justified follow-up: A final ioPTH over 40 pg/mL is associated with an increased risk of persistence and recurrence in primary hyperparathyroidism

PubMed Central

Rajaei, Mohammad H.; Bentz, Alex M.; Schneider, David F.; Sippel, Rebecca S.; Chen, Herbert; Oltmann, Sarah C.

2014-01-01

Introduction After parathyroidectomy for sporadic primary hyperparathyroidism (PHPT), overall rates of persistence/recurrence are extremely low. A marker of increased risk for persistence/recurrence is needed. We hypothesized that final intraoperative parathyroid hormone (FioPTH) ≥40 pg/mL is indicative of increased risk for disease persistence/recurrence, and can be used to selectively determine degree of follow up. Method A retrospective review of PHPT patients undergoing parathyroidectomy with ioPTH monitoring was performed. An ioPTH decline of 50% was the only criteria for operation termination. Patients were grouped based on FioPTH of <40pg/mL, 40 to 59, and >60. Results Between 2001 and 2012, 1371 patients were included. Mean age was 61±0.4 years.78% were female. Overall persistence rate was 1.4%, with 2.9% recurrence rate. 976 (71%) had FioPTH<40, 228 (16.6%) had FioPTH 40-59, and 167 (12.2%) had FioPTH≥60. Mean follow-up was 21±0.6 months. FioPTH<40 were younger, with lower preoperative serum calcium, PTH and creatinine (all p≤0.001). FioPTH<40 had the lowest persistence rate (0.2%) versus FioPTH 40-59 (3.5%) or FioPTH≥60 (5.4%, p<0.001). Recurrence rate was also lowest in FioPTH<40 (1.3% vs. 5.9% vs. 8.2% respectively, p<0.001). Disease free status was greatest in FioPTH<40 at 2 years (98.5% vs. 96.8% vs. 90.5%) and 5 years (95.7% vs. 72.3% vs. 74.8%, p<0.01). Conclusion Patients with FioPTH<40 pg/mL had lower rates of persistence and recurrence, than FioPTH 40-59, or ≥60. Differences became more apparent after 2 years of follow-up. Patients with FioPTH ≥40 pg/mL warrant close and prolonged follow-up. PMID:25192677

Parathyroid hormone-dependent signaling pathways regulating genes in bone cells

NASA Technical Reports Server (NTRS)

Swarthout, John T.; D'Alonzo, Richard C.; Selvamurugan, Nagarajan; Partridge, Nicola C.

2002-01-01

Parathyroid hormone (PTH) is an 84-amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone resorption. During this process, PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone resorption. In addition to these catabolic effects, PTH has been demonstrated to be an anabolic factor in skeletal tissue and in vitro. As a result, PTH has potential medical application to the treatment of osteoporosis, since intermittent administration of PTH stimulates bone formation. Activation of osteoblasts by PTH results in expression of genes important for the degradation of the extracellular matrix, production of growth factors, and stimulation and recruitment of osteoclasts. The ability of PTH to drive changes in gene expression is dependent upon activation of transcription factors such as the activator protein-1 family, RUNX2, and cAMP response element binding protein (CREB). Much of the regulation of these processes by PTH is protein kinase A (PKA)-dependent. However, while PKA is linked to many of the changes in gene expression directed by PTH, PKA activation has been shown to inhibit mitogen-activated protein kinase (MAPK) and proliferation of osteoblasts. It is now known that stimulation of MAPK and proliferation by PTH at low concentrations is protein kinase C (PKC)-dependent in both osteoblastic and kidney cells. Furthermore, PTH has been demonstrated to regulate components of the cell cycle. However, whether this regulation requires PKC and/or extracellular signal-regulated kinases or whether PTH is able to stimulate other components of the cell cycle is unknown. It is possible that stimulation of this signaling pathway by PTH mediates a unique pattern of gene expression resulting in proliferation in osteoblastic and kidney cells; however, specific examples of this are still unknown. This review will focus on what is known about PTH-mediated cell signaling, and discuss the established or putative PTH-regulated pattern of gene expression in osteoblastic cells following treatment with catabolic (high) or anabolic (low) concentrations of the hormone.

Prostaglandin E2 acts via bone marrow macrophages to block PTH-stimulated osteoblast differentiation in vitro

PubMed Central

Choudhary, Shilpa; Blackwell, Katherine; Voznesensky, Olga; Roy, Abhijit Deb; Pilbeam, Carol

2014-01-01

Intermittent PTH is the major anabolic therapy for osteoporosis while continuous PTH causes bone loss. PTH acts on the osteoblast (OB) lineage to regulate bone resorption and formation. PTH also induces cyclooxygenase-2 (COX-2), producing prostaglandin E2 (PGE2) that can act on both OBs and osteoclasts (OCs). Because intermittent PTH is more anabolic in Cox-2 knockout (KO) than wild type (WT) mice, we hypothesized COX-2 might contribute to the effects of continuous PTH by suppressing PTH-stimulated differentiation of mesenchymal stem cells into OBs. We compared effects of continuous PTH on bone marrow stromal cells (BMSCs) and primary OBs (POBs) from Cox-2 KO mice, mice with deletion of PGE2 receptors (Ptger4 and Ptger2 KO mice), and WT controls. PTH increased OB differentiation in BMSCs only in the absence of COX-2 expression or activity. In the absence of COX-2, PTH stimulated differentiation if added during the first week of culture. In Cox-2 KO BMSCs, PTH-stimulated differentiation was prevented by adding PGE2 to cultures. Co-culture of POBs with M-CSF-expanded bone marrow macrophages (BMMs) showed that the inhibition of PTH-stimulated OB differentiation required not only COX-2 or PGE2 but also BMMs. Sufficient PGE2 to mediate the inhibitory effect was made by either WT POBs or WT BMMs. The inhibitory effect mediated by COX-2/PGE2 was transferred by conditioned media from RANKL-treated BMMs and could be blocked by osteoprotegerin, which interferes with RANKL binding to its receptor on OC lineage cells. Deletion of Ptger4, but not Ptger2, in BMMs prevented the inhibition of PTH-stimulated OB differentiation. As expected, PGE2 also stimulated OB differentiation, but when given in combination with PTH, the stimulatory effects of both were abrogated. These data suggest that PGE2, acting via EP4R on BMMs committed to the OC lineage, stimulated secretion of a factor or factors that acted to suppress PTH-stimulated OB differentiation. This suppression of OB differentiation could contribute to the bone loss seen with continuous PTH in vivo. PMID:23639875

Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pioszak, Augen A.; Parker, Naomi R.; Gardella, Thomas J.

2009-12-01

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic {alpha}-helix to the same hydrophobic groove in the ECD as occupied by PTH,more » but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally 'unwound.' The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.« less

Dimeric Arrangement of the Parathyroid Hormone Receptor and a Structural Mechanism for Ligand-induced Dissociation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pioszak, Augen A.; Harikumar, Kaleeckal G.; Parker, Naomi R.

2010-06-25

The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an {alpha}-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure,more » PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein.« less

Effects of vitamin D supplementation on strength, physical function, and health perception in older, community-dwelling men.

PubMed

Kenny, Anne M; Biskup, Bradley; Robbins, Bertha; Marcella, Glenn; Burleson, Joseph A

2003-12-01

To study the effects of vitamin D supplementation in healthier populations of men. : Randomized, controlled trial. General clinical research center. Sixty-five healthy, community-dwelling men (mean age+/-standard deviation=76+/-4, range 65-87). Cholecalciferol (1,000 IU/d) or placebo supplementation for 6 months; all received 500 mg supplemental calcium. Upper and lower extremity muscle strength and power, physical performance and activity, health perception, calcium and vitamin D intake, and biochemical assessment, including 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and ionized calcium levels. The levels of 25OHD increased and PTH decreased in the cholecalciferol group, whereas there were no significant changes in the control group (P<.001). Baseline 25OHD levels correlated with baseline single-leg stance time and physical activity score. Baseline PTH levels correlated with baseline 8-foot walk time and physical activity score. No significant difference in strength, power, physical performance, or health perception was found between groups. The 25OHD or PTH levels correlated with physical activity and physical performance in older, community-dwelling men with normal 25OHD status. Vitamin D supplementation increased 25OHD levels and decreased PTH levels but did not increase muscle strength or improve physical performance or health perception in this group of healthy, older men. Further investigations of the effects of vitamin D supplementation should focus on individuals with low levels of vitamin D.

Risk factors for post-tonsillectomy hemorrhage.

PubMed

Ikoma, Ryo; Sakane, Sayaka; Niwa, Kazutomo; Kanetaka, Sayaka; Kawano, Toshiro; Oridate, Nobuhiko

2014-08-01

The aim of the present study was to investigate the rate of post-tonsillectomy hemorrhage (PTH) in a single institution and to evaluate the clinical risk factors for PTH. We reviewed the records of 692 patients who underwent tonsillectomy (TE) at Yokohama Minami Kyosai Hospital in Japan. PTH grades were grouped into three categories according to the severity of the hemorrhagic episode: (I) minimal hemorrhage that stopped after noninvasive treatment, (II) hemorrhage requiring treatment with local anesthesia, and (III) hemorrhage requiring reoperation under general anesthesia in the operating room. Clinical risk factors such as sex, age (adults vs. children), TE indication, surgeon's skill level, operative time, ligature type, and duration of antibiotic administration for PTH were investigated. Among the 692 patients, 80 (11.6%) showed PTH, with primary and secondary hemorrhage accounting for 1.6% and 10.0%, respectively. A category III PTH was observed in 18 patients; thus, the overall risk of reoperation was 2.6%. The PTH episode most frequently occurred on postoperative days 5 and 6. The frequency of PTH was significantly higher in male patients and in adults (P<0.01, for both factors). Surgeon's skill was also associated with PTH rate. A stepwise multivariate logistic regression revealed that adult age (odds ratio [OR]=18.9) and male gender (OR=3.78) were the clinical risk factors for PTH. It also revealed that male gender (OR=82065335), adult age (OR=10.6), and surgeon's skill level (OR=7.50) were the clinical risk factors for the category III PTH. The risk of PTH was higher in this report compared with previous reports, which may be associated with the definition of PTH. Clinical risk factors for PTH were adult age and male gender. The surgeon's skill level was an additional risk factor for category III PTH. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures.

PubMed

Kakar, Sanjeev; Einhorn, Thomas A; Vora, Siddharth; Miara, Lincoln J; Hon, Gregory; Wigner, Nathan A; Toben, Daniel; Jacobsen, Kimberly A; Al-Sebaei, Maisa O; Song, Michael; Trackman, Philip C; Morgan, Elise F; Gerstenfeld, Louis C; Barnes, George L

2007-12-01

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. Since FDA approval of PTH [PTH(1-34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 microg/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. Quantitative muCT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to osteogenesis over the course of the repair process. In addition, chondrocyte hypertrophy occurred earlier in the PTH-treated callus tissues. Analysis of the expression of potential mediators of PTH actions showed that PTH treatment significantly induced the expression of Wnts 4, 5a, 5b, and 10b and increased levels of unphosphorylated, nuclear localized beta-catenin protein, a central feature of canonical Wnt signaling. These results showed that the PTH-mediated enhancement of fracture repair is primarily associated with an amplification of chondrocyte recruitment and maturation in the early fracture callus. Associated with these cellular effects, we observed an increase in canonical Wnt signaling supporting the conclusion that PTH effects on bone repair are mediated at least in part through the activation of Wnt-signaling pathways.

Association of Relatively Low Serum Parathyroid Hormone with Malnutrition-Inflammation Complex and Survival in Maintenance Hemodialysis Patients

PubMed Central

Dukkipati, Ramanath; Kovesdy, Csaba P.; Kim, Youngmee; Colman, Sara; Budoff, Matthew J; Nissenson, Allen R.; Sprague, Stuart M.; Kopple, Joel D; Kalantar-Zadeh, Kamyar

2011-01-01

Background Low serum parathyroid hormone (PTH) has been implicated as a primary biochemical marker of adynamic bone disease in individuals with chronic kidney disease (CKD) who undergo maintenance hemodialysis (MHD) treatment. We hypothesized that the malnutrition-inflammation complex is associated with low PTH levels in these patients and confounds the PTH-survival association. Methods We examined 748 stable MHD outpatients in Southern California and followed them for up to 5 years (10/2001-12/2006). Results In 748 MHD patients, serum PTH <150 pg/ml was more prevalent among non-Blacks and diabetics. There was no association between serum PTH and coronary artery calcification score, bone mineral density or dietary protein or calorie intake. Low serum PTH was associated with markers of protein-energy wasting and inflammation, and this association confounded the relationship between serum PTH and alkaline phosphatase. Although 5-year crude mortality rates were similar across PTH increments, after adjustment for the case-mix and surrogates of malnutrition and inflammation, a moderately low serum PTH in 100 to 150 pg/ml range was associated with the greatest survival compared to other serum PTH levels, i.e., a death hazard ratio of 0.52 (95% confidence interval: 0.29-0.92, p<0.001) compared to PTH of 300 to 600 pg/ml (reference). Conclusions Low serum PTH may be another facet of the malnutrition-inflammation complex in CKD, and after controlling for this confounder, a moderately low PTH in 100 to 150 pg/ml range appears associated with the greatest survival. Limitations of observational studies should be considered. PMID:20199875

Anabolic actions of PTH (1-34): use of a novel tissue engineering model to investigate temporal effects on bone.

PubMed

Pettway, Glenda J; Schneider, Abraham; Koh, Amy J; Widjaja, Effendi; Morris, Michael D; Meganck, Jeffrey A; Goldstein, Steven A; McCauley, Laurie K

2005-06-01

PTH is in clinical use for the treatment of osteoporosis and is under intensive investigation for its potential in applications of tissue engineering, fracture healing, and implant integration. However, the mechanisms of its action to stimulate bone formation are still unclear. A novel bone tissue engineering model was used to elucidate basic mechanisms of PTH anabolic actions. Ectopic ossicles containing cortical bone, trabecular bone, and a hematopoietic marrow were generated from implanted bone marrow stromal cells (BMSC). One week after implantation, nude mice were administered PTH or vehicle for 1 week (group 1), 3 weeks (group 2), or 7 weeks (group 3). Another group was also treated for 3 weeks, initiated 12 weeks after implantation (group 4). Micro-radiography and histomorphometry revealed increased marrow cellularity in group 1 PTH-treated ossicles, increased bone in group 2 PTH-treated ossicles, and similar amounts of bone in both group 3 and 4 ossicles regardless of treatment. Incidence of phosphate mineral and phosphate mineral to hydroxyproline ratio via Raman spectroscopy were significantly higher after 3 weeks versus 1 week of PTH treatment, but there was no difference between PTH- and vehicle-treated ossicles. Early events of PTH action in group 1 ossicles and the effects of a single injection of PTH on 1- and 2-week-old ossicles were evaluated by Northern blot analysis. Osteocalcin (OC) mRNA was increased after 1 week of intermittent PTH treatment in ossicles and calvaria but an acute injection did not alter OC mRNA. In contrast, a single injection of PTH increased matrix gamma-carboxyglutamic acid protein (MGP) mRNA in 2-week-old ossicles. Differential and temporal-dependent effects of PTH on OC and MGP suggest at the molecular level, that PTH acts to inhibit osteoblast mineralization. However, this does not translate into tissue level alterations. These data indicate that anabolic actions of PTH in ectopic ossicles are temporally dependent on the BMSC implanted and suggest that cell implantation strategies are particularly responsive to PTH.

Interaction between parathyroid hormone and endogenous estrogen in normal women.

PubMed

Buchanan, J R; Santen, R J; Cavaliere, A; Cauffman, S W; Greer, R B; Demers, L M

1986-06-01

It has been hypothesized that estrogens conserve bone substance by blocking the resorbing effect of parathyroid hormone (PTH). We evaluated this hypothesis by examining the relation of circulating PTH to endogenous estrogen fluctuation during four quarters of a single menstrual cycle in 20 normal women. The hypothesis predicts that PTH should vary directly with estrogen, since PTH should increase following estrogen elevation to satisfy physiologic demands for calcium. Contrary to the predicted direct variation, PTH remained constant throughout the menstrual cycle despite sharply fluctuating estrogen levels. Furthermore, PTH was negatively associated with estrone during the early follicular (r = -.65, P less than 0.005) and late follicular (r = -.84, P less than 0.0001) phases. We attempted to determine whether this unexpected relationship between estrone and PTH signified a direct physiologic link, by excluding factors which could have spuriously engendered the inverse correlation. Stepwise multiple regression and partial correlation showed that estrone contributed significantly to circulating PTH independent of the effects of dietary calcium, 25-hydroxyvitamin D, serum calcium, 1,25-dihydroxyvitamin D, phosphate, estradiol, progesterone, and body weight. Therefore, it is possible that the inverse correlation between estrone and PTH signified a direct physiologic link, as an artifactual cause for the relationship could not be identified. These data imply that estrone interacts with PTH, but not by blocking PTH-mediated bone resorption. We conclude that estrone is associated with reduced circulating PTH through an as yet undetermined mechanism.

The effects of excipients and particle engineering on the biophysical stability and aerosol performance of parathyroid hormone (1-34) prepared as a dry powder for inhalation.

PubMed

Shoyele, Sunday A; Sivadas, Neeraj; Cryan, Sally-Ann

2011-03-01

Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this study, we investigated the effect of spray-drying (SD) and spray freeze-drying processes on the stability and aerosol performance of parathyroid hormone (PTH) (1-34) microparticles. In this study, the stabilisation effect of trehalose (a non-reducing sugar) and Brij 97 (a non-ionic surfactant) on spray-dried PTH particles was assessed using analytical techniques including circular dichroism (CD), fluorescence spectroscopy, modulated differential scanning calorimetry and an in vitro bioactivity assay. Physical characterisation also included electron microscopy, tap density measurement and laser light diffraction. The aerosol aerodynamic performance of the formulations was assessed using the Andersen cascade impactor. Based on these studies, a formulation for spray freeze-drying was selected and the effects of the two particle engineering techniques on the biophysical stability and aerosol performance of the resulting powders was determined. CD, fluorescence spectroscopy and bioactivity data suggest that trehalose when used alone as a stabilising excipient produces a superior stabilising effect than when used in combination with a non-ionic surfactant. This highlights the utility of CD and fluorescence spectroscopy studies for the prediction of protein bioactivity post-processing. Therefore, a method and formulation suitable for the preparation of PTH as a dry powder was developed based on spray-drying PTH with trehalose as a stabiliser with the bioactivity of SD PTH containing trehalose being equivalent to that of unprocessed PTH. © 2011 American Association of Pharmaceutical Scientists

Immortalization and characterization of osteoblast cell lines generated from wild-type and Nmp4-null mouse bone marrow stromal cells using murine telomerase reverse transcriptase (mTERT).

PubMed

Alvarez, Marta B; Childress, Paul; Philip, Binu K; Gerard-O'Riley, Rita; Hanlon, Michael; Herbert, Brittney-Shea; Robling, Alexander G; Pavalko, Fredrick M; Bidwell, Joseph P

2012-05-01

Intermittent parathyroid hormone (PTH) adds new bone to the osteoporotic skeleton; the transcription factor Nmp4/CIZ represses PTH-induced bone formation in mice and as a consequence is a potential drug target for improving hormone clinical efficacy. To explore the impact of Nmp4/CIZ on osteoblast phenotype, we immortalized bone marrow stromal cells from wildtype (WT) and Nmp4-knockout (KO) mice using murine telomerase reverse transcriptase. Clonal lines were initially chosen based on their positive staining for alkaline phosphatase and capacity for mineralization. Disabling Nmp4/CIZ had no gross impact on osteoblast phenotype development. WT and KO clones exhibited identical sustained growth, reduced population doubling times, extended maintenance of the mature osteoblast phenotype, and competency for differentiating toward the osteoblast and adipocyte lineages. Additional screening of the immortalized cells for PTH-responsiveness permitted further studies with single WT and KO clones. We recently demonstrated that PTH-induced c-fos femoral mRNA expression is enhanced in Nmp4-KO mice and in the present study we observed that hormone stimulated either an equivalent or modestly enhanced increase in c-fos mRNA expression in both primary null and KO clone cells depending on PTH concentration. The null primary osteoblasts and KO clone cells exhibited a transiently enhanced response to bone morphogenetic protein 2 (BMP2). The clones exhibited lower and higher expressions of the PTH receptor (Pthr1) and the BMP2 receptor (Bmpr1a, Alk3), respectively, as compared to primary cells. These immortalized cell lines will provide a valuable tool for disentangling the complex functional roles underlying Nmp4/CIZ regulation of bone anabolism. Copyright © 2011 Wiley Periodicals, Inc.

Multicenter evaluation of a new immunoassay for intact PTH measurement on the Elecsys System 2010 and 1010.

PubMed

Hermsen, Derik; Franzson, Leifur; Hoffmann, Jean Paul; Isaksson, Anders; Kaufman, Jean M; Leary, Elizabeth; Müller, Christian; Nakatsuka, Kiyoshi; Nishizawa, Yoshiki; Reinauer, Hans; Riesen, Walter; Roth, Heinz-Jürgen; Steinmüller, Thomas; Troch, Tanja; Bergmann, Pierre

2002-01-01

The determination of parathyroid hormone (PTH) is of great clinical relevance in the assessment of calcium metabolic disorders. Although PTH was one of the first hormones measured by immunoassays, there are still many difficulties in its determination due to the low concentration of the hormone in blood and due to the heterogeneity of PTH resulting from different circulating hormone fragments. The aim of our multicenter-study was to evaluate the technical performance and the clinical validity of a new immunoassay for intact PTH measurement on the Elecsys Systems 2010 and 1010. The multicenter evaluation was performed in 11 clinical laboratories. The Elecsys PTH assay is a one step sandwich electrochemiluminescence immunoassay based upon the streptavidin-biotin technology. Two monoclonal antibodies are used in the assay providing detection of intact PTH. The imprecision study yielded within-run and between-days coefficients of variation of 3.1% - 6.6% and 3.4% - 15.6%, respectively using a three level control (PreciControl Bone, Roche Diagnostics) and human pool sera at two different concentrations (HS-low: 20 - 60 pg/ml, HS-high > 65 pg/ml). The analytical sensitivity calculated as the mean value plus 2 standard deviations of a within-run imprecision was below 2.70 pg/ml using zero calibrator matrix. Dilution linearity was observed up to 4890 pg/ml using zero calibrator matrix or human pool sera. Recoveries ranged between 85% - 115%. Serum, EDTA- and heparin plasma were evaluated for PTH measurement. Due to a better analyte stability (48h at 21 degrees C; 3d at 4 degrees C) EDTA plasma was recommended for PTH measurement. Results of the Elec sys PTH immunoassay correlated well (r = 0.926 - 0.994) with three different immunoradiometric assays (N-tact PTH SP, DiaSorin; Nichols Allegro Intact PTH, Nichols Institute Diagnostics; ELSA-PTH, CISBio International) and two different immunochemiluminometric assays (PTH-Intact-Immulite, DPC Biermann; Nichols Advantage Intact PTH, Nichols Institute Diagnostics) in technical and clinical method comparisons. The Passing/Bablok regression analysis yielded slopes of 0.692 - 1.729 and intercepts of -13.982 - +15.763 pg/ml. Deviations from slope 1.0 and intercept 0.0 were not unexpected due to differences in immunoassay standardization and probably due to the presence of different PTH fragments and a variable affinity of the used antibodies to these PTH fragments. Highly similar PTH concentration pattern of the Elecsys immunoassay and the Quick-Intraoperative Intact PTH immunoassay (Nichols Institute Diagnostics) obtained from specimens taken intraoperatively support the applicability of the Elecsys immunoassay to monitor the success of parathyroid resection. A reference range of 12.3 - 56.0 pg/ml calculated from PTH values of 43 apparently healthy individuals confirms reference limits published in the literature. The partition of collectives according to age showed, that individuals > 50 years have slightly higher PTH concentrations, independently of gender. This shift could be due to age itself or to an increased prevalence of individuals without obvious calcium metabolic disorders in this collective. The Elecsys PTH assay is a useful and reliable tool for determination of intact PTH. Our data support the intended use of the assay in clinical applications related to disorders of calcium metabolism.

Effects of intermittent versus continuous parathyroid hormone administration on condylar chondrocyte proliferation and differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Qi; Wan, Qilong; Yang, Rongtao

Highlights: Black-Right-Pointing-Pointer Different PTH administration exerts different effects on condylar chondrocyte. Black-Right-Pointing-Pointer Intermittent PTH administration suppresses condylar chondrocyte proliferation. Black-Right-Pointing-Pointer Continuous PTH administration maintains condylar chondrocyte proliferating. Black-Right-Pointing-Pointer Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presentedmore » enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular asymmetry.« less

Combination therapy with ONO-KK1-300-01, a cathepsin K inhibitor, and parathyroid hormone results in additive beneficial effect on bone mineral density in ovariectomized rats.

PubMed

Ochi, Yasuo; Yamada, Hiroyuki; Mori, Hiroshi; Kawada, Naoki; Tanaka, Makoto; Imagawa, Akira; Ohmoto, Kazuyuki; Kawabata, Kazuhito

2016-01-01

This study examined the effects of a novel cathepsin K inhibitor, ONO-KK1-300-01 (KK1-300), used concurrently with parathyroid hormone (PTH) in ovariectomized (OVX) rats. KK1-300 (3 mg/kg, twice daily), alendronate (1 mg/kg, once daily) or vehicle were orally administered to OVX rats for 56 days, starting the day after ovariectomy, followed by combination treatment with or without PTH (3 μg/kg, subcutaneously three times a week) for another 28 days. OVX control animals exhibited a significant increase in both bone resorption (urinary deoxypyridinoline; DPD) and formation markers (serum osteocalcin) as well as microstructural changes associated with decreased bone mineral density (BMD). Combination treatment with KK1-300 and PTH significantly decreased urinary DPD and increased serum osteocalcin, indicating a sustained beneficial effect compared to the effect of each mono-therapy. On the other hand, combination therapy with alendronate and PTH weakened the PTH-induced increase in osteocalcin. In proximal tibia, combination treatment with KK1-300 and PTH increased BMD to a level significantly higher than that achieved following single treatment with KK1-300 or PTH alone. On the other hand, combination treatment with alendronate and PTH failed to produce any significant additive effect on BMD following single treatment with alendronate or PTH alone. Microstructural analysis revealed that the PTH-induced increase in bone formation (MS/BS and BFR/BS) was fully maintained following combination treatment with KK1-300 and PTH, but not following combination treatment with alendronate and PTH. These findings indicate that KK1-300, unlike alendronate, has an additive effect on the preventive action of PTH on bone loss in OVX rats.

Association of relatively low serum parathyroid hormone with malnutrition-inflammation complex and survival in maintenance hemodialysis patients.

PubMed

Dukkipati, Ramanath; Kovesdy, Csaba P; Colman, Sara; Budoff, Matthew J; Nissenson, Allen R; Sprague, Stuart M; Kopple, Joel D; Kalantar-Zadeh, Kamyar

2010-07-01

Low serum parathyroid hormone (PTH) has been implicated as a primary biochemical marker of adynamic bone disease in individuals with chronic kidney disease (CKD) who undergo maintenance hemodialysis (MHD) treatment. We hypothesized that the malnutrition-inflammation complex is associated with low PTH levels in these patients and confounds the PTH-survival association. We examined 748 stable MHD outpatients in southern California and followed them for up to 5 years (October 2001-December 2006). In 748 MHD patients, serum PTH <150pg/mL was more prevalent among non-blacks and diabetics. There was no association between serum PTH and coronary artery calcification score, bone mineral density, or dietary protein or calorie intake. Low serum PTH was associated with markers of protein-energy wasting and inflammation, and this association confounded the relationship between serum PTH and alkaline phosphatase. Although 5-year crude mortality rates were similar across PTH increments, after adjustment for the case-mix and surrogates of malnutrition and inflammation, a moderately low serum PTH in 100-150pg/mL range was associated with the greatest survival compared to other serum PTH levels, i.e., a death hazard ratio of 0.52 (95% confidence interval: 0.29-0.92, p<0.001) compared to PTH of 300-600pg/mL (reference). Low serum PTH may be another facet of the malnutrition-inflammation complex in CKD, and after controlling for this confounder, a moderately low PTH in 100-150pg/mL range appears associated with the greatest survival. Limitations of observational studies should be considered. Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone.

PubMed

Brown, Jenifer M; Williams, Jonathan S; Luther, James M; Garg, Rajesh; Garza, Amanda E; Pojoga, Luminita H; Ruan, Daniel T; Williams, Gordon H; Adler, Gail K; Vaidya, Anand

2014-02-01

Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.

Additive roles of PthAs in bacterial growth and pathogenicity associated with nucleotide polymorphisms in effector-binding elements of citrus canker susceptibility genes.

PubMed

Abe, Valeria Yukari; Benedetti, Celso Eduardo

2016-10-01

Citrus canker, caused by Xanthomonas citri, affects most commercial citrus varieties. All X. citri strains possess at least one transcription activator-like effector of the PthA family that activates host disease susceptibility (S) genes. The X. citri strain 306 encodes four PthA effectors; nevertheless, only PthA4 is known to elicit cankers on citrus. As none of the PthAs act as avirulence factors on citrus, we hypothesized that PthAs 1-3 might also contribute to pathogenicity on certain hosts. Here, we show that, although PthA4 is indispensable for canker formation in six Brazilian citrus varieties, PthAs 1 and 3 contribute to canker development in 'Pera' sweet orange, but not in 'Tahiti' lemon. Deletions in two or more pthA genes reduce bacterial growth in planta more pronouncedly than single deletions, suggesting an additive role of PthAs in pathogenicity and bacterial fitness. The contribution of PthAs 1 and 3 in canker formation in 'Pera' plants does not correlate with the activation of the canker S gene, LOB1 (LATERAL ORGAN BOUNDARIES 1), but with the induction of other PthA targets, including LOB2 and citrus dioxygenase (DIOX). LOB1, LOB2 and DIOX show differential PthA-dependent expression between 'Pera' and 'Tahiti' plants that appears to be associated with nucleotide polymorphisms found at or near PthA-binding sites. We also present evidence that LOB1 activation alone is not sufficient to elicit cankers on citrus, and that DIOX acts as a canker S gene in 'Pera', but not 'Tahiti', plants. Our results suggest that the activation of multiple S genes, such as LOB1 and DIOX, is necessary for full canker development. © 2015 BSPP and John Wiley & Sons Ltd.

Aldosterone, Parathyroid Hormone, and the Use of Renin-Angiotensin-Aldosterone System Inhibitors: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

Brown, Jenifer; de Boer, Ian H.; Robinson-Cohen, Cassianne; Siscovick, David S.; Kestenbaum, Bryan; Allison, Matthew

2015-01-01

Context: Aldosterone and PTH are implicated in the pathogenesis of cardiovascular and skeletal diseases. An expanding body of evidence supports a bidirectional and positive physiologic relationship between aldosterone and PTH. Large population-based studies confirming this relationship, and whether it may be targeted as a potential method to mitigate the clinical consequences associated with excess aldosterone and PTH, are needed. Objective: We hypothesized that higher aldosterone levels would associate with higher PTH, and that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors would predict lower PTH in a large, multi-ethnic, community-based cohort. Design, Setting, Participants: We conducted cross-sectional analyses of participants in the Multi-Ethnic Study of Atherosclerosis without apparent primary hyperparathyroidism or chronic kidney disease (n = 5668). We evaluated associations of RAAS inhibitor use with PTH concentration among 1888 treated hypertensive participants. We also tested associations of serum aldosterone concentration with PTH concentration among 1547 participants with these measurements. Outcome: Serum PTH concentration. Results: Higher aldosterone associated with higher PTH (β = 0.19 pg/ml per 1 ng/dl of aldosterone, P < .0001), and this finding was most pronounced among those with a primary hyperaldosteronism-like phenotype. There was a stepwise increment in PTH when comparing untreated normotensives, hypertensives using RAAS inhibitors, untreated hypertensives, and treated hypertensives using non-RAAS inhibitors (40.8, 45.0, 46.2, 47.1 pg/ml, respectively). The use of any RAAS inhibitor independently associated with lower PTH (β = −2.327 pg/ml per use of RAAS inhibitor, P = .006), when compared with the use of any non-RAAS inhibitor medication. Conclusions: Higher serum aldosterone concentration is associated with higher serum PTH concentration, and the use of RAAS inhibitors is associated with lower PTH concentration. These results extend prior evidence from observational and intervention studies suggesting a potentially important and modifiable relationship between the RAAS and PTH in humans. PMID:25412416

A single injection of the anabolic bone agent, parathyroid hormone-collagen binding domain (PTH-CBD), results in sustained increases in bone mineral density for up to 12 months in normal female mice.

PubMed

Ponnapakkam, Tulasi; Katikaneni, Ranjitha; Suda, Hirofumi; Miyata, Shigeru; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert C

2012-09-01

Parathyroid hormone (PTH) is the most effective osteoporosis treatment, but it is only effective if administered by daily injections. We fused PTH(1-33) to a collagen binding domain (PTH-CBD) to extend its activity, and have shown an anabolic bone effect with monthly dosing. We tested the duration of action of this compound with different routes of administration. Normal young C57BL/6J mice received a single intraperitoneal injection of PTH-CBD (320 μg/kg). PTH-CBD treated mice showed a 22.2 % increase in bone mineral density (BMD) at 6 months and 12.8 % increase at 12 months. When administered by subcutaneous injection, PTH-CBD again caused increases in BMD, 15.2 % at 6 months and 14.3 % at 12 months. Radiolabeled PTH-CBD was concentrated in bone and skin after either route of administration. We further investigated skin effects of PTH-CBD, and histological analysis revealed an apparent increase in anagen VI hair follicles. A single dose of PTH-CBD caused sustained increases in BMD by >10 % for 1 year in normal mice, regardless of the route of administration, thus showing promise as a potential osteoporosis therapy.

Analysing the effect of multiple sclerosis on vitamin D related biochemical markers of bone remodelling.

PubMed

McKenna, Malachi J; Murray, Barbara; Lonergan, Roisin; Segurado, Ricardo; Tubridy, Niall; Kilbane, Mark T

2018-03-01

The Irish population is at risk of vitamin D deficiency during the winter months, but the secular trend over the past 40 years is for marked improvement. Multiple sclerosis (MS) is common in Ireland with a latitudinal pattern favouring highest incidence in northern regions; MS is linked strongly with vitamin D status as a causal factor. We sought firstly to study the relationship between vitamin D status and vitamin D-related bone biochemistry, and secondly to evaluate if MS had an independent effect on vitamin D related markers of bone remodelling. Using a case-control design of 165 pairs (MS patient and matched control) residing in three different geographic regions during winter months, we measured serum 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), C-terminal telopeptide of type I collagen (CTX) and total procollagen type I amino-terminal propeptide (PINP). Given the paired case-control design, associations were explored using mixed-effects linear regression analysis with the patient-control pair as a random effect and after log transformation of 25OHD. A two-way interaction effect was tested for vitamin D status (25OHD <30nmol/L) and the presence of MS on PTH, CTX, and PINP. In the total group, just over one-third (34.5%) had 25OHD <30nmol/L. PTH was elevated in 7.6%. CTX was not elevated in any case, and PINP was elevated in 4.5%. On mixed-effects linear regression analysis after adjusting for confounders (age, sex, renal function, and serum albumin), we demonstrated the principal determinant of 25OHD was geographical location (p<0.001), of PTH was 25OHD (p<0.001), of CTX was PTH (p<0.001), and of PINP was PTH (p<0.001). MS did not have an independent effect on PTH (p=0.921), CTX (p=0.912), or PINP (p=0.495). As regards an interaction effect, the presence of MS and 25OHD <30nmol/L was not significant but tended towards having lower PTH (p=0.207). In conclusion, in Ireland in winter only a minority had any abnormality in the secondary indices of vitamin D deficiency, and MS had no independent effect on parathyroid status or bone remodelling activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Post-thyroidectomy hypocalcemia is related to parathyroid dysfunction even in patients with normal parathyroid hormone concentrations early after surgery.

PubMed

Raffaelli, Marco; De Crea, Carmela; D'Amato, Gerardo; Moscato, Umberto; Bellantone, Chiara; Carrozza, Cinzia; Lombardi, Celestino Pio

2016-01-01

Hypocalcemia may develop even in the presence of normal postoperative parathyroid hormone (PTH) concentrations. We aimed to identify risk factors of hypocalcemia in patients with normal PTH concentration early after total thyroidectomy (TT). We included 1,504 consecutive patients who underwent TT between January 2012 and December 2013. Significant hypocalcemia was defined as serum calcium concentrations of <8.0 mg/dL. Overall, 333 patients had subnormal PTH 4 hours after surgery (4-hour PTH; <10 pg/mL) and received oral calcium (OC) and calcitriol supplementation. Among the 1,171 patients with normal 4-hour PTH (≥ 10 pg/mL; euparathyroid), 211 experienced hypocalcemia and required OC administration. Among the euparathyroid patients, no difference was found between normocalcemic and hypocalcemic patients in terms of age, hormonal status, preoperative PTH, 25-hydroxy vitamin D (25OH-VD), magnesium, and phosphate concentrations. On univariate analysis, euparathyroid hypocalcemic patients were more frequently females, had significantly lower preoperative serum calcium and 4-hour PTH concentrations, and greater decreases in PTH. Independent risk factors for hypocalcemia with normal 4-hour PTH were preoperative serum calcium concentration and PTH decline of ≥ 50%. Female sex, toxic goiter, and 25OH-VD deficiency are not risk factors for post-TT hypocalcemia. Relative parathyroid insufficiency seems to be the principal mechanism of post-thyroidectomy hypocalcemia, even in patients with normal postoperative PTH concentrations. Copyright © 2016 Elsevier Inc. All rights reserved.

[Therapeutic agents for disorders of bone and calcium metabolism--Parathyroid hormone in weekly subcutaneous injection].

PubMed

Uzawa, Toyonobu

2007-01-01

The parathyroid hormone (PTH) that is marketed outside Japan is for daily administration. It has been proven to increase bone mass and prevent fractures, and the effects are very strong. However, data suggest that daily administration of PTH increases bone resorption. By contrast, weekly administration of PTH, which is being developed in Japan, actually decreases bone resorption, and data suggest that this regimen maintains a good balance between bone formation (predominant) and bone resorption. Furthermore, it has been reported that weekly administration of PTH increases bone mass as much as every day administration of PTH, and as such, weekly administration of PTH has the potential to be a useful regimen with characteristics that are different from those of daily administration of PTH.

Hydrocephalus during rehabilitation following severe TBI. Relation to recovery, outcome, and length of stay.

PubMed

Linnemann, Mia; Tibæk, Maiken; Kammersgaard, Lars Peter

2014-01-01

Post traumatic hydrocephalus (PTH) is a frequent complication during rehabilitation following severe TBI. However, the diagnosis of PTH is not straightforward and despite shunting recovery may be delayed. To study the influence of PTH on recovery and outcome during rehabilitation. We studied 417 patients with severe TBI admitted consecutively to a single hospital-based neurorehabilitation department serving Eastern Denmark between 2000 and 2010. Demographics (age and gender) and clinical characteristics (length of acute treatment, post traumatic amnesia (PTA), level of consciousness, injury severity (ISS), and admission FIM™), and PTH were related to recovery (discharge FIM™), outcome (GOS), and length of rehabilitation stay. Patients with PTH were older, brain injury more severe, and acute treatment was longer. At discharge they had more disability, longer rehabilitation stays, and unfavorable outcome. However, after adjusted multiple regression analyses PTH was not associated with disability at discharge or outcome. Instead, PTH was associated with longer stay for rehabilitation. Shunting for PTH does not affect recovery and outcome per se, but prolongs lengths of stay by almost 3 weeks. Therefore, patients treated for PTH are as likely to benefit from rehabilitation as patients without, but require longer rehabilitation stays.

Effects of PTH (1-84) on bone quality in a validated model of osteoporosis due to androgenic deprivation.

PubMed

Martín-Fernández, Marta; Martínez, Elena; Díaz-Curiel, Manuel; Guede, David; Caeiro, José Ramón; De la Piedra, Concepción

2014-03-01

The purpose of this study was to evaluate the effect of parathyroid hormone (PTH) (1-84) in a model of male osteoporosis induced by orchidectomy in rats. Six-month-old Wistar rats were used as follows: SHAM (simulated orchidectomy), orchidectomized (ORX), ORX + PTH1 (ORX and treated with 10 µg/Kg/d of PTH 1-84) and ORX + PTH2 (ORX and treated with 50 µg/Kg/d of PTH 1-84) over 3 months, with treatment beginning three months after orchidectomy. Orchidectomy resulted in a decreased of femoral and lumbar bone mineral density (BMD), a worsening of trabecular and cortical microarchitecture and a decrease in biomechanical properties. Both doses of PTH (1-84) partially (low dose) or totally (high dose) restored the ORX-induced changes. Serum C-telopeptide of type I collagen/5b isoenzyme of tartrate-resistant acid phosphatase (CTX/TRAP) resorption index increased after orchidectomy. Osteocalcin (bone Gla protein; BGP) levels were not affected by orchidectomy. PTH (1-84) treatment did not produce any changes in the levels of CTX/TRAP with respect to the ORX group. BGP levels increased with PTH treatment. PTH (1-84) is able to restore the adverse effects of orchidectomy on bone as measured by BMD, microstructural and biomechanical properties and bone remodeling markers.

Synergistic effects of high dietary calcium and exogenous parathyroid hormone in promoting osteoblastic bone formation in mice.

PubMed

Feng, Yuxu; Zhou, Min; Zhang, Qunhu; Liu, Huan; Xu, Yong; Shu, Lei; Zhang, Jue; Miao, Dengshun; Ren, Yongxin

2015-03-28

In the present study, we investigated whether high dietary Ca and exogenous parathyroid hormone 1-34 fragments (PTH 1-34) have synergistic effects on bone formation in adult mice, and explored the related mechanisms. Adult male mice were fed a normal diet, a high-Ca diet, a PTH-treated diet, or a high-Ca diet combined with subcutaneously injected PTH 1-34 (80 μg/kg per d) for 4 weeks. Bone mineral density, trabecular bone volume, osteoblast number, alkaline phosphatase (ALP)- and type I collagen-positive areas, and the expression levels of osteoblastic bone formation-related genes and proteins were increased significantly in mice fed the high-Ca diet, the PTH-treated diet, and, even more dramatically, the high-Ca diet combined with PTH. Osteoclast number and surface and the ratio of receptor activator for nuclear factor-κB ligand (RANKL):osteoprotegerin (OPG) were decreased in the high-Ca diet treatment group, increased in the PTH treatment group, but not in the combined treatment group. Furthermore, third-passage osteoblasts were treated with high Ca (5 mM), PTH 1-34 (10⁻⁸ M) or high Ca combined with PTH 1-34. Osteoblast viability and ALP activity were increased in either the high Ca-treated or PTH-treated cultures and, even more dramatically, in the cultures treated with high Ca plus PTH, with consistent up-regulation of the expression levels of osteoblast proliferation and differentiation-related genes and proteins. These results indicate that dietary Ca and PTH play synergistic roles in promoting osteoblastic bone formation by stimulating osteoblast proliferation and differentiation.

Sustained signalling by PTH modulates IP3 accumulation and IP3 receptors through cyclic AMP junctions

PubMed Central

Meena, Abha; Tovey, Stephen C.; Taylor, Colin W.

2015-01-01

ABSTRACT Parathyroid hormone (PTH) stimulates adenylyl cyclase through type 1 PTH receptors (PTH1R) and potentiates the Ca2+ signals evoked by carbachol, which stimulates formation of inositol 1,4,5-trisphosphate (IP3). We confirmed that in HEK cells expressing PTH1R, acute stimulation with PTH(1-34) potentiated carbachol-evoked Ca2+ release. This was mediated by locally delivered cyclic AMP (cAMP), but unaffected by inhibition of protein kinase A (PKA), exchange proteins activated by cAMP, cAMP phosphodiesterases (PDEs) or substantial inhibition of adenylyl cyclase. Sustained stimulation with PTH(1-34) causes internalization of PTH1R–adenylyl cyclase signalling complexes, but the consequences for delivery of cAMP to IP3R within cAMP signalling junctions are unknown. Here, we show that sustained stimulation with PTH(1-34) or with PTH analogues that do not evoke receptor internalization reduced the potentiated Ca2+ signals and attenuated carbachol-evoked increases in cytosolic IP3. Similar results were obtained after sustained stimulation with NKH477 to directly activate adenylyl cyclase, or with the membrane-permeant analogue of cAMP, 8-Br-cAMP. These responses were independent of PKA and unaffected by substantial inhibition of adenylyl cyclase. During prolonged stimulation with PTH(1-34), hyperactive cAMP signalling junctions, within which cAMP is delivered directly and at saturating concentrations to its targets, mediate sensitization of IP3R and a more slowly developing inhibition of IP3 accumulation. PMID:25431134

How the reference values for serum parathyroid hormone concentration are (or should be) established?

PubMed

Souberbielle, J-C; Brazier, F; Piketty, M-L; Cormier, C; Minisola, S; Cavalier, E

2017-03-01

Well-validated reference values are necessary for a correct interpretation of a serum PTH concentration. Establishing PTH reference values needs recruiting a large reference population. Exclusion criteria for this population can be defined as any situation possibly inducing an increase or a decrease in PTH concentration. As recommended in the recent guidelines on the diagnosis and management of asymptomatic primary hyperparathyroidism, PTH reference values should be established in vitamin D-replete subjects with a normal renal function with possible stratification according to various factors such as age, gender, menopausal status, body mass index, and race. A consensus about analytical/pre-analytical aspects of PTH measurement is also needed with special emphasis on the nature of the sample (plasma or serum), the time and the fasting/non-fasting status of the blood sample. Our opinion is that blood sample for PTH measurement should be obtained in the morning after an overnight fast. Furthermore, despite longer stability of the PTH molecule in EDTA plasma, we prefer serum as it allows to measure calcium, a prerequisite for a correct interpretation of a PTH concentration, on the same sample. Once a consensus is reached, we believe an important international multicentre work should be performed to recruit a very extensive reference population of apparently healthy vitamin D-replete subjects with a normal renal function in order to establish the PTH normative data. Due to the huge inter-method variability in PTH measurement, a sufficient quantity of blood sample should be obtained to allow measurement with as many PTH kits as possible.

Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis.

PubMed

Polyzos, Stergios A; Makras, Polyzois; Efstathiadou, Zoe; Anastasilakis, Athanasios D

2015-02-01

Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative. In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis. β-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 - 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 - 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future.

Oral breathing challenge in participants with vocal attrition.

PubMed

Sivasankar, Mahalakshmi; Fisher, Kimberly V

2003-12-01

Vocal folds undergo osmotic challenge by mouth breathing during singing, exercising, and loud speaking. Just 15 min of obligatory oral breathing, to dry the vocal folds, increases phonation threshold pressure (Pth) and expiratory vocal effort in healthy speakers (M. Sivasankar & K. Fisher, 2002). We questioned whether oral breathing is more detrimental to phonation in healthy participants with a history of temporary vocal attrition. The effects of a 15-min oral or nasal breathing challenge on Pth and perceived expiratory vocal effort were compared for participants reporting symptoms of vocal attrition (N = 18, ages 19-38 years) and normal controls (N = 20, ages 19-33 years). Post-challenge-prechallenge differences in Pth (deltaPth) and effort (deltaEffort) revealed that oral breathing, but not nasal breathing, increased Pth (p < .001 ) and effort (p < .001) at low, comfortable, and high pitch. deltaPth was significantly greater in participants with vocal attrition than in normal controls (p < .001). Nasal breathing reduced Pth for all controls but not for all participants reporting vocal attrition. deltaPth was significantly and linearly correlated with deltaEffort (rvocal attrition = .81, p < .001; rcontrol = .84, p < .001). We speculate that the greater increases in Pth in participants reporting vocal attrition may result from delayed or inadequate compensatory response to superficial laryngeal dehydration. Obligatory oral breathing may place voice users at risk for exacerbating vocal attrition. That sol layer depletion by obligatory oral breathing increased Pth and vocal effort provides support for the role of superficial hydration in maintaining ease of phonation.

Effects of Lowering Dialysate Calcium Concentration on Mineral and Bone Disorders in Chronic Hemodialysis Patients: Conversion from 3.0 mEq/L to 2.75 mEq/L.

PubMed

Yamada, Shunsuke; Ueki, Kenji; Tokumoto, Masanori; Suehiro, Takaichi; Kimura, Hiroshi; Taniguchi, Masatomo; Fujimi, Satoru; Kitazono, Takanari; Tsuruya, Kazuhiko

2016-02-01

Selection of a lower dialysate calcium concentration (DCa) can reduce calcium burden and prevent vascular calcification in hemodialysis patients. However, decreased DCa can worsen mineral and bone disorders. This 1-year retrospective observational study evaluated 121 hemodialysis patients at Fukuoka Renal Clinic who underwent conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. The primary outcomes were changes in serum levels of calcium, phosphate, and parathyroid hormone (PTH). The effects of baseline serum calcium and PTH levels on changes in biochemical parameters were also determined. One year after DCa conversion, mean serum calcium level decreased, while serum phosphate, alkaline phosphatase, and PTH concentrations increased. The rate of achievement of target PTH was higher in patients with lower serum PTH level at baseline, while patients with higher baseline serum PTH level tended to exceed the upper limit of the PTH target range. Patients with higher baseline serum calcium concentration showed a greater decrease in serum calcium level and a greater increase in serum PTH level at 1 year. Patients with a lower baseline serum PTH level can benefit from optimal PTH control following conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. However, secondary hyperparathyroidism may be exacerbated in some patients with higher baseline serum calcium (Ca) and PTH levels. These results indicate that an individualized approach can maximize the benefits of Ca unloading after conversion to lower DCa. © 2015 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.

Proteoglycan 4: A Dynamic Regulator of Skeletogenesis and Parathyroid Hormone Skeletal Anabolism

PubMed Central

Novince, Chad M; Michalski, Megan N; Koh, Amy J; Sinder, Benjamin P; Entezami, Payam; Eber, Matthew R; Pettway, Glenda J; Rosol, Thomas J; Wronski, Thomas J; Kozloff, Ken M; McCauley, Laurie K

2014-01-01

Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure. PMID:21932346

Establishment of reference values in a healthy population and interpretation of serum PTH concentrations in hemodialyzed patients according to the KDIGO Guidelines using the Lumipulse® G whole PTH (3rd generation) assay.

PubMed

Cavalier, Etienne; Salsé, Margot; Dupuy, Anne-Marie; Bargnoux, Anne-Sophie; Watar, Florence; Souberbielle, Jean-Claude; Delanaye, Pierre; Cristol, Jean-Paul

2018-04-01

3rd generation PTH assays only detect the bioactive 1-84 fragment. Since standardization is still lacking, each new PTH assay requires to establish reference values and to assess the impact in the medical care of the mineral and bone disorders in hemodialyzed patients. Using Fujirebio Lumipulse G wPTH assay, serum PTH levels were measured in a population of 439 healthy subjects from France and Belgium PTH levels were also determined in 119 hemodialyzed patients. These patients were classified according to the KDIGO recommendation. Reference range was found to be 6.5 (90%CI: 6.0-7.0) - 41.8 (90% CI: 38.1-43.7). In hemodialysis patients, Passing-Bablock regression between 3rd generation PTH from Fujirebio and DiaSorin was DiaSorin = 1.01 xFujirebio-2.4 with a slope not different from 1.0(95%CI: 0.96-1.04) and a non-significant intercept, ranging from -6.0 to 0.1. Hemodialysis patients with a PTH concentration below 2-fold the Upper Limit of Normality (ULN), within the KDIGO range and upper 9-fold upper limit were respectively 33.6%, 54.6%, 11.8% (Fujirebio Lumipulse) and 36.1%, 51.3% and 12.6% (Diasorin Liaison). We determined a reference range with the 3rd generation PTH assay from Fujirebio. In a hemodialysis population, 3rd generation assays from Fujirebio and DiaSorin provide similar results. To the best of our knowledge, this is the first time that we can show similar PTH results obtained by 2 different 3rd generation PTH assays in healthy subjects and hemodialyzed patients without mathematically processing them. Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

An iPTH based protocol for the prevention and treatment of symptomatic hypocalcemia after thyroidectomy

PubMed Central

Carter, Yvette; Chen, Herbert; Sippel, Rebecca S.

2013-01-01

Background Symptomatic hypocalcemia after thyroidectomy is a barrier to same day surgery, and the cause of ER visits. A standard protocol of calcium and vitamin D supplementation, dependent on intact parathyroid hormone (iPTH) levels, can address this issue. How effective is it? When does it fail? Methods We performed a retrospective review of the prospective Thyroid Database from January 2006 to December 2010. 620 patients underwent completion (CT) or total thyroidectomy (TT), and followed our post-operative protocol of calcium carbonate administration for iPTH levels ≥10pg/ml and calcium carbonate and 0.25μg calcitriol BID for iPTH <10pg/ml. Calcium and iPTH values, pathology and medication, were compared to evaluate protocol efficacy. A p value <0.05 was considered statistically significant. Results Using the protocol, sixty-one (10.2%) patients were chemically hypocalcemic but never developed symptoms and twenty-four (3.9%) patients developed breakthrough symptomatic hypocalcemia. The symptomatic (SX) and asymptomatic (ASX) groups were similar with regard to gender, cancer diagnosis, and pre-operative calcium and iPTH. The symptomatic group was significantly younger (39.6 ± 2.8 vs. 49 ± 0.6 years, p=0.01), with lower post-operative iPTH levels. 33% (n=8) of SX patients had an iPTH ≤5 pg/ml vs. only 6% (n=37) of ASX patients. While the majority of patients with a PTH <5 pg/ml were asymptomatic, 62.5% (n=5) of SX patients with iPTH levels ≤5 pg/ml, required an increased in calcitriol dose to achieve both biochemical correction and symptom relief. Conclusion Prophylactic calcium and vitamin D supplementation based on post-operative iPTH levels can minimize symptomatic hypocalcemia after thyroidectomy. An iPTH ≤ 5pg/ml may warrant higher initial doses of calcitriol in order to prevent symptoms. PMID:24144426

Interrelated aldosterone and parathyroid hormone mutually modify cardiovascular mortality risk.

PubMed

Tomaschitz, Andreas; Pilz, Stefan; Rus-Machan, Jutta; Meinitzer, Andreas; Brandenburg, Vincent M; Scharnagl, Hubert; Kapl, Martin; Grammer, Tanja; Ritz, Eberhard; Horina, Jörg H; Kleber, Marcus E; Pieske, Burkert; Kraigher-Krainer, Elisabeth; Hartaigh, Bríain Ó; Toplak, Hermann; van Ballegooijen, Adriana J; Amrein, Karin; Fahrleitner-Pammer, Astrid; März, Winfried

2015-04-01

Inappropriate aldosterone and parathyroid hormone (PTH) secretion is associated with increased cardiovascular risk. Accumulating evidence suggests bidirectional interplay between aldosterone and PTH. We evaluated the cross-sectional relationship between plasma aldosterone concentration (PAC), aldosterone to renin ratio (ARR) and PTH and subsequently tested whether the interaction between PAC and PTH modified the risk of cardiovascular death. PAC [78.0 (48.0-123.0) pg/mL], ARR [6.4 (2.9-12.9) pg/mL/pg/mL] and PTH concentration [median: 29.0 (22.0-40.0) pg/mL] were measured in 3074 patients (mean age: 62.5 ± 10.6 years; 30.3% women) referred to coronary angiography in a tertiary care center in Southwest Germany. Using multiple linear regression analysis, PAC and ARR emerged as an independent predictor of higher PTH concentrations (β=0.12 and 0.21, P<0.001 for both) irrespective of intake of antihypertensive treatment, 25(OH)D, kidney function, serum calcium, phosphate, magnesium, cortisol, NT-pro-BNP, soluble α-klotho and FGF-23 concentration. After a median follow-up of 9.9 years, 512 (16.7%) participants had died due to fatal cardiovascular events. Multivariate Cox proportional hazard analysis revealed that both PAC and PTH were independently associated with cardiovascular mortality, with a potential synergistic interaction (P=0.028). PAC and PTH are exclusively associated with cardiovascular death in subjects with PTH and PAC concentrations above the median, respectively (PAC: HR per log SD: 1.14; 95% CI 1.02-1.29; P=0.026; PTH: HR per log SD: 1.18; 95% CI 1.02-1.37; P=0.031). Higher PAC and ARR were independently associated with PTH. PAC was independently related to incident cardiovascular mortality exclusively in patients with elevated PTH and vice versa. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

THE RESULTS OF PARATHYROID HORMONE ASSAY IN PARATHYROID ASPIRATES IN PRE-OPERATIVE LOCALIZATION OF PARATHYROID ADENOMAS FOR FOCUSED PARATHYROIDECTOMY IN PATIENTS WITH NEGATIVE OR SUSPICIOUS TECHNETIUM-99M-SESTAMIBI SCANS.

PubMed

Ozderya, Aysenur; Temizkan, Sule; Cetin, Kenan; Ozugur, Sule; Gul, Aylin Ege; Aydin, Kadriye

2017-09-01

This study aimed to evaluate the results of parathyroid hormone (PTH) assay in parathyroid aspirates to determine uniglandular disease by an endocrinologist-performed ultrasound (US) in patients with discordant or negative technetium-sestamibi scans and to evaluate whether this procedure increases the number of focused parathyroidectomies (FPs). We analyzed the data of 65 patients who underwent an endocrinologist-performed US-guided parathyroid fine-needle aspiration (FNA) with PTH wash-out, retrospectively. The results of PTH wash-out procedure and the reports of parathyroid surgery and pathology were reviewed. Of 65 patients, 54 had positive PTH wash-out results. The median serum PTH level of patients with positive and negative PTH wash-out results was 143 (25 and 75% interquartile range [IQR], 114 to 197) versus 154 (IQR, 115 to 255) pg/mL (P = .45), and the median PTH in FNA was 3,533 (IQR, 1,481 to 3,534) versus 6.0 (IQR, 1 to 6) pg/mL (P<.001), respectively. Forty-five patients underwent surgery. Of the operated patients, 42 had positive PTH wash-out results and had successful FP. Four patients with redo surgery had positive PTH wash-out results and were successfully re-operated with FP. Of 11 patients with negative PTH wash-out results, 3 had bilateral neck exploration (BNE) surgery and 2 patients were successfully operated, while surgery was unsuccessful in 1 patient, despite BNE. Our study results suggest that endocrinologist-performed US and parathyroid FNA with PTH wash-out increases the number and success of FPs. In particular, patients with redo surgery may benefit from this procedure. 4D-CT = four-dimensional computed tomography BNE = bilateral neck exploration FNA = fine-needle aspiration FNAB = fine-needle aspiration biopsy FP = focused parathyroidectomy IQR = 25 and 75% inter-quartile range PHPT = primary hyperparathyroidism PPV = positive predictive value PTH = parathyroid hormone 99m Tc = technetium US = ultrasound.

Parathyroid hormone induces the Nrna family of nuclear orphan receptors in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pirih, Flavia Q.; Aghaloo, Tara L.; Bezouglaia, Olga

2005-07-01

Parathyroid hormone (PTH) has both anabolic and catabolic effects on bone metabolism, although the molecular mechanisms mediating these effects are largely unknown. Among the transcription factors induced by Pth in osteoblasts are the nerve growth factor-inducible factor B (NR4A; NGFI-B) family of orphan nuclear receptors: Nurr1, Nur77, and NOR-1. PTH induces NR4A members through the cAMP-protein kinase A (PKA) pathway in vitro. We report here that PTH rapidly and transiently induced expression of all three NR4A genes in PTH-target tissues in vivo. In calvaria, long bones, and kidneys, NR4A induction was maximal 0.5-1 h after a single intraperitoneal (i.p.) injectionmore » of 80 {mu}g/kg PTH. Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1. In calvaria and long bone, PTH-induced expression of each NR4A gene was detectable at 10 {mu}g/kg i.p. with maximum induction at 40-80 {mu}g/kg. PTH (3-34) did not induce NR4A mRNA levels in calvaria, long bone, and kidney in vivo, confirming our in vitro results that NR4A genes are induced primarily through the cAMP-PKA pathway. The magnitude of PTH-induced NR4A expression was comparable in vivo and in vitro. However, NR4A mRNA levels peaked and returned to baseline faster in vivo. Both in vivo and in vitro, PTH induced NR4A pre-mRNA levels suggesting that induction of these genes is, at least in part, through activation of mRNA synthesis. The in vivo induction of the NR4A family members by PTH suggests their involvement in, at least some, PTH-induced changes in bone metabolism.« less

Parathyroid hormone inhibition of Na{sup +}/H{sup +} exchanger 3 transcription: Intracellular signaling pathways and transcription factor expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neri, Elida Adalgisa; Bezerra, Camila Nogueira Alves, E-mail: camilab@icb.usp.br; Queiroz-Leite, Gabriella Duarte

2015-06-12

The main transport mechanism of reabsorption of sodium bicarbonate and fluid in the renal proximal tubules involves Na{sup +}/H{sup +} exchanger 3 (NHE3), which is acutely and chronically downregulated by parathyroid hormone (PTH). Although PTH is known to exert an inhibitory effect on NHE3 expression and transcription, the molecular mechanisms involved remain unclear. Here, we demonstrated that, in opossum kidney proximal tubule (OKP) cells, PTH-induced inhibition of Nhe3 gene promoter occurs even in the core promoter that controls expression of the reporter gene. We found that inhibition of the protein kinase A (PKA) and Janus kinase/signal transducer and activator ofmore » transcription (JAK/STAT) pathways transformed PTH from an inhibitor of promoter activity into an activator of that same activity, as did point mutations in the EGR1, Sp1, and Sp3 binding consensus elements in the promoter. In nuclear extracts of PTH-treated OKP cells, we also observed increased expression of EGR1 mRNA and of some Sp3 isoforms. Electrophoretic mobility shift assay showed a supershift of the −61 to −42-bp probe with an anti-EGR1 antibody in PTH-treated cells, suggesting that EGR1 binding is relevant for the inhibitory activity of PTH. We conclude that PTH-induced inhibition of NHE3 transcription is related to higher EGR1 expression; to EGR1 binding to the proximal and core promoters; and to PKA and JAK/STAT pathway activation. This mechanism might be responsible, at least in part, for lower NHE3 expression and sodium reabsorption in renal proximal tubules in the presence of high PTH levels. - Highlights: • PTH regulation of Nhe3 promoter depends on EGR1 binding. • EGR1, PKA and JAK/STAT are involved in PTH inhibition of the Nhe3 promoter. • PTH alters expression of EGR1 and Sp3. • PTH inhibits the Nhe3 promoter by regulating PKA and JAK/STAT signaling.« less

Endogenous PKI gamma limits the duration of the anti-apoptotic effects of PTH and beta-adrenergic agonists in osteoblasts.

PubMed

Chen, Xin; Song, In-Hwan; Dennis, James E; Greenfield, Edward M

2007-05-01

PKI gamma knockdown substantially extended the anti-apoptotic effects of PTH and beta-adrenergic agonists, whereas PKI gamma overexpression decreased these effects. Therefore, inhibition of PKI gamma activity may provide a useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. PTH has both catabolic and anabolic effects on bone, which are primarily caused by cAMP/protein kinase A (PKA) signaling and regulation of gene expression. We previously showed that protein kinase inhibitor-gamma (PKI gamma) is required for efficient termination of cAMP/PKA signaling and gene expression after stimulation with PTH or beta-adrenergic agonists. Inhibition of osteoblast apoptosis is thought to be an important, but transient, mechanism partly responsible for the anabolic effects of intermittent PTH. Therefore, we hypothesized that endogenous PKI gamma also terminates the anti-apoptotic effect of PTH. PKI gamma knockdown by antisense transfection or siRNA was used to examine the ability of endogenous PKI gamma to modulate the anti-apoptotic effects of PTH and beta-adrenergic agonists in ROS 17/2.8 cells. Knockdown of PKI gamma substantially extended the anti-apoptotic effects of PTH, whether apoptosis was induced by etoposide or dexamethasone. In contrast, overexpression of PKI gamma decreased the anti-apoptotic effect of PTH pretreatment. This study is also the first demonstration that beta-adrenergic agonists mimic the anti-apoptotic effects of PTH in osteoblasts. Moreover, PKI gamma knockdown also substantially extended this anti-apoptotic effect of beta-adrenergic agonists. Taken together, these results show that endogenous PKI gamma limits the duration of the anti-apoptotic effects of cAMP/PKA signaling in osteoblasts. Because significant individual variability exists in the anabolic responses to PTH therapy in current clinical treatment of osteoporosis, inhibition of PKI gamma activity may provide a useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. However, the potential use of such a co-therapy would depend on it not adversely affecting bone formation or other organ systems.

Direct suppressive effect of acute metabolic and respiratory alkalosis on parathyroid hormone secretion in the dog.

PubMed

Lopez, Ignacio; Rodriguez, Mariano; Felsenfeld, Arnold J; Estepa, Jose Carlos; Aguilera-Tejero, Escolastico

2003-08-01

Acute alkalosis may directly affect PTH secretion. The effect of acute metabolic and respiratory alkalosis was studied in 20 dogs. PTH values were lower in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml). Acute alkalosis is an independent factor that decreases PTH values during normocalcemia and delays the PTH response to hypocalcemia. We recently showed that acute metabolic and respiratory acidosis stimulated PTH secretion. This study was designed to evaluate whether acute metabolic and respiratory alkalosis suppressed parathyroid hormone (PTH) secretion. Three groups of 10 dogs were studied: control, acute metabolic alkalosis, and acute respiratory alkalosis. Metabolic alkalosis was induced with an infusion of sodium bicarbonate and respiratory alkalosis by hyperventilation. Calcium chloride was infused to prevent alkalosis-induced hypocalcemia during the first 60 minutes. During the next 30 minutes, disodium EDTA was infused to induce hypocalcemia and to evaluate the PTH response to hypocalcemia. Because the infusion of sodium bicarbonate resulted in hypernatremia, the effect of hypernatremia was studied in an additional group that received hypertonic saline. After 60 minutes of a normocalcemic clamp, PTH values were less (p < 0.05) in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml); the respective blood pH values were 7.61 +/- 0.01, 7.59 +/- 0.02, and 7.39 +/- 0.02. The maximal PTH response to hypocalcemia was similar among the three groups. However, the maximal PTH response was observed after a decrease in ionized calcium of 0.20 mM in the control group but not until a decrease of 0.40 mM in the metabolic and respiratory alkalosis groups. In contrast to the metabolic alkalosis group, hypernatremia (157 +/- 2 mEq/liter) in the hypertonic saline group was associated with an increased PTH value (46 +/- 4 pg/ml). Finally, the half-life of intact PTH was not different among the control and two alkalosis groups. Acute metabolic and respiratory alkalosis markedly decreased PTH values during normocalcemia and delayed the PTH response to hypocalcemia. Whether acute metabolic and respiratory alkalosis affect PTH and calcium metabolism in such settings as the postprandial alkaline tide (metabolic alkalosis) and acute sepsis (respiratory alkalosis) deserves to be evaluated in future studies.

Biased random walks on Kleinberg's spatial networks

NASA Astrophysics Data System (ADS)

Pan, Gui-Jun; Niu, Rui-Wu

2016-12-01

We investigate the problem of the particle or message that travels as a biased random walk toward a target node in Kleinberg's spatial network which is built from a d-dimensional (d = 2) regular lattice improved by adding long-range shortcuts with probability P(rij) ∼rij-α, where rij is the lattice distance between sites i and j, and α is a variable exponent. Bias is represented as a probability p of the packet to travel at every hop toward the node which has the smallest Manhattan distance to the target node. We study the mean first passage time (MFPT) for different exponent α and the scaling of the MFPT with the size of the network L. We find that there exists a threshold probability pth ≈ 0.5, for p ≥pth the optimal transportation condition is obtained with an optimal transport exponent αop = d, while for 0 < p pth, and increases with L less than a power law and get close to logarithmical law for 0 < p

Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone

NASA Technical Reports Server (NTRS)

Bikle, Daniel D.; Sakata, Takeshi; Leary, Colin; Elalieh, Hashem; Ginzinger, David; Rosen, Clifford J.; Beamer, Wesley; Majumdar, Sharmila; Halloran, Bernard P.

2002-01-01

Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.

PTH promotes allograft integration in a calvarial bone defect.

PubMed

Sheyn, Dmitriy; Cohn Yakubovich, Doron; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M; Gazit, Dan; Gazit, Zulma

2013-12-02

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and microcomputed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in allograft + PTH treated mice comparing to allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the allograft + PTH treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment.

Parathyroid hormone measurement in prediction of hypocalcaemia following thyroidectomy.

PubMed

Mehrvarz, Shaban; Mohebbi, Hassan Ali; Kalantar Motamedi, Mohammad Hosein; Khatami, Seyed Masoud; Rezaie, Ramzanali; Rasouli, Hamid Reza

2014-02-01

To determine the risk of postthyroidectomy hypocalcaemia by measuring parathyroid hormone (PTH) level after thyroidectomy. Cross-sectional study. Baqiyatallah Hospital, Tehran, Iran, from March 2008 to July 2010. All included patients were referred for total or near bilateral thyroidectomy. Serum Calcium (Ca) and PTH levels were measured before and 24 hours after surgery. In low Ca cases or development of hypocalcaemia symptoms, daily monitoring of Ca levels were continued. Data were analyzed using SPSS 20 software (SPSS, Chicago, IL, USA). A p-value less than 0.05 were considered statistically significant. To assess the standard value of useful predictive factors, we used receiver operating characteristic (ROC) curves. Of total 99 patients who underwent bilateral thyroidectomy, 47 patients (47.5%) developed hypocalcaemia, out of them, 12 (25.5%) became symptomatic while 2 patients developed permanent hypoparathyroidism. After surgery, mean rank of PTH level within the normocalcaemic and hypocalcaemic patients was 55.34 and 44.1 respectively, p=0.052. Twenty four hours after surgery, 62% drop in PTH was associated with 83.3% of symptomatic hypocalcaemic. For diagnosis of symptomatic hypocalcaemia, 62% PTH drop had sensitivity and specificity were 83.3% and 90.80%. The area under the ROC curve for the PTH postoperative and PTH drop for diagnostic symptomatic hypocalcaemia were 0.835 and 0.873 respectively. Measuring PTH levels after 24 hours postthyroidectomy is not reliable factor for predicting hypocalcaemia itself. For predicting the risk of hypocalcaemia after thyroidectomy it is more reliable to measure the serum PTH level before and after operation and compare the reduction level of percentage of PTH drop for predicting the risk of hypocalcaemia.

Parathyroid hormone induces c-fos and c-jun messenger RNA in rat osteoblastic cells

NASA Technical Reports Server (NTRS)

Clohisy, J. C.; Scott, D. K.; Brakenhoff, K. D.; Quinn, C. O.; Partridge, N. C.

1992-01-01

PTH is a potent regulator of osteoblast gene expression, yet the nuclear events that mediate PTH action are poorly understood. We were interested in identifying immediate early genes which may regulate PTH-altered gene expression in the osteoblast. Therefore, we examined the effects of PTH on c-fos and c-jun gene expression in a rat osteoblastic cell line (UMR 106-01). Under control conditions, c-fos and c-jun mRNAs were present at low basal levels. After PTH treatment, c-fos mRNA abundance dramatically increased, with a maximal and transient response at 30 min. PTH also stimulated an increase in c-jun mRNA, but in a biphasic manner, with maximal levels at 30 min and 2 h. These responses were dose dependent, not altered by cotreatment with the protein synthesis inhibitor cycloheximide, and preceded PTH-induced expression of matrix metallo-proteinase-1 mRNA. Nuclear run-on assays demonstrated an increased rate of c-fos and c-jun transcription after PTH exposure. To determine the signal transduction pathways involved, second messenger analogs were tested for their ability to mimic the effects of PTH. 8-Bromo-cAMP and phorbol 12-myristate 13-acetate (PMA) caused increases in the abundance of c-fos and c-jun transcripts. Ionomycin had no effect on the expression of these genes. Pretreatment of the cells with PMA resulted in a decrease in basal c-jun expression, but did not alter the PTH-mediated increase in c-fos, c-jun, or matrix metalloproteinase-1 mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS).

[Usefullness of intraoperatory parathyroid hormone measurement in surgical management of primary hyperparathyroidism due to a parathyroid adenoma].

PubMed

Obiols, Gabriel; Catalán, Roberto; Alasà, Cristian; Baena, Juan Antonio; Fort, José Manuel; Gémar, Enrique; Mesa, Jordi

2003-09-13

Surgical neck exploration of the 4 parathyroid glands is quite an aggressive procedure for most patients with primary hyperparathyroidism (PHPT) due to a parathyroid adenoma. Intraoperatory measurement of parathyroid hormone (PTH) seems to be a useful tool for the management of these cases, allowing the use of minimally invasive surgical techniques with a lower morbidity. Our aims was to assess the usefulness of PTH intraoperatory measurement for the surgical management of PHPT. We studied 27 consecutive patients, diagnosed with PHPT secondary to parathyroid adenoma. Localization studies included neck ultrasonography and Tc-MIBI scintigraphy. PTH at the stage of anesthesia induction as well as 5 and 10 minutes after the removal of the adenoma was determined. A PTH decrement greater than 50% at 10 minutes was considered as curative. PTH was measured by an immunoluminometric method (Advantage, Nichols). In all cases, calcium levels were normal 24 hours after the operation, and therefore all them were considered as cured. PTH levels decreased more than 50% in all patients. In one case, PTH levels remained high after the exeresis of a preoperatively localized lesion. The pathologic study confirmed that it was a normal parathyroid gland. We then continued the surgical exploration which eventually allowed us to find a contralateral adenoma. A further PTH measurement showed an over 50% decrease. Therefore, PTH was predictive of surgical success in all 28 measurements. Intraoperatory determination of PTH is useful for the surgical management of PHPT and it could allow the use of minimally invasive surgical techniques.

Effectiveness of an i-PTH Measurement in Predicting Post Thyroidectomy Hypocalcemia: Prospective Controlled Study

PubMed Central

Kim, Jin Pyeong; Park, Jung Je; Son, Hee Young; Kim, Rock Bum; Kim, Ho Youp

2013-01-01

Purpose Hypocalcemia is the most common complication after total thyroidectomy. The purpose of this study was to determine whether measurement of intact parathyroid hormone (i-PTH) level in thyroidectomy patients could predict hypocalcemia. Materials and Methods We performed a prospective study of patients undergoing total thyroidectomy. Serum concentration of i-PTH, total calcium (Ca), ionized calcium (Ca2+), phosphate (P), magnesium (Mg), and albumin were measured preoperatively and at 0 hour, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours postoperatively. Results 108 patients were recruited to the study. A total of 50 patients (46%) experienced hypocalcemia. The serum i-PTH concentration was linearly related to the time of measurement, while concentrations of P, Mg, albumin, Ca, and Ca2+ were not. We compared odds ratios, and found that the concentration of i-PTH at 6 hours post operation was the most closely related to the occurrence of hypocalcemic symptom. On ROC analysis using i-PTH level at 6 hours, an i-PTH level of 10.6 mg/dL was found to maximize both sensitivity and specificity at the same time point. Conclusion We found that i-PTH was a predictor of hypocalcemia, and that the earliest predictor of hypocalcemic symptoms was an i-PTH concentration lower than 10.6 mg/dL obtained 6 hours after total thyroidectomy. PMID:23549808

Postoperative PTH measurement as a predictor of hypocalcaemia after thyroidectomy.

PubMed

Proczko-Markuszewska, M; Kobiela, J; Stefaniak, T; Lachiński, A J; Sledziński, Z

2010-01-01

Hypocalcaemia after thyroidectomy is the most common postoperative complication, with a reported incidence from 0.5% to even 50% of the operated patients. Hypoparathyroidism could be a result of careless or inadequate preparation during the surgical procedure. There is a variety of proposed options for the prediction of the incidence of hypocalcaemia. The most effective of them are the peri-operative and intra-operative measurements of the parathyroid hormone (PTH) level. A prospective study was performed on 100 patients who underwent total thyroidectomy from January 2007 to June 2008. The total calcium level and intact human PTH (iPTH) levels were measured 24 hours before as well as 1 hour and 24 hours after the surgery. The goal of the study was to assess the potential correlation between the iPTH levels after the operation and the development of hypocalcaemia. The possible prediction value of postoperative iPTH levels was to be assessed. We have presented a significant correlation between early iPTH measurement and the risk of hypocalcaemia. Moreover, a significant correlation between the iPTH level one hour after operation with the calcium level 24 hours after the operation was demonstrated. Early postoperative assessment of iPTH levels can be used to identify the group of patients at risk of hypocalcaemia after thyroidectomy. Pre-emptive calcium supplementation can lead to the avoidance of complications causing prolonged hospital stay and most importantly to prevent severe hypocalcaemia.

Persistent disorders of mineral metabolism after one year of kidney transplantation.

PubMed

Gomes, Larissa Kruger; Custódio, Melani Ribeiro; Contieri, Fabiana Loss de Carvalho; Riella, Miguel C; Nascimento, Marcelo Mazza do

2016-01-01

The persistence of mineral metabolism disorders after renal transplant (RT) appears to possess a negative impact over graft and patient's survival. To evaluate the parameters of mineral metabolism and the persistence of hyperparathyroidism (HPT) in transplanted patients for a 12-month period after the procedure. Retrospective analysis of 41 transplants (18 women- 44%, mean age of 39 ± 15 years) performed in a University Hospital, evaluating changes of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) and the prevalence of persistent HPT. The patients were divided into two groups accordingly to PTH levels prior to Tx: Group 1 with PTH ≤ 300 pg/mL (n = 21) and Group 2 with PTH > 300 pg/mL (n = 20). The persistency of HPT after transplant was defined as PTH ≥ 100 pg/mL. The evolution of biochemical parameters and the persistency of HPT were analyzed in each group after 1 year of transplant. After a one-year of follow up, 5% of the patients presented hypophosphatemia (p < 2.7 mg/dL), 24% hypercalcemia (Ca > 10.2 mg/dL) and 48% persistency of HPT (PTH ≥ 100 pg/mL). There was a positive correlation between the PTH pre and post Tx (r = 0.42/p = 0.006) and a negative correlation between PTH and Ca pre-Tx (r = -0.45/p = 0.002). However, there was no significant difference among groups 1 and 2 regarding PTH levels pre and post Tx. The findings in this article suggest that mineral metabolism alterations and the persistency of HPT may occur after one year of renal Tx, mainly in patients which present high PTH levels prior toTx. A persistência de distúrbios do metabolismo mineral ósseo após o transplante renal (Tx) parece possuir um impacto negativo sobre a sobrevida do enxerto e do paciente. avaliar os parâmetros do metabolismo mineral e a persistência de hiperparatiroidismo (pHPT) 12 meses após o Tx. Análise retrospectiva de 41 transplantes (18 mulheres- 44%, idade de 39 ± 15 anos) realizados em um Hospital Universitário, avaliando cálcio (Ca), fósforo (P), hormônio da paratireóide (PTH) e a prevalência de pHPT. Pacientes foram divididos em dois grupos de acordo com os níveis de PTH pré Tx: Grupo 1: PTH ≤ 300 pg/ml (n = 21) e Grupo 2: PTH > 300 pg/ml (n = 20). pHPT foi definida como PTH ≥ 100pg/mL após o Tx. A evolução dos parâmetros bioquímicos e a pHPT foram analisadas após 1 ano de Tx. Resultados: após um ano, 5% dos pacientes apresentaram hipofosfatemia (p < 2,7mg/dL), 24% hipercalcemia (Ca > 10,2 mg/dL) e 48% persistência de HPT (PTH ≥ 100 pg/mL ). Houve correlação positiva entre PTH pré e pós Tx (r = 0,42/p = 0,006) e correlação negativa entre PTH e Ca pré-Tx (r = -0,45/p = 0,002). Entretanto, não houve diferença significativa entre os grupos 1 e 2 em relação aos níveis de PTH pré e pós-Tx. Os resultados sugerem que alterações do metabolismo mineral e a pHPT podem ocorrer após um ano do Tx, principalmente em pacientes com níveis elevados de PTH pré-Tx.

Identification of putative TAL effector targets of the citrus canker pathogens shows functional convergence underlying disease development and defense response

PubMed Central

2014-01-01

Background Transcriptional activator-like (TAL) effectors, formerly known as the AvrBs3/PthA protein family, are DNA-binding effectors broadly found in Xanthomonas spp. that transactivate host genes upon injection via the bacterial type three-secretion system. Biologically relevant targets of TAL effectors, i.e. host genes whose induction is vital to establish a compatible interaction, have been reported for xanthomonads that colonize rice and pepper; however, citrus genes modulated by the TAL effectors PthA“s” and PthC“s” of the citrus canker bacteria Xanthomonas citri (Xc) and Xanthomonas aurantifolii pathotype C (XaC), respectively, are poorly characterized. Of particular interest, XaC causes canker disease in its host lemon (Citrus aurantifolia), but triggers a defense response in sweet orange. Results Based on, 1) the TAL effector-DNA binding code, 2) gene expression data of Xc and XaC-infiltrated sweet orange leaves, and 3) citrus hypocotyls transformed with PthA2, PthA4 or PthC1, we have identified a collection of Citrus sinensis genes potentially targeted by Xc and XaC TAL effectors. Our results suggest that similar with other strains of Xanthomonas TAL effectors, PthA2 and PthA4, and PthC1 to some extent, functionally converge. In particular, towards induction of genes involved in the auxin and gibberellin synthesis and response, cell division, and defense response. We also present evidence indicating that the TAL effectors act as transcriptional repressors and that the best scoring predicted DNA targets of PthA“s” and PthC“s” in citrus promoters predominantly overlap with or localize near to TATA boxes of core promoters, supporting the idea that TAL effectors interact with the host basal transcriptional machinery to recruit the RNA pol II and start transcription. Conclusions The identification of PthA“s” and PthC“s” targets, such as the LOB (LATERAL ORGAN BOUNDARY) and CCNBS genes that we report here, is key for the understanding of the canker symptoms development during host susceptibility, or the defenses of sweet orange against the canker bacteria. We have narrowed down candidate targets to a few, which pointed out the host metabolic pathways explored by the pathogens. PMID:24564253

Identification of putative TAL effector targets of the citrus canker pathogens shows functional convergence underlying disease development and defense response.

PubMed

Pereira, Andre L A; Carazzolle, Marcelo F; Abe, Valeria Y; de Oliveira, Maria L P; Domingues, Mariane N; Silva, Jaqueline C; Cernadas, Raul A; Benedetti, Celso E

2014-02-25

Transcriptional activator-like (TAL) effectors, formerly known as the AvrBs3/PthA protein family, are DNA-binding effectors broadly found in Xanthomonas spp. that transactivate host genes upon injection via the bacterial type three-secretion system. Biologically relevant targets of TAL effectors, i.e. host genes whose induction is vital to establish a compatible interaction, have been reported for xanthomonads that colonize rice and pepper; however, citrus genes modulated by the TAL effectors PthA"s" and PthC"s" of the citrus canker bacteria Xanthomonas citri (Xc) and Xanthomonas aurantifolii pathotype C (XaC), respectively, are poorly characterized. Of particular interest, XaC causes canker disease in its host lemon (Citrus aurantifolia), but triggers a defense response in sweet orange. Based on, 1) the TAL effector-DNA binding code, 2) gene expression data of Xc and XaC-infiltrated sweet orange leaves, and 3) citrus hypocotyls transformed with PthA2, PthA4 or PthC1, we have identified a collection of Citrus sinensis genes potentially targeted by Xc and XaC TAL effectors. Our results suggest that similar with other strains of Xanthomonas TAL effectors, PthA2 and PthA4, and PthC1 to some extent, functionally converge. In particular, towards induction of genes involved in the auxin and gibberellin synthesis and response, cell division, and defense response. We also present evidence indicating that the TAL effectors act as transcriptional repressors and that the best scoring predicted DNA targets of PthA"s" and PthC"s" in citrus promoters predominantly overlap with or localize near to TATA boxes of core promoters, supporting the idea that TAL effectors interact with the host basal transcriptional machinery to recruit the RNA pol II and start transcription. The identification of PthA"s" and PthC"s" targets, such as the LOB (lateral organ boundary) and CCNBS genes that we report here, is key for the understanding of the canker symptoms development during host susceptibility, or the defenses of sweet orange against the canker bacteria. We have narrowed down candidate targets to a few, which pointed out the host metabolic pathways explored by the pathogens.

Effect of chronic ethanol consumption on the response of parathyroid hormone to hypocalcemia in the pregnant rat.

PubMed

Duggal, Shalu; Simpson, Mary Elizabeth; Keiver, Kathy

2007-01-01

Chronic alcohol (ethanol) consumption during pregnancy results in maternal/fetal hypocalcemia, which may underlie some of ethanol's adverse effects on maternal and fetal bone, and fetal/neonatal health. Ethanol appears to alter the relationship between parathyroid hormone (PTH) and blood calcium (Ca) level, and PTH does not increase in response to ethanol-induced hypocalcemia. However, it is not known whether ethanol actually prevents PTH from responding, or whether the ability to regulate blood Ca is intact, but ethanol lowers the level of Ca maintained. The objective of this study was to determine whether chronic ethanol consumption impairs the ability of the pregnant female to increase PTH in response to acute hypocalcemia. Rats were fed isocaloric diets with ethanol (36% ethanol-derived calories, E group) or without ethanol [pair-fed (PF) and control (C) groups], before and throughout 21 days of gestation. On day 21 gestation, rats received an intraperitoneal injection of ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (300 or 500 mumol/kg body weight) or saline (saline group), or no injection (baseline group). Blood was collected from the baseline group, and at 30 or 60 minutes postinjection (saline and EGTA groups), and analyzed for ionized Ca (iCa), pH, and PTH. Consistent with previous studies, ethanol consumption decreased blood iCa levels at baseline, but PTH levels did not differ among groups. Administration of EGTA significantly decreased blood iCa levels by 30 minutes, but ethanol did not prevent PTH from increasing in response to the hypocalcemia. In all diet groups, PTH levels were significantly increased by 30 minutes. Ethanol did, however, appear to decrease the maximum PTH level achievable in blood. These data suggest that chronic ethanol consumption does not impair the ability of the pregnant rat to raise serum PTH levels in response to acute hypocalcemia, but ethanol's effect on maximal PTH secretion could impair the ability of the pregnant female to sustain high PTH levels in response to chronic hypocalcemia.

Aging Periosteal Progenitor Cells have Reduced Regenerative Responsiveness to Bone Injury and to the Anabolic Actions of PTH 1-34 Treatment

PubMed Central

Yukata, Kiminori; Xie, Chao; Li, Tian-Fang; Takahata, Masahiko; Hoak, Donna; Kondabolu, Sirish; Zhang, Xinping; Awad, Hani A.; Schwarz, Edward M.; Beck, Christopher A.; Jonason, Jennifer H.; O’Keefe, Regis J.

2014-01-01

A stabilized tibia fracture model was used in young (8-week old) and aged (1-year old) mice to define the relative bone regenerative potential and the relative responsiveness of the periosteal progenitor population with aging and PTH 1-34 (PTH) systemic therapy. Bone regeneration was assessed through gene expressions, radiographic imaging, histology/histomorphometry, and biomechanical testing. Radiographs and microCT showed increased calcified callus tissue and enhanced bone healing in young compared to aged mice. A key mechanism involved reduced proliferation, expansion, and differentiation of periosteal progenitor cell populations in aged mice. The experiments showed that PTH increased calcified callus tissue and torsional strength with a greater response in young mice. Histology and quantitative histomorphometry confirmed that PTH increased callus tissue area due primarily to an increase in bone formation, since minimal changes in cartilage and mesenchyme tissue area occurred. Periosteum examined at 3, 5, and 7 days showed that PTH increased cyclin D1 expression, the total number of cells in the periosteum, and width of the periosteal regenerative tissue. Gene expression showed that aging delayed differentiation of both bone and cartilage tissues during fracture healing. PTH resulted in sustained Col10a1 expression consistent with delayed chondrocyte maturation, but otherwise minimally altered cartilage gene expression. In contrast, PTH 1-34 stimulated expression of Runx2 and Osterix, but resulted in reduced Osteocalcin. β-catenin staining was present in mesenchymal chondroprogenitors and chondrocytes in early fracture healing, but was most intense in osteoblastic cells at later times. PTH increased active β-catenin staining in the osteoblast populations of both young and aged mice, but had a lesser effect in cartilage. Altogether the findings show that reduced fracture healing in aging involves decreased proliferation and differentiation of stem cells lining the bone surface. While PTH 1-34 enhances the proliferation and expansion of the periosteal stem cell population and accelerates bone formation and fracture healing, the effects are proportionately reduced in aged mice compared to young mice. β-catenin is induced by PTH in early and late fracture healing and is a potential target of PTH 1-34 effects. PMID:24530870

PTH (1-34) affects bone turnover governed by osteocytes exposed to fluoride.

PubMed

Yu, Xiuhua; Yu, Haolan; Jiang, Ningning; Zhang, Xiuyun; Zhang, Mengmeng; Xu, Hui

2018-05-15

Exposure to fluoride from environmental sources remains an overlooked, but serious public health risk. In this study, we looked into the role osteocytes play on the mechanism underlying fluoride induced osteopathology. We analyzed bone formation and resorption related genes generated by osteocytes that were exposed to varied doses of fluoride with and without PTH in vitro. Correspondingly, osteogenesis and osteoclastogenesis related genes were also investigated in rats exposed to fluoride for 8 weeks, and the PTH(1-34)was applied at the last 3 weeks to observe its role in regulating bone turnover upon fluoride treatment. The data in vitro indicated that fluoride treatment inhibited Sost expression of mRNA and protein and stimulated RANKL mRNA protein expression as well as the RANKL/OPG ratio in the primary osteocytes. Single PTH treatment played the similar role on expression of these genes and proteins. The PTH combined administration enhanced the action of fluoride treatment on RNAKL/OPG and SOST/Sclerostin. The up-regulation of RANKL and decreasing of Sost induced by fluoride and/or PTH treatment was validated in vivo and suggests that osteocytes are a major source of RANKL and Sost, both of which play essential roles in fluoride affecting osteogenesis and osteoclastogenesis. Expression of Wnt/β-catenin was up-regulated in both in vitro osteocytes treated with high dose of fluoride and bone tissue of rats in the presence of fluoride and PTH. In vivo, fluoride and single PTH stimulated bone turnover respectively, furthermore, PTH combined with low dose of fluoride treatment reinforced the osteogenesis and osteoclastogenesis genes expression, however, co-treatment of PTH reversed the effect of high dose of fluoride on osteogenesis and osteoclastogenensis related factors. In conclusion, this study demonstrated that osteocytes play a key role in fluoride activated bone turnover, and PTH participates in the process of fluoride modulating SOST/Sclerostin and RANKL expression. Copyright © 2018 Elsevier B.V. All rights reserved.

Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes.

PubMed

Gooi, J H; Pompolo, S; Karsdal, M A; Kulkarni, N H; Kalajzic, I; McAhren, S H M; Han, B; Onyia, J E; Ho, P W M; Gillespie, M T; Walsh, N C; Chia, L Y; Quinn, J M W; Martin, T J; Sims, N A

2010-06-01

The therapeutic goal of increasing bone mass by co-treatment of parathyroid hormone (PTH) and an osteoclast inhibitor has been complicated by the undefined contribution of osteoclasts to the anabolic activity of PTH. To determine whether active osteoclasts are required at the time of PTH administration, we administered a low dose of the transient osteoclast inhibitor salmon calcitonin (sCT) to young rats receiving an anabolic PTH regimen. Co-administration of sCT significantly blunted the anabolic effect of PTH as measured by peripheral quantitative computer tomography (pQCT) and histomorphometry in the femur and tibia, respectively. To determine gene targets of sCT, we carried out quantitative real time PCR and microarray analysis of metaphyseal samples 1.5, 4 and 6.5h after administration of a single injection of PTH, sCT or PTH+sCT. Known targets of PTH action, IL-6, ephrinB2 and RANKL, were not modified by co-administration with sCT. Surprisingly, at all time points, we noted a significant upregulation of sclerostin mRNA by sCT treatment, as well as down-regulation of two other osteocyte gene products, MEPE and DMP1. Immunohistochemistry confirmed that sCT administration increased the percentage of osteocytes expressing sclerostin, suggesting a mechanism by which sCT reduced the anabolic effect of PTH. Neither mRNA for CT receptor (Calcr) nor labeled CT binding could be detected in sclerostin-enriched cells differentiated from primary calvarial osteoblasts. In contrast, osteocytes freshly isolated from calvariae expressed a high level of Calcr mRNA. Furthermore immunohistochemistry revealed co-localization of CT receptor (CTR) and sclerostin in some osteocytes in calvarial sections. Taken together these data indicate that co-treatment with sCT can blunt the anabolic effect of PTH and this may involve direct stimulation of sclerostin production by osteocytes. These data directly implicate calcitonin as a negative regulator of bone formation through a previously unsuspected mechanism. Copyright 2010 Elsevier Inc. All rights reserved.

Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo

PubMed Central

Quinn, Stephen J.; Thomsen, Alex R. B.; Pang, Jian L.; Kantham, Lakshmi; Bräuner-Osborne, Hans; Pollak, Martin; Goltzman, David

2013-01-01

Calcium and phosphorus homeostasis are highly interrelated and share common regulatory hormones, including FGF23. However, little is known about calcium's role in the regulation of FGF23. We sought to investigate the regulatory roles of calcium and phosphorus in FGF23 production using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR; PTH-CaSR DKO). In wild-type, PTH KO, and PTH-CaSR DKO mice, elevation of either serum calcium or phosphorus by intraperitoneal injection increased serum FGF23 levels. In PTH KO and PTH-CaSR DKO mice, however, increases in serum phosphorus by dietary manipulation were accompanied by severe hypocalcemia, which appeared to blunt stimulation of FGF23 release. Increases in dietary phosphorus in PTH-CaSR DKO mice markedly decreased serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] despite no change in FGF23, suggesting direct regulation of 1,25(OH)2D3 synthesis by serum phosphorus. Calcium-mediated increases in serum FGF23 required a threshold level of serum phosphorus of about 5 mg/dl. Analogously, phosphorus-elicited increases in FGF23 were markedly blunted if serum calcium was less than 8 mg/dl. The best correlation between calcium and phosphorus and serum FGF23 was found between FGF23 and the calcium × phosphorus product. Since calcium stimulated FGF23 production in the PTH-CaSR DKO mice, this effect cannot be mediated by the full-length CaSR. Thus the regulation of FGF23 by both calcium and phosphorus appears to be fundamentally important in coordinating the serum levels of both mineral ions and ensuring that the calcium × phosphorus product remains within a physiological range. PMID:23233539

[Role of parathyroid hormone measurement in prediction for symptomatic hypocalcaemia after total thyroidectomy].

PubMed

An, Chang-ming; Tang, Ping-zhang; Xu, Zhen-gang; Zhang, Bin; Zhang, Zong-min; Yan, Dan-gui; Li, Zheng-jiang

2010-03-01

To evaluate the role of parathyroid hormone (PTH) and serum calcium in prediction for hypocalcaemia after total thyroidectomy. One hundred and sixty-five patients undergoing total or complete total thyroidectomy were reviewed retrospectively. The indications included bilateral carcinoma, undifferential carcinoma, surroundings invasion, distant metastasis and huge benign lesions. Preoperative and postoperative PTH, calcium concentrations and their decline levels were compared between Jan. 2005 and May 2009. The role of PTH value and decline level predicting for symptomatic hypocalcaemia were analyzed by receiver operator characteristics (ROC) curve. After total thyroidectomy, 85 patients (51.5%) developed hypocalcemia. Symptoms were reported by 36 patients (21.8%). The mean concentration of PTH for normocalcaemia (80 cases), asymptomatic hypocalcaemia (49 cases) and symptomatic patients (36 cases) were 31.0 ng/L, 19.6 ng/L and 11.9 ng/L, respectively. The mean decline level for the three groups were 28.6%, 52.6% and 78.0%, respectively. PTH value and its decline level had a poor predicting value for symptomatic hypocalcaemia and high negative predicting value for asymptomatic patients. The serum calcium concentration more than 2.0 mmol/L, PTH level higher than 15 ng/L and PTH decline less than 50% had the good negative predicting value of 97.6%, 90.3% and 96.5%, respectively. Postoperative PTH and its decline level were significantly correlated with postoperative serum calcium concentration but had a low accuracy for predicting symptomatic hypocalcaemia. The serum calcium concentration more than 2.0 mmol/L, PTH level higher than 15 ng/L and PTH decline less than 50% had the good predicting value for asymptomatic patients. Calcium should be routinely supplemented in the first 24 h after total thyroidectomy to reduce the rate of hypocalcemia and the severity of hypocalcemia symptoms.

Pregnancy-associated plasma protein-A modulates the anabolic effects of parathyroid hormone in mouse bone.

PubMed

Clifton, Kari B; Conover, Cheryl A

2015-12-01

Intermittent parathyroid hormone (PTH) is a potent anabolic therapy for bone, and several studies have implicated local insulin-like growth factor (IGF) signaling in mediating this effect. The IGF system is complex and includes ligands and receptors, as well as IGF binding proteins (IGFBPs) and IGFBP proteases. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloprotease expressed by osteoblasts in vitro that has been shown to enhance local IGF action through cleavage of inhibitory IGFBP-4. This study was set up to test two specific hypotheses: 1) Intermittent PTH treatment increases the expression of IGF-I, IGFBP-4 and PAPP-A in bone in vivo, thereby increasing local IGF activity. 2) In the absence of PAPP-A, local IGF activity and the anabolic effects of PTH on bone are reduced. Wild-type (WT) and PAPP-A knock-out (KO) mice were treated with 80 μg/kg human PTH 1-34 or vehicle by subcutaneous injection five days per week for six weeks. IGF-I, IGFBP-4 and PAPP-A mRNA expression in bone were significantly increased in response to PTH treatment. PTH treatment of WT mice, but not PAPP-A KO mice, significantly increased expression of an IGF-responsive gene. Bone mineral density (BMD), as measured by DEXA, was significantly decreased in femurs of PAPP-A KO compared to WT mice with PTH treatment. Volumetric BMD, as measured by pQCT, was significantly decreased in femoral midshaft (primarily cortical bone), but not metaphysis (primarily trabecular bone), of PAPP-A KO compared to WT mice with PTH treatment. These data suggest that stimulation of PAPP-A expression by intermittent PTH treatment contributes to PTH bone anabolism in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

Extracellular nucleotides potentiate the cytosolic Ca2+, but not cyclic adenosine 3', 5'-monophosphate response to parathyroid hormone in rat osteoblastic cells.

PubMed

Kaplan, A D; Reimer, W J; Feldman, R D; Dixon, S J

1995-04-01

Binding to PTH to its cell surface receptor activates both adenylyl cyclase and phospholipase-C, leading to elevation of cytosolic cAMP and free Ca2+. We have shown previously that extracellular nucleotides interact with P2U and P2Y subtypes of purinoceptor on osteoblastic cells, both linked to Ca2+ mobilization. In the present study, we investigated possible interactions between nucleotide and PTH signaling pathways in osteoblastic cells. The cytosolic free Ca2+ concentration ([Ca2+]i) of UMR-106 osteoblastic cells was monitored by fluorescence spectrophotometry. PTH (0.01-1 microM; bovine 1-84 or human 1-34) induced a small transient elevation of [Ca2+]i, lasting less than 1 min. A number of nucleotides, including ATP, UTP, and UDP, induced transient elevation of [Ca2+]i and potentiated the subsequent Ca2+ response to PTH. Of the nucleotides tested, UDP was the most effective at potentiating the PTH-induced Ca2+ transient. Treatment of cells with UDP (100 microM for 2.5 min), but not inorganic phosphate or uridine, reversibly potentiated the Ca2+ response to PTH (0.1 microM) by 11 +/- 2-fold (mean +/- SEM; n = 39). In contrast, UDP did not affect the cAMP response to PTH, indicating a selective action on Ca2+ signaling. Potentiation of the Ca2+ signal was still observed in the absence of extracellular Ca2+, establishing that nucleotides enhance PTH-induced release of Ca2+ from intracellular stores. Studies using selective purinoceptor agonists suggest that potentiation of PTH signaling is mediated by the P2U receptor subtype. In vivo, nucleotides released during trauma or inflammation may modulate PTH-induced Ca2+ signaling in osteoblasts.

Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I

NASA Technical Reports Server (NTRS)

Kostenuik, P. J.; Harris, J.; Halloran, B. P.; Turner, R. T.; Morey-Holton, E. R.; Bikle, D. D.

1999-01-01

Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) cells in vitro. We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced factor. We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone. These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.

Parathyroid hormone induces transcription of collagenase in rat osteoblastic cells by a mechanism using cyclic adenosine 3',5'-monophosphate and requiring protein synthesis

NASA Technical Reports Server (NTRS)

Scott, D. K.; Brakenhoff, K. D.; Clohisy, J. C.; Quinn, C. O.; Partridge, N. C.

1992-01-01

Collagenase is synthesized and secreted by rat osteoblastic cells in response to PTH. We have previously demonstrated that this effect involves a substantial increase in collagenase mRNA via transcription. Northern blots and nuclear run-on assays were performed to further investigate the induction of collagenase by PTH in the rat osteoblastic cell line UMR 106-01. Detectable amounts of collagenase mRNA were not apparent until 2 h of PTH treatment, showed the greatest abundance at 4 h, and declined to approximately 30% of maximum by 8 h. The changes in the rate of transcription of the collagenase gene in response to PTH paralleled and preceded the changes in the steady state mRNA levels. After an initial lag period of about 1 h, collagenase transcription rates increased from very low levels to a maximal response at 2 h, returning to about 50% of maximum by 10 h. The increased transcriptional rate of the collagenase gene was found to be dependent on the concentration of PTH, with a half-maximal response at approximately 7 x 10(-10) M rat PTH-(1-34) and a maximal effect with a dose of 10(-8) M. The PTH-mediated induction of collagenase transcriptional activity was completely abolished by cycloheximide, while transcription of the beta-actin gene was unaffected by the translation inhibitor. These data suggest that a protein factor(s) is required for PTH-mediated transcriptional induction of collagenase. Since PTH increases intracellular levels of several potential second messengers, agents that mimic these substances were employed to determine which signal transduction pathway is predominant in the PTH-mediated stimulation of collagenase transcription.(ABSTRACT TRUNCATED AT 250 WORDS).

[Drugs inhibiting parathyroid hormone (PTH) secretion by control of the calcium receptor (calcimimetics)--effect on the set point of calcium-regulated PTH secretion].

PubMed

Nagano, Nobuo

2005-01-01

Calcimimetics are positive allosteric modulators that activate the parathyroid calcium receptor (CaR) and thereby immediately suppress parathyroid hormone (PTH) secretion. Preclinical studies have demonstrated that calcimimetics inhibit PTH secretion and parathyroid gland hyperplasia and ameliorates bone qualities in rats with chronic renal insufficiency. Clinical trials with cinacalcet hydrochloride, a calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum phosphorus levels in dialysis patients with secondary hyperparathyroidism (2HPT). Thus, calcimimetics have considerable potential as an innovative medical approach to manage 2HPT. In this review, the similarities are extrapolated between the pharmacological effect of calcimimetics on the set point of Ca-regulated PTH secretion and clinical observations in affected subjects with activating CaR mutations.

Long-term effects of intermittent equine parathyroid hormone fragment (ePTH-1-37) administration on bone metabolism in healthy horses.

PubMed

Weisrock, Katharina U; Winkelsett, Sarah; Martin-Rosset, William; Forssmann, Wolf-Georg; Parvizi, Nahid; Coenen, Manfred; Vervuert, Ingrid

2011-11-01

Intermittent administration of parathyroid hormone (PTH) is an anabolic therapy for osteoporotic conditions in humans. This study evaluated the effects of equine PTH fragment (ePTH-1-37) administration on bone metabolism in 12 healthy horses. Six horses each were treated once daily for 120days with subcutaneous injections of 0.5μg/kg ePTH-1-37 or placebo. Blood was collected to determine ionized calcium (Ca(++)), total Ca (Ca(T)), inorganic phosphorus, serum equine osteocalcin (eOC), carboxy-terminal telopeptide of type I collagen (ICTP), bone-specific alkaline phosphatase, and carboxy-terminal cross-linked telopeptide of type I collagen. Bone mineral density (BMD) was determined with dual X-ray absorptiometry of the metacarpus and calcaneus. Significantly higher blood Ca(++) and plasma Ca(T) concentrations were measured 5h after ePTH-1-37 administration compared to placebo. Higher serum eOC concentrations were found for ePTH-1-37 treatment at days 90 (P<0.05) and 120 (P=0.05). Significantly higher serum ICTP levels were observed with ePTH-1-37 treatment at days 60 and 90. For both study groups, BMD increased significantly in the calcaneus. Long-term use of ePTH-1-37 seemed to have no negative effects on bone metabolism in healthy horses. The absence of undesirable side effects is the premise to ensure safety for further clinical investigations in horses with increased bone resorption processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effect of parathyroid hormone on transport by toad and turtle bladder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sabatini, S.; Kurtzman, N.A.

1987-01-01

The authors recently demonstrated that parathyroid hormone (PTH) inhibited both vasopressin- and cyclic AMP-stimulated water transport in the toad bladder. This was associated with an increase in calcium uptake by isolated epithelial cells. They postulated that PTH exerts its action on H/sub 2/O transport by directly stimulating calcium uptake. The current study was designed to compare the effects of PTH and the calcium ionophore, A23187, on H/sub 2/O and Na transport and H..mu.. secretion in toad and turtle bladders. In toad bladder, PTH and A23187 decreased arginine vasopressin (AVP)-stimulated H/sub 2/O flow and short-circuit current (SCC) after 60 min serosalmore » incubation. In turtle bladder A23187 decreased SCC to 79.3 +/- 3.6% of base line (P < 0.05), and significantly decreased RSCC as well. PTH had no effect on SCC or H/sup +/ secretion in turtle bladders. Both PTH and A23187 increased /sup 45/Ca uptake in toad bladder epithelial cells; only A23187 increased /sup 45/Ca uptake in the turtle bladder. The different action of PTH in these two membranes, compared with that of the calcium ionophore, illustrates the selectivity of PTH on membrane transport. PTH increases calcium uptake and decreases transport only in a hormone-sensitive epithelium, whereas the ionophore works in virtually all living membranes. The mode of action of these two agents to increase calcium uptake is, therefore likely different.« less

Parathyroid hormone and bone healing.

PubMed

Ellegaard, M; Jørgensen, N R; Schwarz, P

2010-07-01

Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union. Impaired healing is prevalent in certain risk groups, such as the elderly, osteoporotics, people with malnutrition, and women after menopause. Currently, no pharmacological treatments are available. There is therefore an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis, and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures and could thus be a potentially new treatment option for induction of fracture healing in humans. Furthermore, fractures in animals with experimental conditions of impaired healing such as aging, estrogen withdrawal, and malnutrition can heal in an expedited manner after PTH treatment. Interestingly, fractures occurring at both cancellous and cortical sites can be treated successfully, indicating that both osteoporotic and nonosteoporotic fractures can be the target of PTH-induced healing. Finally, the data suggest that PTH partly prevents the delay in fracture healing caused by aging. Recently, the first randomized, controlled clinical trial investigating the effect of PTH on fracture healing was published, indicating a possible clinical benefit of PTH treatment in inducing fracture healing. The aim of this article is therefore to review the evidence for the potential of PTH in bone healing, including the underlying mechanisms for this, and to provide recommendations for the clinical testing and use of PTH in the treatment of impaired fracture healing in humans.

Dynamic Nanocomposite Self-Deactivating Fabrics for the Individual and Collective Protection

DTIC Science & Technology

2006-11-01

poly-ß-cyclodextrins (PCDs) and poly- trehalose (PTH) as polymeric supports, the incorporated enzymes will be able to repair themselves through a re...POLY- TREHALOSE (PTH) In a similar manner, polymeric trehalose (PTH) was also prepared in a different molar ratio optimized to maximize...MPT), polymeric trehalose (PTH) particles were prepared as a complementary substrate to poly-ß- CD particles in various aspects serving as an

Direct Inhibitory Effect of Hypercalcemia on Renal Actions of Parathyroid Hormone

PubMed Central

Beck, Nama; Singh, Harbans; Reed, Sarah W.; Davis, Bernard B.

1974-01-01

The effects of calcium on the renal actions of parathyroid hormone (PTH) were studied in vivo and in vitro. In parathyroidectomized rats, variable levels of blood calcium concentration were induced by intravenous infusion of calcium. The renal responses to the injected PTH, i.e. phosphate and cyclic AMP excretion, were compared in these animals. After PTH injection, the increases of both phosphate and cyclic AMP excretion were less in the calcium-infused animals than in the control group without calcium infusion. There was an inverse correlation between the renal responses to PTH and plasma calcium concentration of 4.2-13.5 mg/100 ml. But calcium had no effect on phosphate excretion induced by infusion of dibutyryl cyclic AMP. In the in vitro experiments, the increase of cyclic AMP concentration in response to PTH was less in renal cortical slices taken from the calcium-infused animals than in ones from the control group without calcium infusion. Calcium also inhibited the activation of renal cortical adenylate cyclase in response to PTH, but calcium had no effect on phosphodiesterase. The data indicate that calcium directly inhibits renal actions of PTH both in vivo and in vitro. Such inhibitory mechanism is probably at or before the step of PTH-dependent cyclic AMP generation in the kidney. PMID:4359938

The volume dependence of thermal pressure in perovskite and other minerals

NASA Astrophysics Data System (ADS)

Anderson, Orson L.

1999-04-01

This is a review paper concerning the thermal pressure, PTH, of solids and the conditions under which it is independent of volume. When PTH is independent of V, the general equation of state (EoS) reduces from P(V,T)=P 1(V,0)+P TH(V,T) to P(V,T)=P 1(V,0)+P THV 0,T , and thus is separated into two independent mathematical functions. P1( V,0) is the isothermal EoS. Four tests of thermoelastic data are shown to determine the T and V range in which PTH is independent of volume. Eighteen solids are examined. Most of these are minerals, but two metals, three alkali metals and three noble gases are also included. The focus is on three lower mantle minerals, MgSiO 3, MgO, and CaSiO 3. For these three minerals (∂ PTH/∂ V) T vanishes at conditions of the lower mantle, but PTH is a function of V at ambient conditions. However, for most solids, (∂ PTH/∂ V) T becomes zero at high temperature. The behavior of (∂ PTH/∂ V) T is apparently not correlated with such properties as crystal class, chemical composition, bonding type, and anharmonicity. The vanishing of (∂ PTH/∂ V) T is strictly a high temperature property of solids.

Inhibition of parathyroid hormone release by maitotoxin, a calcium channel activator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fitzpatrick, L.A.; Yasumoto, T.; Aurbach, G.D.

1989-01-01

Maitotoxin, a toxin derived from a marine dinoflagellate, is a potent activator of voltage-sensitive calcium channels. To further test the hypothesis that inhibition of PTH secretion by calcium is mediated via a calcium channel we studied the effect of maitotoxin on dispersed bovine parathyroid cells. Maitotoxin inhibited PTH release in a dose-dependent fashion, and inhibition was maximal at 1 ng/ml. Chelation of extracellular calcium by EGTA blocked the inhibition of PTH by maitotoxin. Maitotoxin enhanced the effects of the dihydropyridine calcium channel agonist (+)202-791 and increased the rate of radiocalcium uptake in parathyroid cells. Pertussis toxin, which ADP-ribosylates and inactivatesmore » a guanine nucleotide regulatory protein that interacts with calcium channels in the parathyroid cell, did not affect the inhibition of PTH secretion by maitotoxin. Maitotoxin, by its action on calcium channels allows entry of extracellular calcium and inhibits PTH release. Our results suggest that calcium channels are involved in the release of PTH. Inhibition of PTH release by maitotoxin is not sensitive to pertussis toxin, suggesting that maitotoxin may act distal to the site interacting with a guanine nucleotide regulatory protein, or maitotoxin could interact with other ions or second messengers to inhibit PTH release.« less

Parathyroid hormone related to bone regeneration in grafted and nongrafted tooth extraction sockets in rats.

PubMed

Kuroshima, Shinichiro; Al-Salihi, Zeina; Yamashita, Junro

2013-02-01

The quality and quantity of bone formed in tooth extraction sockets impact implant therapy. Therefore, the establishment of a new approach to enhance bone formation and to minimize bone resorption is important for the success of implant therapy. In this study, we investigated whether intermittent parathyroid hormone (PTH) therapy enhanced bone formation in grafted sockets. Tooth extractions of the maxillary first molars were performed in rats, and the sockets were grafted with xenograft. Intermittent PTH was administered either for 7 days before extractions, for 14 days after extractions, or both. The effect of PTH therapy on bone formation in the grafted sockets was assessed using microcomputed tomography at 14 days after extractions. PTH therapy for 7 days before extractions was not effective to augment bone fill, whereas PTH therapy for 14 days after operation significantly augmented bone formation in the grafted sockets. Intermittent PTH therapy starting right after tooth extractions significantly enhanced bone fill in the grafted sockets, suggesting that PTH therapy can be a strong asset for the success of the ridge preservation procedure.

The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women.

PubMed

Hämmerle, Sibylle P; Mindeholm, Linda; Launonen, Aino; Kiese, Beate; Loeffler, Rolf; Harfst, Evita; Azria, Moise; Arnold, Michel; John, Markus R

2012-04-01

Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide). Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients. In this single-center, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women. 16 subjects were randomized to receive 4 single doses out of 6 different treatments: placebo, teriparatide 20 μg sc, or 1, 2.5, 5 or 10 mg of oral PTH134 formulated with 200 mg 5-CNAC. Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20 μg sc, or 2.5 or 5 mg of oral PTH134 formulated with either 100 or 200 mg 5-CNAC. Doses were given ≥6 days apart. All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5 mg PTH134 (containing 200 mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20 μg (Forsteo®). Mean+/-SD hPTH134 Cmax values were, respectively, 74+/-59, 138+/-101, 717+/-496, and 1624+/-1579 pg/mL for 1, 2.5, 5, and 10 mg doses of this peptide administered with 200 mg 5-CNAC; while mean+/-SD AUC (0-last) values were, respectively, 30+/-40, 62+/-69, 320+/-269, and 627+/-633 h*pg/mL. The corresponding estimates for teriparatide 20 μg sc were 149+/-35 for Cmax and 236+/-58 for AUC (0-last) Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5 mg: three withdrew for symptomatic hypotension (two of whom were in the 200 mg 5-CNAC group), three because of delayed vomiting (two from the 200 mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5 mg/100 mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported. In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5 mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20 μg sc, with a comparable incidence of AEs in healthy postmenopausal women. Copyright © 2012 Elsevier Inc. All rights reserved.

Hormone synthesis and secretion by rat parathyroid glands in tissue culture.

PubMed

Au, W Y; Poland, A P; Stern, P H; Raisz, L G

1970-09-01

Rat parathyroid glands maintained in organ culture secrete biologically active parathyroid hormone (PTH) and synthesize and secrete labeled proteins from (3)H- or (14)C-labeled amino acids added to the medium. The amounts of biological activity and labeled protein in the medium are both inversely proportional to the calcium concentration. Some of the labeled low molecular weight protein was identified as PTH which had been synthesized and secreted in culture by preliminary isolation on Sephadex G-100 columns and further purification using an antibody to bovine PTH which cross-reacted with rat PTH. The cross-reacting antibody inhibited the biological effects of rat PTH and caused hypocalcemia in intact rats. The antibody bound some of the labeled low molecular weight protein of the medium at neutral pH so that it migrated as a large molecular weight complex on Sephadex. Biologically active, labeled PTH was recovered by dissociation of this complex in acid and rechromatography.

Impacts of the N-terminal fragment analog of human parathyroid hormone on structure, composition and biomechanics of bone.

PubMed

Chunxiao, Wang; Yu, Zhang; Wentao, Liu; Jingjing, Liu; Jiahui, Ye; Qingmei, Chen

2012-12-18

Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, and it is a serious threat to human lives. We previously showed that the N-terminal peptide analog of human parathyroid hormone (Pro-Pro-PTH(1-34)) enhanced plasma calcium concentration. In this paper, we study the impact of PTH N-terminal fragment analog on the structure, component, and mechanical properties of the rat bones. Daily subcutaneous injections of Pro-Pro-hPTH (1-34) induces 26.5-32.8% increase in femur bone mineral density (BMD), 23.0-34.2% decrease the marrow cavity or increase in trabecular bone area. The peptide also increases 16.0-59.5%, 28.8-48.2% and 14.0-17.8% of bone components of calcium, phosphorus and collagen, respectively. In terms of mechanic properties, administration of the peptide elevates the bone rigidity by 45.4-76.6%, decreases the flexibility by 23.0-31.6%, and improves modulus of elasticity by 32.8-63.4%. The results suggest that Pro-Pro-hPTH (1-34) has a positive effect on bone growth and strength, and possesses anti-fracture capability, thus a potential candidate for the application for the treatment of osteoporosis. Copyright © 2012 Elsevier B.V. All rights reserved.

Patient handling system for carbon ion beam scanning therapy

PubMed Central

Shirai, Toshiyuki; Takei, Yuka; Furukawa, Takuji; Inaniwa, Taku; Matsuzaki, Yuka; Kumagai, Motoki; Murakami, Takeshi; Noda, Koji

2012-01-01

Our institution established a new treatment facility for carbon ion beam scanning therapy in 2010. The major advantages of scanning beam treatment compared to the passive beam treatment are the following: high dose conformation with less excessive dose to the normal tissues, no bolus compensator and patient collimator/ multi‐leaf collimator, better dose efficiency by reducing the number of scatters. The new facility was designed to solve several problems encountered in the existing facility, at which several thousand patients were treated over more than 15 years. Here, we introduce the patient handling system in the new treatment facility. The new facility incorporates three main systems, a scanning irradiation system (S‐IR), treatment planning system (TPS), and patient handling system (PTH). The PTH covers a wide range of functions including imaging, geometrical/position accuracy including motion management (immobilization, robotic arm treatment bed), layout of the treatment room, treatment workflow, software, and others. The first clinical trials without respiratory gating have been successfully started. The PTH allows a reduction in patient stay in the treatment room to as few as 7 min. The PTH plays an important role in carbon ion beam scanning therapy at the new institution, particularly in the management of patient handling, application of image‐guided therapy, and improvement of treatment workflow, and thereby allows substantially better treatment at minimum cost. PACS numbers: 87.56.‐v; 87.57.‐s; 87.55.‐x PMID:23149784

Parathyroid hormone regulation of the human bone sialoprotein gene transcription is mediated through two cAMP response elements.

PubMed

Araki, Shouta; Mezawa, Masaru; Sasaki, Yoko; Yang, Li; Li, Zhengyang; Takai, Hideki; Nakayama, Youhei; Ogata, Yorimasa

2009-03-01

Parathyroid hormone (PTH) regulates serum calcium and inorganic phosphate levels through its actions on kidney and bone. Bone sialoprotein (BSP) is an early marker of osteoblast differentiation and bone metabolism. We here report that two cAMP response elements (CRE) in the human BSP gene promoter are target of PTH. In human osteoblast-like Saos2 cells, PTH (human 1-34 PTH, 10 nM) increased BSP mRNA and protein levels at 3 h. From transient transfection assays, 2- to 2.5-fold increase in transcription by PTH was observed at 3 and 6 h in -184, -211, -428, -868, and -927 luciferase constructs that included the human BSP gene promoter. Effect of PTH was abrogated by 2 bp mutations in either the CRE1 (-79 to -72) or CRE2 (-674 to -667). Luciferase activities induced by PTH were blocked by protein kinase A inhibitor H89 and tyrosine kinase inhibitor herbimycin A. Gel shift analyses showed that PTH increased binding of nuclear proteins to the CRE1 and CRE2 elements. The CRE1-protein and CRE2-protein complexes were disrupted by CRE binding protein 1 (CREB1) antibodies and supershifted by phospho-CREB1 antibody. ChIP assays detected binding of CREB1 and phospho-CREB1 to a chromatin fragment containing CRE1 and CRE2, and increased binding of phospho-CREB1 to the both sites. These studies demonstrate that PTH stimulates human BSP gene transcription by targeting the two CREs in the promoter of the human BSP gene.

CaSR-mediated interactions between calcium and magnesium homeostasis in mice.

PubMed

Quinn, Stephen J; Thomsen, Alex R B; Egbuna, Ogo; Pang, Jian; Baxi, Khanjan; Goltzman, David; Pollak, Martin; Brown, Edward M

2013-04-01

Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading.

[Serum PTH levels as a predictive factor of hypocalcaemia after total thyroidectomy].

PubMed

Díez Alonso, Manuel; Sánchez López, José Daniel; Sánchez-Seco Peña, María Isabel; Ratia Jiménez, Tomás; Arribas Gómez, Ignacio; Rodríguez Pascual, Angel; Martín-Duce, Antonio; Guadalix Hidalgo, Gregorio; Hernández Domínguez, Sara; Granell Vicent, Javier

2009-02-01

Postoperative parathyroid hormone (PTH) levels as a predictor of hypocalcaemia in patients subjected to total thyroidectomy is analyzed. Prospective study involving 67 patients who underwent total thyroidectomy due to a benign disease. Serum PTH and ionised calcium were measured 20 h after surgery. Sensitivity, specificity and predictive values of PTH and ionised calcium levels were calculated to predict clinical and analytical hypocalcaemia. A total of 42 (62.7%) patients developed hypocalcaemia (ionised calcium<0.95 mmol/l), but only 20 (29.9%) presented with symptoms. PTH concentration the day after surgery was significantly lower in the group that developed symptomatic hypocalcaemia (5.57+/-6.4 pg/ml) than in the asymptomatic (21.5+/-15.3 pg/ml) or normocalcaemic (26.8+/-24.9 pg/ml) groups (p=0.001). Taking the value of 13 pg/ml as a cut-off point of PTH levels, sensitivity, specificity, positive predictive value and negative predictive value were 54%, 72%, 76% and 48%, respectively. On the other hand, sensitivity for predicting symptomatic hypocalcaemia was 95% and specificity was 76%. The test showed a high incidence of false positives (11/30, 36%). Negative predictive value was 97% and positive predictive value was 65%. In multivariate analysis, PTH and ionised calcium were the only perioperative factors that showed an independent predictive value as risk indicators of symptomatic hypocalcaemia. Normal PTH levels 20 h after surgery practically rule out the subsequent appearance of hypocalcaemia symptoms. On the other hand, low PTH levels are not necessarily associated to symptomatic hypocalcaemia due to the high number of false positives.

Hypoparathyroidism after total thyroidectomy: prospective evaluation and relation with early hypocalcemia.

PubMed

D'Alessandro, Nicola; Tramutola, Giuseppe; Fasano, Giovanni Michele; Gilio, Francesco; Iside, Giovanni; Izzo, Maria Lucia; Loffredo, Andrea; Pici, Mariano; Pinto, Margherita; Tramontano, Salvatore; Citro, Giuseppe

2016-01-01

Definitive hypoparathyrodism (hypo-PTH) represents one of the most dangerous complication after total thyroidectomy. Partial or total lesion or accidental removal of parathyroid glands is an unpredictable adverse event, although real incidence is not well defined, such as management of this deficit. We started a prospective evaluation of patients treated with total thyroidectomy in our centre, to identify incidence of hypo-PTH, symptomatic or not, in relation to incidence of early postoperative hypocalcemia in our experience. We prospectively evaluated 177 patients treated for benign and malign pathology, measuring calcium before surgery and calcium and PTH at least three months after surgery. Postoperative hypocalcemia was observed in 37.3% of cases. Eight patients (4.5% of cohort) presented low level of PTH, at mean follow-up of 9.1 months. Positive predictive value for postoperative hypocalcemia was 12.1%, while negative predictive was 95.4%; confirming high sensitivity (100%) and low specificity (65.4%) for detecting hypo-PTH. All patients with late hypo-PTH presented hypocalcemia on early analysis, while no case with normal postoperative calcemia accounted with hypo-PTH: this may indicate calcemia as valid prognostic factor of good gland production, when is in the range. Moreover, isolated analysis is too limited to determine real predictability. Technical standardization represents the best method for prevention of hypo-PTH. Early hypocalcemia is a prognostic factor, even with a low specificity, of deficit of PTH-production. This observation must be related to other known prognostic factors. Postoperative normal calcemia should be a positive prognostic factor of an acceptable PTHfunction, supported by large cohorts. Hypocalcemia, Parathormone, Thyroidectomy.

Effectiveness of Intraoperative Parathyroid Monitoring (ioPTH) in predicting a multiglandular or malignant parathyroid disease.

PubMed

Dobrinja, C; Santandrea, G; Giacca, M; Stenner, Elisabetta; Ruscio, Maurizio; de Manzini, Nicolò

2017-05-01

The main goal of our study was to confirm the usefulness of intra-operative parathyroid hormone (PTH) monitoring (ioPTH) when using minimally invasive techniques for treatment of sporadic Primary hyperparathyroidism (pHTP). Furthermore, we aimed to evaluate if ioPTH monitoring may help to predict the etiology of primary hyperparathyroidism, especially in malignant or multiglandular parathyroid disease. A retrospective review of 125 consecutive patients with pHPT who underwent parathyroidectomy between 2001 and 2016 at the Department of General Surgery was performed. For each patient, the specific preoperative work-up consisted of: high-resolution US of the neck by a skilled sonographer, sestamibi parathyroid scan, laryngoscopy, and serum measurement of PTH, serum calcium levels, and serum 25(OH)D levels. The study included 125 consecutive patients who underwent surgery for pHPT. At the histological examination, we registered 113 patients with simple adenomatous pathology (90,4%), 5 atypical adenomas (4%), 3 cases of parathyroid carcinoma (2,4%),, , and 4 histological exams of different nature (3,2%). Overall, 6 cases (4,8%) of multiglandular disease were found. We reported 10 cases (8%) of recurrent/persistent hyperparathyroidism: 1/10 in a patient affected by atypical adenoma, 9/10 in patients with benign pathology. Regarding these 10 cases, in three (30%) patients, ioPTH wasn't dosed (only frozen section (FS) exam was taken), in 5 cases (50%) ioPTH dropped more than 50% compared to basal value (false negative results), and in 2 (20%) cases, ioPTH did not drop >50% from the first samples taken, the extemporary exam had confirmed the presence of adenoma and the probable second hyperfunctioning adenoma was not found. IoPTH determinations ensure operative success of surgical resection in almost all hyperfunctioning tissue; in particular it is very important during minimally invasive parathyroidectomy, as it allows avoiding bilateral neck exploration. The use of ioPTH monitoring offer increased sensitivity in detecting multiglandular disease and can minimize the need and risk associated with recurrent operations, and may facilitate cost-effective minimally invasive surgery. Moreover, intraoperative PTH monitoring could be a reliable marker to predict a malignant disease during parathyroidectomy, showing higher ioPTH baseline value and superior drop compared to benign disease. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

PTH modulation of NCC activity regulates TRPV5 Ca2+ reabsorption.

PubMed

Hoover, Robert S; Tomilin, Viktor; Hanson, Lauren; Pochynyuk, Oleh; Ko, Benjamin

2016-01-15

Since parathyroid hormone (PTH) is known to increase transient receptor potential vanilloid (TRPV)5 activity and decrease Na(+)-Cl(-) cotransporter (NCC) activity, we hypothesized that decreased NCC-mediated Na(+) reabsorption contributes to the enhanced TRPV5 Ca(2+) reabsorption seen with PTH. To test this, we used mDCT15 cells expressing functional TRPV5 and ruthenium red-sensitive (45)Ca(2+) uptake. PTH increased (45)Ca(2+) uptake to 8.8 ± 0.7 nmol·mg(-1)·min(-1) (n = 4, P < 0.01) and decreased NCC activity from 75.4 ± 2.7 to 20.3 ± 1.3 nmol·mg(-1)·min(-1) (n = 4, P < 0.01). Knockdown of Ras guanyl-releasing protein (RasGRP)1 had no baseline effect on (45)Ca(2+) uptake but significantly attenuated the response to PTH from a 45% increase (6.0 ± 0.2 to 8.7 ± 0.4 nmol·mg(-1)·min(-1)) in control cells to only 20% in knockdown cells (6.1 ± 0.1 to 7.3 ± 0.2 nmol·mg(-1)·min(-1), n = 4, P < 0.01). Inhibition of PKC and PKA resulted in further attenuation of the PTH effect. RasGRP1 knockdown decreased the magnitude of the TRPV5 response to PTH (7.9 ± 0.1 nmol·mg(-1)·min(-1) for knockdown compared with 9.1 ± 0.1 nmol·mg(-1)·min(-1) in control), and the addition of thiazide eliminated this effect (a nearly identical 9.0 ± 0.1 nmol·mg(-1)·min(-1)). This indicates that functionally active NCC is required for RasGRP1 knockdown to impact the PTH effect on TRPV5 activity. Knockdown of with no lysine kinase (WNK)4 resulted in an attenuation of the increase in PTH-mediated TRPV5 activity. TRPV5 activity increased by 36% compared with 45% in control (n = 4, P < 0.01 between PTH-treated groups). PKC blockade further attenuated the PTH effect, whereas combined PKC and PKA blockade in WNK4KD cells abolished the effect. We conclude that modulation of NCC activity contributes to the response to PTH, implying a role for hormonal modulation of NCC activity in distal Ca(2+) handling.

A sensitive electrochemical sensor for in vitro detection of parathyroid hormone based on a MoS2-graphene composite

NASA Astrophysics Data System (ADS)

Kim, Hyeong-U.; Kim, Hye Youn; Kulkarni, Atul; Ahn, Chisung; Jin, Yinhua; Kim, Yeongseok; Lee, Kook-Nyung; Lee, Min-Ho; Kim, Taesung

2016-10-01

This paper reports a biosensor based on a MoS2-graphene (MG) composite that can measure the parathyroid hormone (PTH) concentration in serum samples from patients. The interaction between PTH and MG was analysed via an electrochemical sensing technique. The MG was functionalized using L-cysteine. Following this, PTH could be covalently immobilized on the MG sensing electrode. The properties of MG were evaluated using scanning electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectrometry. Following optimization of immobilized materials—such as MG, PTH, and alkaline phosphatase (ALP)—the performance of the MG sensor was investigated via cyclic voltammetry, to assess its linearity, repeatability, and reproducibility. Electrochemical impedance spectroscopy was performed on graphene oxide (GO) and MG-modified electrodes to confirm the capture of a monoclonal antibody (MAb) targeting PTH. Furthermore, the ALP-PTH-MG sensor exhibits a linear response towards PTH from artificial serum over a range of 1-50 pg mL-1. Moreover, patient sera (n = 30) were evaluated using the ALP-PTH-MG sensor and compared using standard equipment (Roche E 170). The P-value is less than 0.01 when evaluated with a t-test using Welch’s correction. This implies that the fabricated sensor can be deployed for medical diagnosis.

[Design and activity verification of human parathyroid hormone (1-34) mutant protein].

PubMed

Qiu, Shuang; Jiang, Yue-Shui; Li, Zhi-Qin; Lei, Jian-Yong; Chen, Yun; Jin, Jian

2012-07-01

Through protein-protein BLAST of homologous sequences in different species in NCBI database and preliminary simulating molecular docking and molecular dynamics by computer software discovery studio 3.1, three amino acids R25K26K27 of natural human parathyroid hormone (1-34) with Q25E26L27 were mutated and the biological activity of the mutant peptide was evaluated. Result showed that: root mean superposition deviation RMSD value between PTH (1-34)-(RKK-QEL) and PTH (1-34) peptide main chain was 2.509 3, indicating that the differences between the two main chain structural conformation was relatively small; the interaction energy between PTH (1-34)-(RKK-QEL) and its receptor protein PTH1R had been enhanced by 7.5% compared to nature PTH (1-34), from -554.083 kcal x mol(-1) to -599.253 kcal x mol(-1); the number of hydrogen bonds was increased from 32 to 38; PTH (1-34)-(RKK-QEL) can significantly stimulate the RANKL gene expression (P < 0.01) while inhibiting the OPG gene expression (P < 0.01) in UAMS-32P cells; in the co-culture system of UAMS-32P cells and mouse primary femur bone marrow cells, PTH (1-34)-(RKK-QEL) stimulated the formation of osteoclasts (P < 0.01) and had a higher biological activity than PTH (1-34) standard reagents.

Parathyroid hormone ablation alters erythrocyte parameters that are rescued by calcium-sensing receptor gene deletion

PubMed Central

Romero, Jose R.; Youte, Rodeler; Brown, Edward M.; Pollak, Martin R.; Goltzman, David; Karaplis, Andrew; Pong, Lie-Chin; Chien, Lawrence; Chattopadhyay, Naibedya; Rivera, Alicia

2013-01-01

The mechanisms by which parathyroid hormone (PTH) produces anemia, are unclear. Parathyroid hormone secretion is regulated by the extracellular Ca2+-sensing receptor. We investigated the effects of ablating PTH on hematological indices and erythrocytes volume regulation in wild-type, PTH-null and Ca2+-sensing receptor-null/PTH-null mice. The erythrocyte parameters were measured in whole mouse blood and volume regulatory systems were determined by plasma membrane K+ fluxes and osmotic fragility was measured by hemoglobin determination at varying osmolarities. We observed that the absence of PTH significantly increases mean erythrocyte volume and reticulocyte counts, while decreasing erythrocyte counts, hemoglobin, hematocrit, and mean corpuscular hemoglobin concentration. These changes were accompanied by increases in erythrocyte cation content, a denser cell population and increased K+ permeability, which were in part mediated by activation of the K+/Cl− cotransporter and Gardos channel. In addition we observed that erythrocyte osmotic fragility in PTH-null compared with wild-type mice was enhanced. When Ca2+-sensing receptor gene was deleted on the background of PTH-null mice, we observed that several of the alterations in erythrocyte parameters of PTH-null mice were largely rescued, particularly those related to erythrocyte volume, K+ fluxes and osmotic fragility, and became similar to those observed in wild-type mice. Our results demonstrate that Ca2+-sensing receptor and parathyroid hormone are functionally coupled to maintain erythrocyte homeostasis. PMID:23528155

Molecular recognition of parathyroid hormone by its G protein-coupled receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pioszak, Augen A.; Xu, H. Eric

Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineeredmore » as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-{angstrom} structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer {alpha}-{beta}-{beta}{alpha} fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.« less

The third/second generation PTH assay ratio as a marker for parathyroid carcinoma: evaluation using an automated platform.

PubMed

Cavalier, Etienne; Betea, Daniela; Schleck, Marie-Louise; Gadisseur, Romy; Vroonen, Laurent; Delanaye, Pierre; Daly, Adrian F; Beckers, Albert

2014-03-01

Parathyroid carcinoma (PCa) is rare and often difficult to differentiate initially from benign disease. Because PCa oversecretes amino PTH that is detected by third-generation but not by second-generation PTH assays, the normal 3rd/2nd generation PTH ratio (<1) is inverted in PCa (ie, >1). The objective of the investigation was to study the utility and advantages of automated 3rd/2nd generation PTH ratio measurements using the Liaison XL platform over existing manual techniques. The study was conducted at a tertiary-referral academic center. This was a retrospective laboratory study. Eleven patients with advanced PCa (mean age 56.0 y). The controls were patients with primary-hyperparathyroidism (n = 144; mean age 53.8 y), renal transplantation (n = 41; mean age 50.6 y), hemodialysis (n = 80; mean age 65.2 y), and healthy elderly subjects (n = 40; mean age 72.6 y). The median (interquartile range) 3rd/2nd generation PTH ratio was 1.16 (1.10-1.38) in the PCa group, which was significantly higher than the control groups: hemodialysis: 0.74 (0.71-0.75); renal transplant: 0.77 (0.73-0.79); primary hyperparathyroidism: 0.76 (0.74-0.78); healthy elderly: 0.80 (0.74-0.83). An inverted 3rd/2nd-generation PTH ratio (>1) was seen in 9 of 11 PCa patients (81.8%) and in 7 of 305 controls (2.3%): 3 of 80 hemodialysis (3.8%), and 4 of 144 primary-hyperparathyroidism patients (2.8%). Of four PCa patients who had a normal PTH ratio with the manual method, two had an inverted 3rd/2nd-generation PTH ratio with the automated method. Study of the 3rd/2nd-generation PTH ratio in large patient populations should be feasible using a mainstream automated platform like the Liaison XL. The current study confirms the utility of the inverted 3rd/2nd-generation PTH ratio as a marker of PCa (sensitivity: 81.8%; specificity: 97.3%).

The parathyroid hormone-regulated transcriptome in osteocytes: parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function.

PubMed

St John, Hillary C; Meyer, Mark B; Benkusky, Nancy A; Carlson, Alex H; Prideaux, Mathew; Bonewald, Lynda F; Pike, J Wesley

2015-03-01

Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examined the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH's effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte-specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA-activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA-mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone-regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage. Copyright © 2014 Elsevier Inc. All rights reserved.

Activation of a non-cAMP/PKA signaling pathway downstream of the PTH/PTHrP receptor is essential for a sustained hypophosphatemic response to PTH infusion in male mice.

PubMed

Guo, Jun; Song, Lige; Liu, Minlin; Segawa, Hiroko; Miyamoto, Ken-Ichi; Bringhurst, F Richard; Kronenberg, Henry M; Jüppner, Harald

2013-05-01

PTH increases urinary Pi excretion by reducing expression of two renal cotransporters [NaPi-IIa (Npt2a) and NaPi-IIc (Npt2c)]. In contrast to acute transporter regulation that is cAMP/protein kinase A dependent, long-term effects require phospholipase C (PLC) signaling by the PTH/PTHrP receptor (PPR). To determine whether the latter pathway regulates Pi through Npt2a and/or Npt2c, wild-type mice (Wt) and animals expressing a mutant PPR incapable of PLC activation (DD) were tested in the absence of one (Npt2a(-/-) or Npt2c(-/-)) or both phosphate transporters (2a/2c-dko). PTH infusion for 8 days caused a rapid and persistent decrease in serum Pi in Wt mice, whereas serum Pi in DD mice fell only transiently for the first 2 days. Consistent with these findings, fractional Pi excretion index was increased initially in both animals, but this increase persisted only when the PPR Wt was present. The hypophosphatemic response to PTH infusion was impaired only slightly in PPR Wt/Npt2c(-/-) or DD/Npt2c(-/-) mice. Despite lower baselines, PTH infusion in PPR Wt/Npt2a(-/-) mice decreased serum Pi further, an effect that was attenuated in DD/Npt2a(-/-) mice. Continuous PTH had no effect on serum Pi in 2a/2c-dko mice. PTH administration increased serum 1,25 dihydroxyvitamin D3 levels in Wt and DD mice and increased levels above the elevated baseline with ablation of either but not of both transporters. Continuous PTH elevated serum fibroblast growth factor 23 and blood Ca(2+) equivalently in all groups of mice. Our data indicate that PLC signaling at the PPR contributes to the long-term effect of PTH on Pi homeostasis but not to the regulation of 1,25 dihydroxyvitamin D3, fibroblast growth factor 23, or blood Ca(2+).

Role of acidosis-induced increases in calcium on PTH secretion in acute metabolic and respiratory acidosis in the dog.

PubMed

López, Ignacio; Aguilera-Tejero, Escolástico; Estepa, José Carlos; Rodríguez, Mariano; Felsenfeld, Arnold J

2004-05-01

Recently, we showed that both acute metabolic acidosis and respiratory acidosis stimulate parathyroid hormone (PTH) secretion in the dog. To evaluate the specific effect of acidosis, ionized calcium (iCa) was clamped at a normal value. Because iCa values normally increase during acute acidosis, we now have studied the PTH response to acute metabolic and respiratory acidosis in dogs in which the iCa concentration was allowed to increase (nonclamped) compared with dogs with a normal iCa concentration (clamped). Five groups of dogs were studied: control, metabolic (clamped and nonclamped), and respiratory (clamped and nonclamped) acidosis. Metabolic (HCl infusion) and respiratory (hypoventilation) acidosis was progressively induced during 60 min. In the two clamped groups, iCa was maintained at a normal value with an EDTA infusion. Both metabolic and respiratory acidosis increased (P < 0.05) iCa values in nonclamped groups. In metabolic acidosis, the increase in iCa was progressive and greater (P < 0.05) than in respiratory acidosis, in which iCa increased by 0.04 mM and then remained constant despite further pH reductions. The increase in PTH values was greater (P < 0.05) in clamped than in nonclamped groups (metabolic and respiratory acidosis). In the nonclamped metabolic acidosis group, PTH values first increased and then decreased from peak values when iCa increased by > 0.1 mM. In the nonclamped respiratory acidosis group, PTH values exceeded (P < 0.05) baseline values only after iCa values stopped increasing at a pH of 7.30. For the same increase in iCa in the nonclamped groups, PTH values increased more in metabolic acidosis. In conclusion, 1) both metabolic acidosis and respiratory acidosis stimulate PTH secretion; 2) the physiological increase in the iCa concentration during the induction of metabolic and respiratory acidosis reduces the magnitude of the PTH increase; 3) in metabolic acidosis, the increase in the iCa concentration can be of sufficient magnitude to reverse the increase in PTH values; and 4) for the same degree of acidosis-induced hypercalcemia, the increase in PTH values is greater in metabolic than in respiratory acidosis.

Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats

NASA Technical Reports Server (NTRS)

Turner, R. T.; Evans, G. L.; Cavolina, J. M.; Halloran, B.; Morey-Holton, E.

1998-01-01

Gonadal insufficiency and reduced mechanical usage are two important risk factors for osteoporosis. The beneficial effects of PTH therapy to reverse the estrogen deficiency-induced bone loss in the laboratory rat are well known, but the influence of mechanical usage in this response has not been established. In this study, the effects of programed administration of PTH on cancellous bone volume and turnover at the proximal tibial metaphysis were determined in hindlimb-unloaded, ovariectomized (OVX), 3-month-old Sprague-Dawley rats. PTH was administered to weight-bearing and hindlimb-unloaded OVX rats with osmotic pumps programed to deliver 20 microg human PTH (approximately 80 microg/kg x day) during a daily 1-h infusion for 7 days. Compared with sham-operated rats, OVX increased longitudinal and radial bone growth, increased indexes of cancellous bone turnover, and resulted in net resorption of cancellous bone. Hindlimb unloading of OVX rats decreased longitudinal and radial bone growth, decreased osteoblast number, increased osteoclast number, and resulted in a further decrease in cancellous bone volume compared with those in weight-bearing OVX rats. Programed administration of PTH had no effect on either radial or longitudinal bone growth in weight-bearing and hindlimb-unloaded OVX rats. PTH treatment had dramatic effects on selected cancellous bone measurements; PTH maintained cancellous bone volume in OVX weight-bearing rats and greatly reduced cancellous bone loss in OVX hindlimb-unloaded rats. In the latter animals, PTH treatment prevented the hindlimb unloading-induced reduction in trabecular thickness, but the hormone was ineffective in preventing either the increase in osteoclast number or the loss of trabecular plates. Importantly, PTH treatment increased the retention of a baseline flurochrome label, osteoblast number, and bone formation in the proximal tibial metaphysis regardless of the level of mechanical usage. These findings demonstrate that programed administration of PTH is effective in increasing osteoblast number and bone formation and has beneficial effects on bone volume in the absence of weight-bearing and gonadal hormones. We conclude that the actions of PTH on cancellous bone are independent of the level of mechanical usage.

Synthesis, characterization, and cytocompatibility of potential cockle shell aragonite nanocrystals for osteoporosis therapy and hormonal delivery.

PubMed

Jaji, Alhaji Zubair; Bakar, Md Zuki Bin Abu; Mahmud, Rozi; Loqman, Mohamad Yusof; Hezmee, Mohamad Noor Mohamad; Isa, Tijani; Wenliang, Fu; Hammadi, Nahidah Ibrahim

2017-01-01

Calcium carbonate is a porous inorganic nanomaterial with huge potential in biomedical applications and controlled drug delivery. This study aimed at evaluating the physicochemical properties and in vitro efficacy and safety of cockle shell aragonite calcium carbonate nanocrystals (ANC) as a potential therapeutic and hormonal delivery vehicle for osteoporosis management. Free and human recombinant parathyroid hormone 1-34 (PTH 1-34)-loaded cockle shell aragonite calcium carbonate nanocrystals (PTH-ANC) were synthesized and evaluated using standard procedures. Transmission electron microscopy and field emission scanning electron microscopy results demonstrated highly homogenized spherical-shaped aragonite nanocrystals of 30±5 nm diameter. PTH-ANC had a zeta potential of -27.6±8.9 mV. The encapsulation efficiency of the formulation was found to be directly proportional to the concentrations of the drug fed. The X-ray diffraction patterns revealed strong crystallizations with no positional change of peaks before and after PTH-ANC synthesis. Fourier transform infrared spectroscopy demonstrated no detectable interactions between micron-sized aragonite and surfactant at molecular level. PTH-ANC formulation was stabilized at pH 7.5, enabling sustained slow release of PTH 1-34 for 168 h (1 week). A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytocompatibility assay in Human Foetal Osteoblast Cell Line hFOB 1.19 showed that ANC can safely support osteoblast proliferation up to 48 h whereas PTH-ANC can safely support the proliferation at 72 h and beyond due to the sustained slow release of PTH 1-34. It was concluded that due to its biogenic nature, ANC is a cytocompatible antiosteoporotic agent. It doubles as a nanocarrier for the enhancement of efficacy and safety of the bone anabolic PTH 1-34. ANC is expected to reduce the cost, dosage, and dose frequency associated with the use of PTH 1-34 management of primary and secondary forms of osteoporosis.

Synthesis, characterization, and cytocompatibility of potential cockle shell aragonite nanocrystals for osteoporosis therapy and hormonal delivery

PubMed Central

Jaji, Alhaji Zubair; Bakar, Md Zuki Bin Abu; Mahmud, Rozi; Loqman, Mohamad Yusof; Hezmee, Mohamad Noor Mohamad; Isa, Tijani; Wenliang, Fu; Hammadi, Nahidah Ibrahim

2017-01-01

Calcium carbonate is a porous inorganic nanomaterial with huge potential in biomedical applications and controlled drug delivery. This study aimed at evaluating the physicochemical properties and in vitro efficacy and safety of cockle shell aragonite calcium carbonate nanocrystals (ANC) as a potential therapeutic and hormonal delivery vehicle for osteoporosis management. Free and human recombinant parathyroid hormone 1-34 (PTH 1-34)-loaded cockle shell aragonite calcium carbonate nanocrystals (PTH-ANC) were synthesized and evaluated using standard procedures. Transmission electron microscopy and field emission scanning electron microscopy results demonstrated highly homogenized spherical-shaped aragonite nanocrystals of 30±5 nm diameter. PTH-ANC had a zeta potential of −27.6±8.9 mV. The encapsulation efficiency of the formulation was found to be directly proportional to the concentrations of the drug fed. The X-ray diffraction patterns revealed strong crystallizations with no positional change of peaks before and after PTH-ANC synthesis. Fourier transform infrared spectroscopy demonstrated no detectable interactions between micron-sized aragonite and surfactant at molecular level. PTH-ANC formulation was stabilized at pH 7.5, enabling sustained slow release of PTH 1-34 for 168 h (1 week). A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytocompatibility assay in Human Foetal Osteoblast Cell Line hFOB 1.19 showed that ANC can safely support osteoblast proliferation up to 48 h whereas PTH-ANC can safely support the proliferation at 72 h and beyond due to the sustained slow release of PTH 1-34. It was concluded that due to its biogenic nature, ANC is a cytocompatible antiosteoporotic agent. It doubles as a nanocarrier for the enhancement of efficacy and safety of the bone anabolic PTH 1-34. ANC is expected to reduce the cost, dosage, and dose frequency associated with the use of PTH 1-34 management of primary and secondary forms of osteoporosis. PMID:28176933

Preoperative normal level of parathyroid hormone signifies an early and mild form of primary hyperparathyroidism.

PubMed

Bergenfelz, Anders; Lindblom, Pia; Lindergård, Birger; Valdemarsson, Stig; Westerdahl, Johan

2003-04-01

Contemporary patients are often diagnosed with mild or intermittent hypercalcemia. In addition, most studies demonstrate patients with parathyroid (PTH) levels in the upper normal range. The aim of the present investigation was to define subgroups of patients with mild primary hyperparathyroidism (pHPT), which could be of importance in the decision for or against surgical treatment. Two-hundred and eleven patients, operated for pHPT were investigated with biochemical variables known to reflect PTH activity, renal function, and bone mineral content. The preoperative diagnosis of pHPT was based on the presence of hypercalcemia combined with an inappropriate serum concentration of PTH. The mean age of the patients was 64 +/- 14 years and the mean serum level of calcium was 2.78 +/- 0.19 mmol/L. One hundred and sixty-two patients (77%) had raised levels of calcium and PTH the day before surgery (overt pHPT), 25 patients (12%) had a normal level of calcium and a raised PTH level (normal calcium group), and 20 patients (9%) had a raised level of calcium and a normal level of PTH (normal PTH group). In four patients the level of calcium and PTH was normal. Between-group analysis demonstrated no major difference in symptom and signs of pHPT. Except for lower adenoma weight, patients in the normal calcium group did not essentially differ from the patients in the overt pHPT group. However, patients in the normal PTH group were a decade younger, and had better renal function, lower bone turnover, and a preserved bone density compared with patients in the overt pHPT group. In conclusion, the data from the present investigation show that pHPT patients with a preoperative normal PTH level have an early and mild form of the disease. Furthermore, the serum calcium concentration does not reflect disease severity in pHPT.

AN OPEN-LABEL EXTENSION STUDY OF PARATHYROID HORMONE RHPTH(1-84) IN ADULTS WITH HYPOPARATHYROIDISM.

PubMed

Lakatos, Peter; Bajnok, Laszlo; Lagast, Hjalmar; Valkusz, Zsuzsanna

2016-05-01

Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and bone abnormalities. Adults with hypoparathyroidism treated with recombinant human PTH, rhPTH(1-84), in the 24-week, phase III REPLACE study maintained serum calcium despite reductions in oral calcium and active vitamin D. This study assessed the long-term efficacy and safety of rhPTH(1-84) for hypoparathyroidism. This was a 24-week, open-label, flexible-dose extension study of REPLACE (REPEAT) conducted in 3 outpatient centers in Hungary. Patients who previously completed or enrolled in REPLACE received 50 μg/day rhPTH(1-84), escalated to 75 and then to 100 μg/day, if needed, to reduce active vitamin D and oral calcium. The primary endpoint was ≥50% reduction in oral calcium (or ≤500 mg/day) and active vitamin D (or calcitriol ≤0.25 μg/day or alfacalcidol ≤0.50 μg/day) with normocalcemia. Twenty-four patients (n = 16 previously treated with rhPTH[1-84]; n = 8 rhPTH[1-84]-naïve) were enrolled and completed the study. At Week 24, 75% of patients (95% confidence interval [CI], 53.3-90.2%) achieved the study endpoint; 58% eliminated oral calcium and active vitamin D. Urinary calcium, serum phosphate, and calcium × phosphate (Ca × P) product decreased by Week 24. Mean serum bone turnover markers increased with rhPTH(1-84). Treatment-emergent adverse events (TEAEs) were reported by 92% of patients. No serious adverse events (AEs) occurred. This study used a simplified treatment algorithm intended to better mimic typical clinical practice and demonstrated the extended efficacy and safety of rhPTH(1-84) in patients with hypoparathyroidism and confirmed the REPLACE findings. Sustained rhPTH(1-84) efficacy up to 48 weeks was observed despite treatment interruption between studies.

Parathyroid hormone(1-34) exhibits more comprehensive effects than celecoxib in cartilage metabolism and maintaining subchondral bone micro-architecture in meniscectomized guinea pigs.

PubMed

Dai, M-W; Chu, J-G; Tian, F-M; Song, H-P; Wang, Y; Zhang, Y-Z; Zhang, L

2016-06-01

To evaluate the effects of PTH(1-34) on cartilage, subchondral bone mass and structure in medial meniscectomized guinea pigs and compare them to those of celecoxib (CLX). Forty-eight 3-month-old male Hartley albino guinea pigs received either sham or medial meniscectomy (MNX) operations. One week after the procedure, meniscectomized animals began 12 weeks of treatment by oral administration of CLX (20 mg/kg, daily), subcutaneous injection of PTH (1-34) (24 μg/kg, 5 days/week), or normal saline for MNX group. All animals were euthanized 12 weeks later, cartilage degeneration and subchondral bone micro-architecture was analyzed. OARSI scores indicated cartilage degeneration was partially inhibited by either CLX or PTH(1-34). Cartilage was significantly thicker in PTH(1-34)-treated animals than in CLX-treated animals. Both CLX and PTH(1-34) treatment were associated with lower ADAMTS-4 and periostin expression than MNX. MMP-13 expression in PTH(1-34) group was significantly lower than that in CLX group. However, AGG expression and the ratio of Col-II/MMP-13 expression in PTH(1-34) group were significantly higher than in the CLX group. Micro-CT analysis showed BMD, BV/TV, and Tb.Th levels to be significantly lower in the MNX group and CLX groups than in the sham group, but these parameters were significantly higher in the PTH(1-34) group than in either the MNX group or CLX group. Both CLX and PTH(1-34) exhibits protective effects on cartilage degeneration in meniscectomized guinea pigs. However, PTH(1-34) exhibited superior performance to CLX not only in metabolism of cartilage tissue but also in maintenance of subchondral bone micro-architecture. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

PTH intermittent administration may be a useful therapeutic agent to avoid premature eruption of the tooth.

PubMed

Vasconcelos, Daniel Fernando Pereira; Vasconcelos, Any Carolina Cardoso Guimarães

2016-03-01

Parathyroid hormone (PTH) acts as a controller of bone remodeling and has influence on periodontal tissues. In addition to the well-established catabolic effects (activation of bone resorption) of PTH, it is recognized that the PTH intermittent administration has anabolic effects (promotion of bone formation). However, there is no information regarding the effects of the PTH intermittent administration on the eruption tooth rate. Studies have shown that tooth eruption depends on the presence of osteoclasts to create an eruption pathway through the alveolar bone. It may also be controlled by osteoblast, precursor of osteoclast, and cells of periodontal ligament. Our hypothesis is based on previous studies showing that the PTH intermittent administration can promote bone formation, particularly in the areas around which the tooth erupts. Furthermore, the PTH intermittent administration influenced periodontal ligament fiber, what may be seen as greater organization, and isomerization, as well as higher birefringence of the periodontal ligament fiber, which then offers increased resistance to the process, delaying tooth eruption. Thus, this article opens new perspectives for the treatment and maintenance of teeth that can erupt early. Published by Elsevier Ltd.

Immobilization of hyaluronic acid on plasma-sprayed porous titanium coatings for improving biological properties.

PubMed

Ao, Haiyong; Xie, Youtao; Qin, An; Ji, Heng; Yang, Shengbing; Huang, Liping; Zheng, Xuebin; Tang, Tingting

2014-01-01

In the present study, hyaluronic acid (HyA) was covalently immobilized onto titanium coatings to improve their biological properties. Diffuse reflectance Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were employed to characterize the HyA-modified titanium coating. HyA-modified titanium coatings possess better cell-material interaction, and human mesenchymal stem cells present good adhesive morphologies on the surface of TC-AAH. The results of subsequent cellular evaluation showed that the immobilization of HyA on titanium coatings could improve hMSC attachment, proliferation, and differentiation. In vivo evaluation of implants in rabbit femur condyle defect model showed improvements of early osseointegration and bone-to-implant contact of TC-AAH. In conclusion, immobilization of HyA could improve biological properties of titanium coatings.

Bifunctional Bisphosphonates for Delivering Biomolecules to Bone

DTIC Science & Technology

2012-01-13

targeted PTH stimulated greater synthesis of cAMP in preosteoblasts compared to surfaces with simply adsorbed PTH. HBPs were also found to have similar pro...targeted PTH stimulated greater synthesis of cAMP in pre- osteoblasts compared to surfaces with simply adsorbed PTH. HBPs were also found to have similar...30 Chapter Two: Synthesis and Characterization of Bifunctional Bisphosphonates….31 Experimental Section……………………………………………………….……38 Reagents

Vitamin D Deficiency and a Blunted Parathyroid Hormone Response in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Avcil, Sibelnur; Uysal, Pinar; Yilmaz, Mustafa; Erge, Duygu; Demirkaya, Sevcan K; Eren, Esra

2017-03-01

Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neuropsychiatric disorder of childhood. The etiopathogenesis of ADHD has not been fully defined. Recent evidence has suggested a pathophysiological role of vitamin D deficiency in ADHD. In this study, we evaluated the serum levels of 25-hydroxy vitamin D (25(OH)D), parathyroid hormone (PTH), calcium (Ca), phosphate (P), and alkaline phosphatase (ALP) in children with ADHD. The study group consisted of 105 children diagnosed with ADHD according to DSM-IV-TR criteria. A control group, matched for age and gender, was composed of 95 healthy children. Venous blood samples were collected, and 25(OH)D, PTH, Ca, P, and ALP levels were measured. The mean serum 25(OH)D, Ca, and P levels of the children with ADHD were significantly lower than those of the healthy controls. There were no significant differences between the groups regarding PTH and ALP. Serum PTH levels were found to be normal, but vitamin D deficiency, hypocalcemia, and hypophosphatemia were observed in children with ADHD. There was no correlation between serum PTH and Ca levels in children with ADHD, whereas, there was a negative correlation between serum PTH and Ca levels in healthy controls. There was no correlation between serum 25(OH)D and PTH levels in children with ADHD, whereas, there was a negative correlation between serum 25(OH)D and PTH levels in healthy controls. There were no significant differences in all parameters' levels among the subtypes of ADHD. The findings suggest that ADHD is associated with vitamin D deficiency, blunted PTH response, and impaired Ca homeostasis in children.

PTH [1-34]-induced alterations of the subchondral bone provoke early osteoarthritis.

PubMed

Orth, P; Cucchiarini, M; Wagenpfeil, S; Menger, M D; Madry, H

2014-06-01

To test the hypothesis that changes in the subchondral bone induced by parathyroid hormone (PTH [1-34]) reciprocally affect the integrity of the articular cartilage within a naïve osteochondral unit in vivo. Daily subcutaneous injections of 10 μg PTH [1-34]/kg were given to adult rabbits for 6 weeks, controls received saline. Blood samples were continuously collected to monitor renal function. The subchondral bone plate and subarticular spongiosa of the femoral heads were separately assessed by micro-computed tomography. Articular cartilage was evaluated by macroscopic and histological osteoarthritis scoring, polarized light microscopy, and immunohistochemical determination of type-I, type-II, type-X collagen contents, PTH [1-34] receptor and caspase-3 expression. Absolute and relative extents of hyaline and calcified articular cartilage layers were measured histomorphometrically. The correlation between PTH-induced changes in subchondral bone and articular cartilage was determined. PTH [1-34] enhanced volume, mineral density, and trabecular thickness within the subarticular spongiosa, and increased thickness of the calcified cartilage layer (all P < 0.05). Moreover, PTH [1-34] led to cartilage surface irregularities and reduced matrix staining (both P < 0.03). These early osteoarthritic changes correlated with and were ascribed to the increased thickness of the calcified cartilage layer (P = 0.026) and enhanced mineral density of the subarticular spongiosa (P = 0.001). Modifications of the subarticular spongiosa by PTH [1-34] cause broadening of the calcified cartilage layer, resulting in osteoarthritic cartilage degeneration. These findings identify a mechanism by which PTH-induced alterations of the normal subchondral bone microarchitecture may provoke early osteoarthritis. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Measurement of intraoperative parathyroid hormone predicts long-term operative success.

PubMed

Westerdahl, Johan; Lindblom, Pia; Bergenfelz, Anders

2002-02-01

A decrease in the intraoperative parathyroid hormone (PTH) level predicts long-term operative success. A case series of consecutive patients undergoing parathyroidectomy with intraoperative PTH measurement. A university hospital. One hundred two patients with sporadic primary hyperparathyroidism underwent parathyroidectomy according to the principles of unilateral exploration with intraoperative PTH measurement. Longitudinal effects on levels of serum calcium and PTH. In 94 of 98 patients who underwent primary exploration because of a solitary adenoma, intraoperative PTH decreased at least 60% 15 minutes after gland excision. The 4 cases in which PTH fell to less than 60% were classified as false negatives. Patients examined for multiglandular disease (n = 4) were correctly predicted not to have an adenoma. Twenty-two patients (22%) were unavailable for 5-year follow-up. These patients were followed up for 2 months to 48 months (median, 24 months), and none developed recurrent primary hyperparathyroidism. Of the remaining 80 patients (78%), all but 1 patient had normal or slightly decreased serum calcium levels (mean +/- SD, 9.24 +/- 0.4 mg/dL [2.31 +/- 0.10 mmol/L]) at 5-year follow-up. One patient with hypercalcemia (10.6 mg/dL [2.65 mmol/L]) was interpreted to have developed renal failure with secondary hyperparathyroidism. Thirty-four patients had elevated serum PTH levels at least once during the postoperative study period, with normal or slightly decreased calcium concentrations. The prediction of late postoperative normocalcemia by means of intraoperative PTH measurement had an overall accuracy of 95%. The measurement of intraoperative PTH during surgery for primary hyperparathyroidism accurately differentiates between single- and multiple-gland disease and ensures good long-term results.

Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease

PubMed Central

Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B.; Yang, Bing; White, Frank F.; Wang, Nian; Jones, Jeffrey B.

2014-01-01

Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccAw, induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations. PMID:24474801

Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease.

PubMed

Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B; Yang, Bing; White, Frank F; Wang, Nian; Jones, Jeffrey B

2014-01-28

Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccA(w), induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations.

Vitamin D, Parathyroid Hormone and Sudden Cardiac Death: Results from the Cardiovascular Health Study

PubMed Central

Deo, Rajat; Katz, Ronit; Shlipak, Michael G.; Sotoodehnia, Nona; Psaty, Bruce M.; Sarnak, Mark J.; Fried, Linda F.; Chonchol, Michel; de Boer, Ian H.; Enquobahrie, Daniel; Siscovick, David; Kestenbaum, Bryan

2012-01-01

Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2,312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations: 2 events per 10,000 for 25-OHD ≥ 20 ng/ml and 4 events per 10,000 for 25-OHD < 20 ng/ml. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations: 2 events per 10,000 for PTH ≤ 65 pg/ml and 4 events per 10,000 for PTH > 65 pg/ml. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a more than 2-fold risk of SCD after adjustment (hazard ratio 2.19, 95% confidence interval 1.17, 4.10, p=0.017) compared to participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease. PMID:22068871

Genetic Variants Associated with Circulating Parathyroid Hormone

PubMed Central

Lutsey, Pamela L.; Kleber, Marcus E.; Nielson, Carrie M.; Mitchell, Braxton D.; Bis, Joshua C.; Eny, Karen M.; Portas, Laura; Eriksson, Joel; Lorentzon, Mattias; Koller, Daniel L.; Milaneschi, Yuri; Teumer, Alexander; Pilz, Stefan; Nethander, Maria; Selvin, Elizabeth; Tang, Weihong; Weng, Lu-Chen; Wong, Hoi Suen; Lai, Dongbing; Peacock, Munro; Hannemann, Anke; Völker, Uwe; Homuth, Georg; Nauk, Matthias; Murgia, Federico; Pattee, Jack W.; Orwoll, Eric; Zmuda, Joseph M.; Riancho, Jose Antonio; Wolf, Myles; Williams, Frances; Penninx, Brenda; Econs, Michael J.; Ryan, Kathleen A.; Ohlsson, Claes; Paterson, Andrew D.; Psaty, Bruce M.; Siscovick, David S.; Rotter, Jerome I.; Pirastu, Mario; Streeten, Elizabeth; März, Winfried; Fox, Caroline; Coresh, Josef; Wallaschofski, Henri; Pankow, James S.; de Boer, Ian H.; Kestenbaum, Bryan

2017-01-01

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10−53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10−17), rs219779 adjacent to CLDN14 (P=3.5 × 10−16), rs4443100 near RTDR1 (P=8.7 × 10−9), and rs73186030 near CASR (P=4.8 × 10−8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued. PMID:27927781

Genetic Variants Associated with Circulating Parathyroid Hormone.

PubMed

Robinson-Cohen, Cassianne; Lutsey, Pamela L; Kleber, Marcus E; Nielson, Carrie M; Mitchell, Braxton D; Bis, Joshua C; Eny, Karen M; Portas, Laura; Eriksson, Joel; Lorentzon, Mattias; Koller, Daniel L; Milaneschi, Yuri; Teumer, Alexander; Pilz, Stefan; Nethander, Maria; Selvin, Elizabeth; Tang, Weihong; Weng, Lu-Chen; Wong, Hoi Suen; Lai, Dongbing; Peacock, Munro; Hannemann, Anke; Völker, Uwe; Homuth, Georg; Nauk, Matthias; Murgia, Federico; Pattee, Jack W; Orwoll, Eric; Zmuda, Joseph M; Riancho, Jose Antonio; Wolf, Myles; Williams, Frances; Penninx, Brenda; Econs, Michael J; Ryan, Kathleen A; Ohlsson, Claes; Paterson, Andrew D; Psaty, Bruce M; Siscovick, David S; Rotter, Jerome I; Pirastu, Mario; Streeten, Elizabeth; März, Winfried; Fox, Caroline; Coresh, Josef; Wallaschofski, Henri; Pankow, James S; de Boer, Ian H; Kestenbaum, Bryan

2017-05-01

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies ( n =22,653 and n =6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 ( P =4.2 × 10 -53 ), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 ( P =6.6 × 10 -17 ), rs219779 adjacent to CLDN14 ( P =3.5 × 10 -16 ), rs4443100 near RTDR1 ( P =8.7 × 10 -9 ), and rs73186030 near CASR ( P =4.8 × 10 -8 ). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued. Copyright © 2017 by the American Society of Nephrology.

Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis

PubMed Central

Hirai, Takao; Kobayashi, Tatsuya; Nishimori, Shigeki; Karaplis, Andrew C.; Goltzman, David

2015-01-01

The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone-specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis. We found that the fetal calcium concentration of Runx2 KO mice was significantly higher than that of control littermates, suggesting that calcium flux into bone had a considerable influence on the circulating calcium concentration. Moreover, Runx2:PTH double mutant fetuses showed calcium levels similar to those of Runx2 KO mice, suggesting that part of the fetal hypocalcemia in PTH KO mice was caused by the increment of the mineralized bone mass allowed by the formation of osteoblasts. Finally, Rank:PTH double mutant mice had a blood calcium concentration even lower than that of the either Rank KO or PTH KO mice alone at embryonic day 18.5. These observations in our genetic models suggest that PTH/PTHrP receptor signaling in bones has a significant role of the regulation of fetal blood calcium concentration and that both placental transport and osteoclast activation contribute to PTH's hypercalcemic action. They also show that PTH-independent deposition of calcium in bone is the major controller of fetal blood calcium level. PMID:26052897

Hormone synthesis and secretion by rat parathyroid glands in tissue culture

PubMed Central

Au, William Y. W.; Poland, Alan P.; Stern, Paula H.; Raisz, Lawrence G.

1970-01-01

Rat parathyroid glands maintained in organ culture secrete biologically active parathyroid hormone (PTH) and synthesize and secrete labeled proteins from 3H- or 14C-labeled amino acids added to the medium. The amounts of biological activity and labeled protein in the medium are both inversely proportional to the calcium concentration. Some of the labeled low molecular weight protein was identified as PTH which had been synthesized and secreted in culture by preliminary isolation on Sephadex G-100 columns and further purification using an antibody to bovine PTH which cross-reacted with rat PTH. The cross-reacting antibody inhibited the biological effects of rat PTH and caused hypocalcemia in intact rats. The antibody bound some of the labeled low molecular weight protein of the medium at neutral pH so that it migrated as a large molecular weight complex on Sephadex. Biologically active, labeled PTH was recovered by dissociation of this complex in acid and rechromatography. PMID:5449703

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate.

PubMed

Fan, Yi; Hanai, Jun-Ichi; Le, Phuong T; Bi, Ruiye; Maridas, David; DeMambro, Victoria; Figueroa, Carolina A; Kir, Serkan; Zhou, Xuedong; Mannstadt, Michael; Baron, Roland; Bronson, Roderick T; Horowitz, Mark C; Wu, Joy Y; Bilezikian, John P; Dempster, David W; Rosen, Clifford J; Lanske, Beate

2017-03-07

Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1 + RANKL + marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH's therapeutic action through its ability to direct mesenchymal cell fate. Copyright © 2017 Elsevier Inc. All rights reserved.

[Algal oligosaccharides ameliorate osteoporosis via up-regulation of parathyroid hormone 1-84 and vascular endothelial growth factor].

PubMed

Wang, Li; Wang, Haiya; Fang, Ningyuan

2016-06-01

To determine whether algal oligosac- charide~ affects the levels of parathyroid hormone 1-84 (PTH1-84) and vascular endothelial growth fac- tor (VEGF). An osteoporosis rat model was estab- lished via bilateral ovariectomy. The model rats were fed algal oligosaccharides (molecular weights: 600-1, 200 Da) for 4 months. Bone mineral density (BMD) was then measured. MG-63 human osteo- blastic cells were treated with algal oligosaccha- rides. The expression of PTH1-84 and VEGF was then examined. Oligosaccharide-treated cells were transfected with PTH1-84 short hairpin RNA (shR- NA), VEGF shRNA, and PTH1-84-VEGF small interfer- ing RNA (siRNA). The growth rates were then com- pared between transfected and non-transfected Algal oligosaccharides increased the BMD of the osteoporosis rat model compared with untreated controls (P < 0.05). When MG-63 cells were treated with algal oligosaccharides, the growth rate increased by 25% compared with the control group at day 3 (P < 0.05). In addition, the ex- pression of P.TH84 and VEGF was. enhanced. Con- versey w hen tecells were tranfected with PTH84 shRNA, VEGF shRNA, or PTH1-84-VEGF siR- NA, the growth rate was decreased by 17%, 35% and 70%, respectively, compared with controls at day 3 (P < 0.05). Algal oligosaccharides ameliorate osteoporosis via up-regulation of PTH1-84 and VEGF. Algal oligosaccharides should be developed as a potential drug for osteoporosis treatment.

Parathyroid hormone ablation alters erythrocyte parameters that are rescued by calcium-sensing receptor gene deletion.

PubMed

Romero, Jose R; Youte, Rodeler; Brown, Edward M; Pollak, Martin R; Goltzman, David; Karaplis, Andrew; Pong, Lie-Chin; Chien, Lawrence; Chattopadhyay, Naibedya; Rivera, Alicia

2013-07-01

The mechanisms by which parathyroid hormone (PTH) produces anemia are unclear. Parathyroid hormone secretion is regulated by the extracellular Ca2+ -sensing receptor. We investigated the effects of ablating PTH on hematological indices and erythrocytes volume regulation in wild-type, PTH-null, and Ca2+ -sensing receptor-null/PTH-null mice. The erythrocyte parameters were measured in whole mouse blood, and volume regulatory systems were determined by plasma membrane K+ fluxes, and osmotic fragility was measured by hemoglobin determination at varying osmolarities. We observed that the absence of PTH significantly increases mean erythrocyte volume and reticulocyte counts, while decreasing erythrocyte counts, hemoglobin, hematocrit, and mean corpuscular hemoglobin concentration. These changes were accompanied by increases in erythrocyte cation content, a denser cell population, and increased K+ permeability, which were in part mediated by activation of the K+ /Cl- cotransporter and Gardos channel. In addition we observed that erythrocyte osmotic fragility in PTH-null compared with wild-type mice was enhanced. When Ca2+ -sensing receptor gene was deleted on the background of PTH-null mice, we observed that several of the alterations in erythrocyte parameters of PTH-null mice were largely rescued, particularly those related to erythrocyte volume, K+ fluxes and osmotic fragility, and became similar to those observed in wild-type mice. Our results demonstrate that Ca2+ -sensing receptor and parathyroid hormone are functionally coupled to maintain erythrocyte homeostasis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Parathyroidectomy in patients with chronic kidney disease: Impacts of different techniques on the biochemical and clinical evolution of secondary hyperparathyroidism.

PubMed

Albuquerque, Roxana de Fátima Camelo; Carbonara, Cinthia Esbrile Moraes; Martin, Rita de Cássia T; Dos Reis, Luciene Machado; do Nascimento, Climério Pereira; Arap, Sérgio Samir; Moysés, Rosa M A; Jorgetti, Vanda; Montenegro, Fábio L M; de Oliveira, Rodrigo Bueno

2018-02-01

Parathyroidectomy (PTx) decreases the mortality rate of refractory secondary hyperparathyroidism (rSHP) due to chronic kidney disease. A consensus regarding which techniques of PTx are associated with better outcomes is not available. The aims of this study are to evaluate the clinical and laboratory evolution of 49 hemodialysis patients with rSHP who underwent PTx using different techniques. Patients underwent subtotal PTx (sub-PTx) or total PTx with autotransplantation (AT) of 45 (PTx-AT 45 ) or 90 parathyroid fragments (PTx-AT 90 ) and were followed for 12 months. We analyzed the expression of proliferating cell nuclear antigen (PCNA), calcium-sensing receptor (CasR), vitamin D receptor (VDR), fibroblast growth factor receptor-1 (FGFR1), sodium-dependent phosphate cotransporter-1 (PIT1), and Klotho in parathyroid glands. Baseline median serum intact parathyroid hormone (iPTH) levels were 1,466 (1,087-2,125) pg/mL; vascular calcification scores correlated with serum iPTH (r = 0.529; P = .002) and serum phosphate levels (r = 0.389; P = .028); and Klotho expression was negatively correlated with serum phosphate levels (r = -0.4; P = .01). After 12 months, serum iPTH and alkaline phosphatase levels were significantly controlled in all groups, as was bone pain. The proportions of patients with serum iPTH levels within the ranges recommended by Kidney Disease: Improving Global Outcomes were similar among the treatment groups. During the hungry bone disease (HBS), patients received 3,786 g (1,412-7,580) of elemental calcium, and a trend toward a positive correlation between the cumulative calcium load at the end of follow up and VC score post-PTx was noted (r = 0.390; P = .06). Two cases evolved to clinically uncontrolled hyperparathyroidism in the sub-PTx group. The expression patterns of PCNA, VDR, CasR, PIT1, FGFR1, and Klotho in parathyroid glands did not correlate with serum systemic iPTH levels or the duration of HBS. All 3 operative techniques were effective at controlling rSHP, both in clinical and laboratory terms. Neither the quantity nor quality of parathyroid fragments influenced serum systemic iPTH and AT-iPTH levels. The cumulative calcium load appeared to correlate with the VC score and may have affected its progression. The effects of phosphate restriction on Klotho expression in human parathyroid glands and the subsequent decrease in FGF23 resistance must be addressed in further studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Investigation on Electrochemical Properties of Polythiophene Nanocomposite with Graphite Derivatives as Supercapacitor Material on Breath Figure-Decorated PMMA Electrode

NASA Astrophysics Data System (ADS)

Azimi, Mona; Abbaspour, Mohsen; Fazli, Ali; Setoodeh, Hamideh; Pourabbas, Behzad

2018-03-01

Breath figures have been formed by the direct breath figure method on polymethyl methacrylate electrode sand hexagonal oriented holes with 0.5- to 10- μm2 surface area have been created. Deposition of materials on the electrodes has been performed by the spray-coating method. polythiophene (PTh) nanoparticles, polythiophene-graphene oxide (PTh-GO) and polythiophene-reduced graphene oxide (PTh-G) nanocomposites were synthesized by emulsion polymerization, while characterization of synthetic materials have been carried out by Fourier transform infrared, Χ-ray diffraction, transmission electron microscopy, UV-Vis spectroscopy and field emission scanning electron microscopy techniques. Also, the electrochemical properties of the designed electrodes were investigated by cyclic voltammetry, galvanostatic charge-discharge and electrochemical impedance spectroscopy techniques. Specific capacitance of porous electrodes coated by PTh nanoparticles, PTh-GO and PTh-G nanocomposites were calculated from cyclic voltammetry curves at 5 mV/s scan rate, andthe values are 3.5 F/g, 16.39 F/g, and 28.68 F/g, respectively. Also, the energy density of each electrode at 5 mV/s scan rate has been calculated and the results show that incorporation of GO and G nanolayers with PTh nanoparticles enhances the electrochemical properties of electrodes.

Oxidation inhibits PTH receptor signaling and trafficking

PubMed Central

Ardura, Juan A.; Alonso, Verónica; Esbrit, Pedro; Friedman, Peter A.

2017-01-01

Reactive Oxygen Species (ROS) increase during aging, potentially affecting many tissues including brain, heart, and bone. ROS alter signaling pathways and constitute potential therapeutic targets to limit oxidative damaging effects in aging-associated diseases. Parathyroid hormone receptors (PTHR) are widely expressed and PTH is the only anabolic therapy for osteoporosis. The effects of oxidative stress on PTHR signaling and trafficking have not been elucidated. Here, we used Fluorescence Resonance Energy Transfer (FRET)-based cAMP, ERK, and calcium fluorescent biosensors to analyze the effects of ROS on PTHR signaling and trafficking by live-cell imaging. PTHR internalization and recycling were measured in HEK-293 cells stably transfected with HA-PTHR. PTH increased cAMP production, ERK phosphorylation, and elevated intracellular calcium. Pre-incubation with H2O2 reduced all PTH-dependent signaling pathways. These inhibitory effects were not a result of PTH oxidation since PTH incubated with H2O2 triggered similar responses. PTH promoted internalization and recycling of the PTHR. Both events were significantly reduced by H2O2 pre-incubation. These findings highlight the role of oxidation on PTHR signaling and trafficking, and suggest the relevance of ROS as a putative target in diseases associated with oxidative stress such as age-related osteoporosis. PMID:27908723

Isolation of 16,000-dalton parathyroid hormone-like proteins from two animal tumors causing humoral hypercalcemia of malignancy.

PubMed

Weir, E C; Burtis, W J; Morris, C A; Brady, T G; Insogna, K L

1988-12-01

A 16K PTH-like protein with a unique primary structure has recently been isolated from several human tumors associated with the syndrome of humoral hypercalcemia of malignancy. Certain spontaneous and transplantable animal tumors also cause this syndrome. The responsible mediator in these animal tumors is not known. We report the isolation of 16K proteins from the rat H500 Leydig cell tumor and the canine apocrine cell adenocarcinoma of the anal sac. Both proteins are potent activators of PTH receptor-coupled adenylate cyclase in bone cells. Both proteins demonstrate similarities in amino acid composition to one another and to the human PTH-like protein. Limited amino-terminal sequence information from the canine protein demonstrates homology with the human PTH-like protein. Antibodies raised to a synthetic human PTH-(1-36)-like peptide cross-react with both the rat and canine proteins in an immunoradiometric assay. These data demonstrate that by physical and immunological criteria PTH-like peptides are present in these animal tumors that appear to be closely related to the human PTH-like peptide. These data further suggest that this protein is not unique to humans, but has an evolutionary origin which extends back at least 65-80 million yr.

Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

PubMed Central

Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson

2012-01-01

Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture. PMID:24710549

Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism.

PubMed

Gafni, Rachel I; Guthrie, Lori C; Kelly, Marilyn H; Brillante, Beth A; Christie, C Michele; Reynolds, James C; Yovetich, Nancy A; James, Robert; Collins, Michael T

2015-11-01

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon. © 2015 American Society for Bone and Mineral Research.

Systemic administration of mesenchymal stem cells combined with parathyroid hormone therapy synergistically regenerates multiple rib fractures.

PubMed

Cohn Yakubovich, Doron; Sheyn, Dmitriy; Bez, Maxim; Schary, Yeshai; Yalon, Eran; Sirhan, Afeef; Amira, May; Yaya, Alin; De Mel, Sandra; Da, Xiaoyu; Ben-David, Shiran; Tawackoli, Wafa; Ley, Eric J; Gazit, Dan; Gazit, Zulma; Pelled, Gadi

2017-03-09

A devastating condition that leads to trauma-related morbidity, multiple rib fractures, remain a serious unmet clinical need. Systemic administration of mesenchymal stem cells (MSCs) has been shown to regenerate various tissues. We hypothesized that parathyroid hormone (PTH) therapy would enhance MSC homing and differentiation, ultimately leading to bone formation that would bridge rib fractures. The combination of human MSCs (hMSCs) and a clinically relevant PTH dose was studied using immunosuppressed rats. Segmental defects were created in animals' fifth and sixth ribs. The rats were divided into four groups: a negative control group, in which animals received vehicle alone; the PTH-only group, in which animals received daily subcutaneous injections of 4 μg/kg teriparatide, a pharmaceutical derivative of PTH; the hMSC-only group, in which each animal received five injections of 2 × 10 6 hMSCs; and the hMSC + PTH group, in which animals received both treatments. Longitudinal in vivo monitoring of bone formation was performed biweekly using micro-computed tomography (μCT), followed by histological analysis. Fluorescently-dyed hMSCs were counted using confocal microscopy imaging of histological samples harvested 8 weeks after surgery. PTH significantly augmented the number of hMSCs that homed to the fracture site. Immunofluorescence of osteogenic markers, osteocalcin and bone sialoprotein, showed that PTH induced cell differentiation in both exogenously administered cells and resident cells. μCT scans revealed a significant increase in bone volume only in the hMSC + PTH group, beginning by the 4 th week after surgery. Eight weeks after surgery, 35% of ribs in the hMSC + PTH group had complete bone bridging, whereas there was complete bridging in only 6.25% of ribs (one rib) in the PTH-only group and in none of the ribs in the other groups. Based on the μCT scans, biomechanical analysis using the micro-finite element method demonstrated that the healed ribs were stiffer than intact ribs in torsion, compression, and bending simulations, as expected when examining bone callus composed of woven bone. Administration of both hMSCs and PTH worked synergistically in rib fracture healing, suggesting this approach may pave the way to treat multiple rib fractures as well as additional fractures in various anatomical sites.

Additive effect of PTH (1-34) and zoledronate in the prevention of disuse osteopenia in rats.

PubMed

Vegger, Jens Bay; Nielsen, Esben Sommer; Brüel, Annemarie; Thomsen, Jesper Skovhus

2014-09-01

Immobilization is known to cause a rapid bone loss due to increased osteoclastic bone resorption and decreased osteoblastic bone formation. Zoledronate (Zln) is a potent anti-resorptive pharmaceutical, while intermittent PTH is a potent bone anabolic agent. The aim of the present study was to investigate whether PTH or Zln alone or in combination could prevent immobilization-induced osteopenia. Immobilization was achieved by injecting 4IU Botox (BTX) into the right hind limb musculature. Seventy-two 16-week-old female Wistar rats were randomized into 6 groups; baseline (Base), control (Ctrl), BTX, BTX+PTH, BTX+Zln, and BTX+PTH+Zln. PTH (1-34) (80μg/kg) was given 5days/week and Zln (100μg/kg) was given once at study start. The animals were killed after 4weeks of treatment. The bone properties were evaluated using DEXA, μCT, dynamic bone histomorphometry, and mechanical testing. BTX resulted in lower femoral trabecular bone volume fraction (BV/TV) (-25%, p<0.05), lower tibial trabecular bone formation rate (BFR/BS) (-29%, p<0.05), and lower bone strength (Fmax) at the distal femur (-19%, p<0.001) compared with Ctrl. BTX+PTH resulted in higher femoral BV/TV (+31%, p<0.05), higher tibial trabecular BFR/BS (+297%, p<0.05), and higher Fmax at the distal femur (+11%, p<0.05) compared with BTX. BTX+Zln resulted in higher femoral BV/TV (+36%, p<0.05), lower tibial trabecular BFR/BS (-93%, p<0.05), and higher Fmax at the distal femur (+10%, p<0.05) compared with BTX. BTX+PTH+Zln resulted in higher femoral BV/TV (+70%, p<0.001), higher tibial trabecular BFR/BS (+59%, p<0.05), and higher Fmax at the distal femur (+32%, p<0.001) compared with BTX. In conclusion, BTX-induced immobilization led to lower BV/TV, BFR/BS, and Fmax. In general, PTH or Zln alone prevented the BTX-induced osteopenia, whereas PTH and Zln given in combination not only prevented, but also increased BV/TV and BFR/BS, and maintained Fmax at the distal femoral metaphysis compared with Ctrl. Copyright © 2014 Elsevier Inc. All rights reserved.

High dose teriparatide (rPTH1-34) therapy increases callus volume and enhances radiographic healing at 8-weeks in a massive canine femoral allograft model.

PubMed

Nishitani, Kohei; Mietus, Zachary; Beck, Christopher A; Ito, Hiromu; Matsuda, Shuichi; Awad, Hani A; Ehrhart, Nicole; Schwarz, Edward M

2017-01-01

Small animal studies have demonstrated significant high-dose recombinant parathyroid hormone1-34 (rPTH1-34) effects on intercalary allograft healing. Towards a human adjuvant therapy to decrease non-unions, we evaluated rPTH1-34 safety and efficacy in a clinically relevant canine femoral allograft model. Adult female mongrel hounds (n = 20) received a 5cm mid-diaphyseal osteotomy reconstructed with a plated allograft, and were randomized to: 1) Placebo (n = 5; daily saline), 2) Continuous rPTH1-34 (n = 7; 5 μg/kg/day s.c. from day 1-55 post-op), or 3) Delayed rPTH1-34 (n = 8; 5 μg/kg/day s.c. from day 14-28 post-op). Safety was assessed by physical behavior and blood calcium monitoring. Cone beam CT (CB-CT) was performed on days 14, 28 and 56 post-op to assess 2D cortical healing, 3D bone volume, and Union Ratio. Biomechanical testing and dynamic histomorphometry were also performed. The high drug dose was poorly tolerated, as most dogs receiving rPTH1-34 had to be given intravenous saline, and one dog died from hypercalcemia. Continuous rPTH1-34 significantly increased 2D healing and callus volumes at 4-weeks versus Placebo, and sustained the significant increase in cortical union at 8-week (p<0.05). These rPTH1-34 effects were confirmed by histomorphometry, revealing significant increases in mineral apposition rates (MAR) on host bone and graft-host junctions (p<0.05). Delayed rPTH1-34 significantly increased callus volume and MAR at 8 weeks (p<0.05). Although no biomechanical differences were observed, as expected for early healing, the results demonstrated that 2D RUST scoring significantly correlated with torsional biomechanics (p<0.01). In conclusion, 8-weeks of intermittent high-dose rPTH1-34 treatment significantly increases callus formation and accelerates bony union of intercalary massive allografts in a clinically relevant canine model, but with serious side-effects from hypercalcemia.

Dopamine enhances the phosphaturic effect of PTH during acute respiratory alkalosis.

PubMed

Berndt, T J; Tucker, R R; Kent, P D; Streiff, P C; Tyce, G M; Knox, F G

1999-12-01

The phosphaturic response to parathyroid hormone (PTH) is blunted during acute respiratory alkalosis. The objective of the present study was to determine the effect of dopamine on the blunted phosphaturic response to PTH during acute respiratory alkalosis. The phosphaturic response to PTH was determined in thyroparathyroidectomized (TPTX) normocapnic and respiratory alkalotic rats in the absence and presence of the infusion of exogenous dopamine (25 microg/kg/min) or of 3,4-dihydroxyphenylalanine (L-DOPA, 250 microg/kg/min) to increase endogenous dopamine synthesis. In normocapnic rats, PTH infusion (33 U/kg plus 1 U/kg/min) significantly increased the fractional excretion of phosphate (FE(Pi)), from 1.5%+/-0.5% to 28.4%+/-4.0%, (deltaFE(Pi) 26.9%+/-4.1%, n = 11, P<.05); in respiratory alkalotic rats, the increase was from 0.4%+/-0.1% to 11.4%+/-1.7% (deltaFE(Pi) 11.0%+/-1.8%, n = 13, P<.05). However, the phosphaturic response to PTH was attenuated in respiratory alkalotic rats (deltaFE(Pi) 26.9%+/-4.1% vs 11.0%+/-1.9%, P<.05). In normocapnic rats, in the presence of dopamine or L-DOPA infusions, PTH infusion significantly increased the FE(Pi) from 6.1%+/-2.3% to 33.4%+/-8.0% (deltaFE(Pi) 27.3%+/-7.0%, n = 5) and from 3.2%+/-0.6% to 32.5%+/-3.3% (deltaFE(Pi) 29.3%+/-3.2%, n = 7), respectively. In respiratory alkalotic rats, in the presence of dopamine infusion, PTH significantly increased the FE(Pi), from 0.6%+/-0.2% to 19.3%+/-3.3% (deltaFE(Pi) 18.7%+/-3.3%, n = 6); in the presence of L-DOPA infusion it increased from 1.0%+/-0.3% to 20.5%+/-2.8% (deltaFE(Pi) 19.5%+/-2.9%, n = 8, P<.05 as compared with PTH alone). Thus the phosphaturic effect of PTH that was attenuated in respiratory alkalotic rats was enhanced by stimulation of endogenous dopamine synthesis by the infusion of L-DOPA.

High dose teriparatide (rPTH1-34) therapy increases callus volume and enhances radiographic healing at 8-weeks in a massive canine femoral allograft model

PubMed Central

Mietus, Zachary; Beck, Christopher A.; Ito, Hiromu; Matsuda, Shuichi; Awad, Hani A.; Ehrhart, Nicole; Schwarz, Edward M.

2017-01-01

Small animal studies have demonstrated significant high-dose recombinant parathyroid hormone1-34 (rPTH1-34) effects on intercalary allograft healing. Towards a human adjuvant therapy to decrease non-unions, we evaluated rPTH1-34 safety and efficacy in a clinically relevant canine femoral allograft model. Adult female mongrel hounds (n = 20) received a 5cm mid-diaphyseal osteotomy reconstructed with a plated allograft, and were randomized to: 1) Placebo (n = 5; daily saline), 2) Continuous rPTH1-34 (n = 7; 5 μg/kg/day s.c. from day 1–55 post-op), or 3) Delayed rPTH1-34 (n = 8; 5 μg/kg/day s.c. from day 14–28 post-op). Safety was assessed by physical behavior and blood calcium monitoring. Cone beam CT (CB-CT) was performed on days 14, 28 and 56 post-op to assess 2D cortical healing, 3D bone volume, and Union Ratio. Biomechanical testing and dynamic histomorphometry were also performed. The high drug dose was poorly tolerated, as most dogs receiving rPTH1-34 had to be given intravenous saline, and one dog died from hypercalcemia. Continuous rPTH1-34 significantly increased 2D healing and callus volumes at 4-weeks versus Placebo, and sustained the significant increase in cortical union at 8-week (p<0.05). These rPTH1-34 effects were confirmed by histomorphometry, revealing significant increases in mineral apposition rates (MAR) on host bone and graft-host junctions (p<0.05). Delayed rPTH1-34 significantly increased callus volume and MAR at 8 weeks (p<0.05). Although no biomechanical differences were observed, as expected for early healing, the results demonstrated that 2D RUST scoring significantly correlated with torsional biomechanics (p<0.01). In conclusion, 8-weeks of intermittent high-dose rPTH1-34 treatment significantly increases callus formation and accelerates bony union of intercalary massive allografts in a clinically relevant canine model, but with serious side-effects from hypercalcemia. PMID:29020057

Gene transfer of heterologous G protein-coupled receptors to cardiomyocytes: differential effects on contractility.

PubMed

Laugwitz, K L; Weig, H J; Moretti, A; Hoffmann, E; Ueblacker, P; Pragst, I; Rosport, K; Schömig, A; Ungerer, M

2001-04-13

In heart failure, reduced cardiac contractility is accompanied by blunted cAMP responses to beta-adrenergic stimulation. Parathyroid hormone (PTH)-related peptide and arginine vasopressin are released from the myocardium in response to increased wall stress but do not stimulate contractility or adenylyl cyclase at physiological concentrations. To bypass the defective beta-adrenergic signaling cascade, recombinant P1 PTH/PTH-related peptide receptors (rPTH1-Rs) and V(2) vasopressin receptors (rV(2)-Rs), which are normally not expressed in the myocardium and which are both strongly coupled to adenylyl cyclase, and recombinant beta(2)-adrenergic receptors (rbeta(2)-ARs) were overexpressed in cardiomyocytes by viral gene transfer. The capacity of endogenous hormones to increase contractility via the heterologous, recombinant receptors was compared. Whereas V(2)-Rs are uniquely coupled to Gs, PTH1-Rs and beta(2)-ARs are also coupled to other G proteins. Gene transfer of rPTH1-Rs or rbeta(2)-ARs to adult cardiomyocytes resulted in maximally increased basal contractility, which could not be further stimulated by adding receptor agonists. Agonists at rPTH1-Rs induced increased cAMP formation and phospholipase C activity. In contrast, healthy or failing rV(2)-R-expressing cardiomyocytes showed unaltered basal contractility. Their contractility and cAMP formation increased only at agonist exposure, which did not activate phospholipase C. In summary, we found that gene transfer of PTH1-Rs to cardiomyocytes results in constitutive activity of the transgene, as does that of beta(2)-ARS: In the absence of receptor agonists, rPTH1-Rs and rbeta(2)-ARs increase basal contractility, coupling to 2 G proteins simultaneously. In contrast, rV(2)-Rs are uniquely coupled to Gs and are not constitutively active, retaining their property to be activated exclusively on agonist stimulation. Therefore, gene transfer of V(2)-Rs might be more suited to test the effects of cAMP-stimulating receptors in heart failure than that of PTH1-Rs or beta(2)-ARS:

Blocking the expression of both bone sialoprotein (BSP) and osteopontin (OPN) impairs the anabolic action of PTH in mouse calvaria bone.

PubMed

Bouleftour, Wafa; Bouet, Guenaelle; Granito, Renata Neves; Thomas, Mireille; Linossier, Marie-Thérèse; Vanden-Bossche, Arnaud; Aubin, Jane E; Lafage-Proust, Marie-Hélène; Vico, Laurence; Malaval, Luc

2015-03-01

Osteopontin (OPN) and bone sialoprotein (BSP) are coexpressed in osteoblasts and osteoclasts, and display overlapping properties. We used daily injection of parathyroid hormone 1-84 (iPTH) over the calvaria of BSP knockout (-/-) mice to investigate further their functional specificity and redundancy. iPTH stimulated bone formation in both +/+ and -/- mice, increasing to the same degree periosteum, osteoid and total bone thickness. Expression of OPN, osterix, osteocalcin (OCN) and DMP1 was also increased by iPTH in both genotypes. In contrast to +/+, calvaria cell cultures from -/- mice revealed few osteoblast colonies, no mineralization and little expression of OCN, MEPE or DMP1. In contrast, OPN levels were 5× higher in -/- versus +/+ cultures. iPTH increased alkaline phosphatase (ALP) activity in cell cultures of both genotypes, with higher OCN and the induction of mineralization in -/- cultures. siRNA blocking of OPN expression did not alter the anabolic action of the hormone in BSP +/+ calvaria, while it blunted iPTH effects in -/- mice, reduced to a modest increase in periosteum thickness. In -/- (not +/+) cell cultures, siOPN blocked the stimulation by iPTH of ALP activity and OCN expression, as well as the induction of mineralization. Thus, full expression of either OPN or BSP is necessary for the anabolic effect of PTH at least in the ectopic calvaria injection model. This suggests that OPN may compensate for the lack of BSP in the response to this hormonal challenge, and provides evidence of functional overlap between these cognate proteins. © 2014 Wiley Periodicals, Inc., A Wiley Company.

Sestamibi scan-directed parathyroid surgery: potentially high failure rate without measurement of intraoperative parathyroid hormone.

PubMed

Westerdahl, Johan; Bergenfelz, Anders

2004-11-01

The present study evaluated sestamibi scan-directed parathyroidectomy with intraoperative parathyroid hormone (PTH) assessment (ioPTH). The preoperative sestamibi scintigraphies were compared with the intraoperative findings for 103 patients undergoing first exploration for sporadic primary hyperparathyroidism (pHPT). Data were collected prospectively. Ninety-nine patients (96%) were cured. Patients with persistent pHPT (n = 4) all had an incorrect scintigram as well as an insufficient decline of ioPTH. At operation, 90 patients (87%) had solitary parathyroid adenoma; 12 patients had multiglandular disease. In one patient no enlarged parathyroid gland was found. Overall 77 of 118 abnormal glands (65%) were correctly identified by sestamibi scintigraphy. The sensitivity for localizing a single parathyroid adenoma was 80%. Patients with incorrect scintigrams had a higher proportion of upper pole adenomas than patients with correct scans. High glandular weight and high level of serum PTH were important factors for detectability. Sestamibi scintigraphy did not predict multiglandular disease. However, the use of ioPTH identified 8 of the 9 patients with a positive scan (a solitary focus) and multiglandular disease. In contrast, false-negative ioPTH led to four unnecessary bilateral explorations in the 63 patients with a scan-identified adenoma. With the help of ioPTH, a focused parathyroidectomy was accomplished in 43% of scan-negative patients with a solitary adenoma. In conclusion, sestamibi scintigraphy is an acceptable method for localizing a solitary parathyroid adenoma. However, the technique alone does not reliably predict multiglandular disease. Potentially the failure rate in scan-directed parathyroidectomy could increase, with up to 10% of patients without ioPTH.

Single-dose local administration of parathyroid hormone (1-34, PTH) with β-tricalcium phosphate/collagen (β-TCP/COL) enhances bone defect healing in ovariectomized rats.

PubMed

Tao, Zhou-Shan; Zhou, Wan-Shu; Wu, Xin-Jing; Wang, Lin; Yang, Min; Xie, Jia-Bing; Xu, Zhu-Jun; Ding, Guo-Zheng

2018-02-01

Parathyroid hormone (1-34, PTH) combined β-tricalcium phosphate (β-TCP) achieves stable bone regeneration without cell transplantation in previous studies. Recently, with the development of tissue engineering slow release technology, PTH used locally to promote bone defect healing become possible. This study by virtue of collagen with a combination of drugs and has a slow release properties, and investigated bone regeneration by β-TCP/collagen (β-TCP/COL) with the single local administration of PTH. After the creation of a rodent critical-sized femoral metaphyseal bone defect, β-TCP/COL was prepared by mixing sieved granules of β-TCP and atelocollagen for medical use, then β-TCP/COL with dripped PTH solution (1.0 µg) was implanted into the defect of OVX rats until death at 4 and 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, and biomechanics. The results of our study show that single-dose local administration of PTH combined local usage of β-TCP/COL can increase the healing of defects in OVX rats. Furthermore, treatments with single-dose local administration of PTH and β-TCP/COL showed a stronger effect on accelerating the local bone formation than β-TCP/COL used alone. The results from our study demonstrate that combination of single-dose local administration of PTH and β-TCP/COL had an additive effect on local bone formation in osteoporosis rats.

Algorithm for early discharge after total thyroidectomy using PTH to predict hypocalcemia: prospective study.

PubMed

Schlottmann, F; Arbulú, A L Campos; Sadava, E E; Mendez, P; Pereyra, L; Fernández Vila, J M; Mezzadri, N A

2015-10-01

Hypocalcemia is the most common complication after total thyroidectomy. The aim of this study was to determine whether postoperative parathyroid hormone (PTH) levels predict hypocalcemia in order to design an algorithm for early discharge. We present a prospective study including patients who underwent total thyroidectomy. Hypocalcemia was defined as serum ionized calcium < 1.09 mmol/L or clinical evidence of hypocalcemia. PTH measurement was performed preoperatively and at 1, 3, and 6 h postoperatively. The percent decline of preoperative values was calculated for each time point. One hundred and six patients were included. Thirty-six (33.9%) patients presented hypocalcemia. A 50% decline in PTH levels at 3 h postoperatively showed the highest sensitivity and specificity to predict hypocalcemia (91 and 73%, respectively). No patients with a decrease <35% developed hypocalcemia (100% sensitivity), and all patients with a decrease >80% had hypocalcemia (100% specificity). PTH determination at 3 h postoperatively is a reliable predictor of hypocalcemia. According to the proposed algorithm, patients with less than 80% drop in PTH levels can be safely discharged the day of the surgery.

Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.

PubMed

Arnadottir, M; Nilsson-Ehle, P

1994-01-01

The reduced lipoprotein lipase (LPL) activities in uraemia are reflected by increased serum triglyceride concentrations and reduced HDL cholesterol concentrations. Both hyperparathyroidism and circulating inhibitor(s) of LPL have been associated with the disturbances of lipid metabolism in uraemia. The aim of the present study was to investigate if parathyroid hormone (PTH) had an inhibitory effect on LPL activity. Plasma post-heparin LPL activities, plasma LPL inhibitory activities, serum PTHintact and serum PTHC-terminal concentrations were analysed in 20 patients on haemodialysis and 20 healthy controls. The effects of purified, human PTHintact and a carboxyterminal fragment of PTH (PTH39-84) on LPL activities in post-heparin plasma from healthy individuals and on the enzyme activity of purified, bovine milk LPL, activated with apolipoprotein CII, were studied. Patients had significantly higher plasma LPL inhibitory activities than controls, but there was no correlation between plasma LPL inhibitory activities and serum PTH concentrations. Neither PTHintact nor PTH39-84 had a significant effect on LPL activities in vitro. Thus there was no evidence of a direct inhibition of LPL activity by PTH under the present in-vivo or in-vitro conditions.

Detection of parathyroid hormone using an electrochemical impedance biosensor based on PAMAM dendrimers.

PubMed

Özcan, Hakkı Mevlüt; Sezgintürk, Mustafa Kemal

2015-01-01

This paper presents a novel hormone-based impedimetric biosensor to determine parathyroid hormone (PTH) level in serum for diagnosis and monitoring treatment of hyperparathyroidism, hypoparathyroidism and thyroid cancer. The interaction between PTH and the biosensor was investigated by an electrochemical method. The biosensor was based on the gold electrode modified by 12-mercapto dodecanoic (12MDDA). Antiparathyroid hormone (anti-PTH) was covalently immobilized on to poly amidoamine dendrimer (PAMAM) which was bound to a 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) couple, self-assembled monolayer structure from one of the other NH2 sites. The immobilization of anti-PTH was monitored by electrochemical impedance spectroscopy, cyclic voltammetry and scanning electron microscope techniques. After the optimization studies of immobilization materials such as 12MDDA, EDC-NHS, PAMAM, and glutaraldehyde, the performance of the biosensor was investigated in terms of linearity, sensitivity, repeatability, and reproducibility. PTH was detected within a linear range of 10-60 fg/mL. Finally the described biosensor was used to monitor PTH levels in artificial serum samples. © 2015 American Institute of Chemical Engineers.

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH).

PubMed

Dong, Bingzi; Endo, Itsuro; Ohnishi, Yukiyo; Kondo, Takeshi; Hasegawa, Tomoka; Amizuka, Norio; Kiyonari, Hiroshi; Shioi, Go; Abe, Masahiro; Fukumoto, Seiji; Matsumoto, Toshio

2015-11-01

Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a novel therapeutic agent for ADH. © 2015 American Society for Bone and Mineral Research.

Vitamin D Deficiency and Secondary Hyperparathyroidism Are Common Complications in Patients with Peripheral Arterial Disease

PubMed Central

Fahrleitner, Astrid; Dobnig, Harald; Obernosterer, Andrea; Pilger, Ernst; Leb, Georg; Weber, Kurt; Kudlacek, Stefan; Obermayer-Pietsch, Barbara M

2002-01-01

OBJECTIVE To investigate via the vitamin D status whether patients with peripheral arterial disease (PAD) tend to develop vitamin D deficiency that in turn influences their clinical symptoms. DESIGN Cross-sectional. SETTING University hospital. PATIENTS AND PARTICIPANTS Three hundred twenty-seven patients were evaluated; subjects with secondary causes of bone disease or bone active medication were excluded. One hundred sixty-one patients with either PAD stage II (n = 84) or stage IV (n = 77) were enrolled and compared to 45 age- and sex-matched healthy controls. MEASUREMENTS AND MAIN RESULTS All patients underwent determinations of serum chemistry, 25-hydroxyvitamin D (vitamin D3) intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and osteocalcin and were further stratified according to an individual restriction score into 3 groups: mildly, moderately, or severely restricted in daily life due to the underlying disease. Patients with PAD IV showed significantly lower vitamin D3 (P = .0001), and calcium (P = .0001) values and significantly higher iPTH (P = .0001), osteocalcin (P = .0001) and ALP (P = .02) levels as compared to patients with PAD II. Patients considering themselves as severely restricted due to the underlying disease showed lower vitamin D3 and higher iPTH levels than those who described only a moderate (vitamin D3: P < .001; iPTH: P < .01) or mild (vitamin D3: P < .001; iPTH: P < .001) restriction in daily life. CONCLUSION Patients with PAD IV, especially those who feel severely restricted due to the disease, are at high risk of developing vitamin D deficiency, secondary hyperparathyroidism, and ultimately osteomalacia due to immobilization and subsequent lack of exposure to sunlight, all of which in turn lead to further deterioration. Monitoring of vitamin D metabolism and vitamin D replacement therapy could be a simple, inexpensive approach to mitigating clinical symptoms and improving quality of life in patients with advanced PAD. PMID:12220361

The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats

NASA Technical Reports Server (NTRS)

Dobnig, H.; Turner, R. T.

1997-01-01

PTH treatment can result in dramatic increases in cancellous bone volume in normal and osteopenic rats. However, this potentially beneficial response is only observed after pulsatile treatment; continuous infusion of PTH leads to hypercalcemia and bone abnormalities. The purpose of these studies was to determine the optimal duration of the PTH pulses. A preliminary study revealed that human PTH-(1-34) (hPTH) is cleared from circulation within 6 h after sc administration of an anabolic dose of the hormone (80 microg/kg). To establish the effects of gradually extending the duration of exposure to hPTH without increasing the daily dose, we programmed implanted Alzet osmotic pumps to deliver the 80 microg/kg x day dose of the hormone during pulses of 1, 2, and 6 h/day, or 40 microg/kg x day continuously. Discontinuous infusion was accomplished by alternate spacing of external tubing with hPTH solution and sesame oil. After 6 days of treatment, we evaluated serum chemistry and bone histomorphometry. As negative and positive controls, groups of rats received pumps that delivered vehicle only and 80 microg/kg x day hPTH by daily sc injection, respectively. Dynamic and static bone histomorphometry revealed that the daily sc injection and 1 h/day infusion dramatically increased osteoblast number and bone formation in the proximal tibial metaphysis, whereas longer infusion resulted in systemic side-effects, including up to a 10% loss in body weight, hypercalcemia, and histological changes in the proximal tibia resembling abnormalities observed in patients with chronic primary hyperparathyroidism, including peritrabecular marrow fibrosis and focal bone resorption. Infusion for as little as 2 h/day resulted in minor weight loss and changes in bone histology that were intermediate between sc and continuous administration. The results demonstrate that the therapeutic interval for hPTH exposure is brief, but that programmed administration of implanted hormone is a feasible alternative to daily injection as a route for administration of the hormone.

Parathyroid Hormone Regulates the Distribution and Osteoclastogenic Potential of Hematopoietic Progenitors in the Bone Marrow

PubMed Central

Jacome-Galarza, Christian E; Lee, Sun-Kyeong; Lorenzo, Joseph A; Aguila, Hector Leonardo

2011-01-01

Parathyroid hormone (PTH) increases both the number of osteoclast in bone and the number of early hematopoietic stem cells (HSCs) in bone marrow. We previously characterized the phenotype of multiple populations of bone marrow cells with in vitro osteoclastogenic potential in mice. Here we examined whether intermittent administration of PTH influences these osteoclast progenitor (OCP) populations. C57BL/6 mice were treated with daily injections of bPTH(1–34) (80 μg/kg/day) for 7 or 14 days. We found that PTH caused a significant increase in the percentage of TN/CD115+CD117high and TN/CD115+CD117int cells ( p <.05) in bone marrow on day 7. In contrast, PTH decreased the absolute number of TN/CD115+CD117low cells by 39% on day 7 ( p <.05). On day 14, there was no effect of PTH on osteoclast progenitor distribution in vivo. However, PTH treatment for 7 and 14 days did increase receptor activator of NF-κB ligand (RANKL)– and macrophage colony-stimulating factor (M-CSF)–stimulated in vitro osteoclastogenesis and bone resorption in TN/CD115+ cells. In the periphery, 14 days of treatment increased the percentage and absolute numbers of HSCs (Lin−CD117+Sca-1+) in the spleen ( p <.05). These data correlated with an increase in the percent and absolute numbers of HSCs in bone marrow on day 14 ( p <.05). Interestingly, the effects on hematopoietic progenitors do not depend on osteoclast resorption activity. These results suggest that in vivo PTH treatment increased in vitro osteoclastogenesis and resorption without altering the number of osteoclast precursors. This implies that in vivo PTH induces sustained changes, possibly through an epigenetic mechanism, in the in vitro responsiveness of the cells to M-CSF and RANKL. PMID:21611963

Effect of intermittent PTH(1-34) on human periodontal ligament cells transplanted into immunocompromised mice.

PubMed

Wolf, Michael; Lossdörfer, Stefan; Abuduwali, Nuersailike; Meyer, Rainer; Kebir, Sied; Götz, Werner; Jäger, Andreas

2012-09-01

Residual periodontal ligament (PDL) cells in the damaged tissue are considered a prerequisite for a successful regeneration of the periodontal architecture with all its components, including gingiva, PDL, cementum, and bone. Among other approaches, current concepts in tissue engineering aim at a hormonal support of the regenerative capacity of PDL cells as well as at a supplementation of lost cells for regeneration. Here, we investigated how far an anabolic, intermittent parathyroid hormone (iPTH) administration would enhance the osteoblastic differentiation of PDL cells and the cellular ability to mineralize the extracellular matrix in an in vivo transplantation model. PDL cells were predifferentiated in a standard osteogenic medium for 3 weeks before subcutaneous transplantation into CD-1 nude mice using gelatin sponges as carrier. Daily injections of 40 μg/kg body weight PTH(1-34) or an equivalent dose of vehicle for 4 weeks were followed by explantation of the specimens and an immunohistochemical analysis of the osteoblastic marker proteins alkaline phosphatase (ALP), osteopontin, and osteocalcin. Signs of biomineralization were visualized by means of alizarin red staining. For verification of the systemic effect of iPTH application, blood serum levels of osteocalcin were determined. The osteogenic medium stimulated the expression of ALP and PTH1-receptor mRNA in the cultures. After transplantation, iPTH resulted in an increased cytoplasmic and extracellular immunoreactivity for all markers investigated. In contrast to only sporadic areas of mineralization under control conditions, several foci of mineralization were observed in the iPTH group. Blood serum levels of osteocalcin were elevated significantly with iPTH. These data indicate that the osteoblastic differentiation of human PDL cells and their ability for biomineralization can be positively influenced by iPTH in vivo. These findings hold out a promising prospect for the support of periodontal regeneration.

Effect of Intermittent PTH(1–34) on Human Periodontal Ligament Cells Transplanted into Immunocompromised Mice

PubMed Central

Wolf, Michael; Abuduwali, Nuersailike; Meyer, Rainer; Kebir, Sied; Götz, Werner; Jäger, Andreas

2012-01-01

Residual periodontal ligament (PDL) cells in the damaged tissue are considered a prerequisite for a successful regeneration of the periodontal architecture with all its components, including gingiva, PDL, cementum, and bone. Among other approaches, current concepts in tissue engineering aim at a hormonal support of the regenerative capacity of PDL cells as well as at a supplementation of lost cells for regeneration. Here, we investigated how far an anabolic, intermittent parathyroid hormone (iPTH) administration would enhance the osteoblastic differentiation of PDL cells and the cellular ability to mineralize the extracellular matrix in an in vivo transplantation model. PDL cells were predifferentiated in a standard osteogenic medium for 3 weeks before subcutaneous transplantation into CD-1 nude mice using gelatin sponges as carrier. Daily injections of 40 μg/kg body weight PTH(1–34) or an equivalent dose of vehicle for 4 weeks were followed by explantation of the specimens and an immunohistochemical analysis of the osteoblastic marker proteins alkaline phosphatase (ALP), osteopontin, and osteocalcin. Signs of biomineralization were visualized by means of alizarin red staining. For verification of the systemic effect of iPTH application, blood serum levels of osteocalcin were determined. The osteogenic medium stimulated the expression of ALP and PTH1-receptor mRNA in the cultures. After transplantation, iPTH resulted in an increased cytoplasmic and extracellular immunoreactivity for all markers investigated. In contrast to only sporadic areas of mineralization under control conditions, several foci of mineralization were observed in the iPTH group. Blood serum levels of osteocalcin were elevated significantly with iPTH. These data indicate that the osteoblastic differentiation of human PDL cells and their ability for biomineralization can be positively influenced by iPTH in vivo. These findings hold out a promising prospect for the support of periodontal regeneration. PMID:22497226

Differential Effects of Teriparatide and Denosumab on Intact PTH and Bone Formation Indices: AVA Osteoporosis Study

PubMed Central

Zhou, Hua; Recker, Robert R.; Brown, Jacques P.; Recknor, Christopher P.; Lewiecki, E. Michael; Miller, Paul D.; Rao, Sudhaker D.; Kendler, David L.; Lindsay, Robert; Krege, John H.; Alam, Jahangir; Taylor, Kathleen A.; Janos, Boris; Ruff, Valerie A.

2016-01-01

Context: Denosumab-induced PTH elevation may stimulate early bone formation. Objective: Our objective was to evaluate whether denosumab-induced changes of intact PTH (iPTH) result in early anabolic effects according to histomorphometry and bone turnover markers (BTMs) compared with teriparatide, an established anabolic agent. Design: This open-label, randomized study used quadruple labeling to label bone before/after treatment, with a transiliac bone biopsy at 3 months. Setting: This study took both in both US and Canadian sites. Participants: Sixty-nine postmenopausal women with osteoporosis were included. Interventions: Teriparatide (20 μg/day) for 6 months and denosumab (60 mg once) were used in this study. Main Outcome Measure: Between-treatment comparison of change from baseline to month 3 in cancellous mineralizing surface/bone surface, histomorphometric indices in four bone envelopes, and BTM and iPTH at baseline, 1, 3, and 6 months was undertaken. Results: After denosumab, iPTH peaked at month 1 (P < .001), then declined, remaining above baseline through month 6 (P ≤ .01); after teriparatide, iPTH declined at all time points (P < .001). From baseline to month 3, cancellous mineralizing surface/bone surface increased with teriparatide and decreased with denosumab and at month 3, was higher with teriparatide. Similar results were observed in other bone envelopes. BTMs increased from baseline in teriparatide-treated subjects (procollagen type 1 N-terminal propeptide at month 1 and carboxyterminal cross-linking telopeptide of type 1 collagen at month 3); procollagen type 1 N-terminal propeptide and carboxyterminal cross-linking telopeptide of type 1 collagen decreased from baseline at all time points in denosumab-treated subjects. Conclusions: Denosumab treatment increased iPTH but inhibited bone formation indices. In contrast, teriparatide treatment decreased iPTH but stimulated bone formation indices. These findings are not consistent with the hypothesis of early indirect anabolic effect with denosumab. PMID:26859106

Independent effects of blood pressure and parathyroid hormone on aortic pulse wave velocity in untreated Chinese patients.

PubMed

Cheng, Yi-Bang; Li, Li-Hua; Guo, Qian-Hui; Li, Fei-Ka; Huang, Qi-Fang; Sheng, Chang-Sheng; Wang, Ji-Guang; Staessen, Jan A; Li, Yan

2017-09-01

Whether or not calcium-regulating hormones stiffen arteries independent of blood pressure (BP) is uncertain. We investigated the independent associations of carotid-femoral pulse wave velocity (PWV) with 25-hydroxy-vitamin D [25(OH)D], parathyroid hormone (PTH) and 24-h ambulatory BP in untreated Chinese patients. Consecutive untreated patients referred for ambulatory BP monitoring were recruited. PWV was measured with a high-fidelity micromanometer and the SphygmoCor software (AtCor Medical, West Ryde, New South Wales, Australia). Serum 25(OH)D and PTH were determined by electrochemiluminescence immunoassay. Analysis of variance, single and multiple regressions were applied for analyses. In 1052 untreated patients (50.7% women; mean age, 51 years), PWV averaged 7.8 m/s, 24-h SBP/DBP 126.5/81.7 mmHg, serum 25(OH)D and PTH 36.0 nmol/l and 61.6 pg/ml, respectively. In multivariable-adjusted analyses, BP (P < 0.001) and PTH (P = 0.012) increased from less than 25th to at least 75th percentile of the PWV distribution. In continuous analyses, PWV independently increased by 0.40/0.23 m/s per 1-SD increment in SBP/DBP (P < 0.001) and by 0.14 m/s for a doubling of serum PTH (P = 0.029). Associations of PWV with BP were tighter than with PTH (P < 0.001). In pathway analysis, the effect of PTH on PWV did not run via serum or urinary calcium (P = 0.65), but PTH had both a direct (P = 0.026) and a BP-mediated indirect effect (P = 0.043) on PWV. In none of our analyses were PWV associated with serum 25(OH)D. Arterial stiffness, as assessed by PWV, independently increased both with BP and with PTH, but BP remains the main driver of arterial stiffening.

Dietary vitamin D intake is not associated with 25-hydroxyvitamin D3 or parathyroid hormone in elderly subjects, whereas the calcium-to-phosphate ratio affects parathyroid hormone.

PubMed

Jungert, Alexandra; Neuhäuser-Berthold, Monika

2013-08-01

This cross-sectional study investigates whether serum 25-hydroxyvitamin D3 [25(OH)D3] and intact parathyroid hormone (iPTH) are affected by vitamin D, calcium, or phosphate intake in 140 independently living elderly subjects from Germany (99 women and 41 men; age, 66-96 years). We hypothesized that habitual dietary intakes of vitamin D, calcium, and phosphate are not associated with 25(OH)D3 or iPTH and that body mass index confounds these associations. Serum 25(OH)D3 and iPTH were measured by an electrochemiluminescence immunoassay. Dietary intake was determined using a 3-day estimated dietary record. The median dietary intake levels of vitamin D, calcium, and phosphate were 3 μg/d, 999 mg/d, and 1250 mg/d, respectively. Multiple regression analyses confirmed that dietary vitamin D and calcium did not affect 25(OH)D3 or iPTH; however, supplemental intakes of vitamin D and calcium were associated with 25(OH)D3 after adjustment for age, sex, body composition, sun exposure, physical activity, and smoking. In addition, phosphate intake and the calcium-to-phosphate ratio were associated with iPTH after multiple adjustments. In a subgroup analysis, calcium and vitamin D supplements, as well as phosphate intake, were associated with 25(OH)D3 and/or iPTH in normal-weight subjects only. Our results indicate that habitual dietary vitamin D and calcium intakes have no independent effects on 25(OH)D3 or iPTH in elderly subjects without vitamin D deficiency, whereas phosphate intake and the calcium-to-phosphate ratio affect iPTH. However, vitamin D and calcium supplements may increase 25(OH)D3 and decrease iPTH, even during the summer, but the impact of supplements may depend on body mass index. Copyright © 2013. Published by Elsevier Inc.

[Compounds modulating parathyroid hormone (PTH) secretion].

PubMed

Nagano, N; Iijima, H

2001-08-01

The control of parathyroid hormone (PTH) secretion is strictly regulated by the parathyroid Ca receptor (CaR). Calcimimetics and calcilytics selectively act on the parathyroid CaR to inhibit and enhance PTH secretion, respectively. According to the recent pharmacological two-state model, calcimimetics act on the CaR as allosteric agonists to stabilize an active conformation of CaR. Conversely, calcilytics act on the CaR as allosteric inverse agonists to stabilize an inactive conformation of CaR. These compounds that can alter circulating levels of PTH and bone turnover might provide novel treatments for adynamic bone disease in patients with chronic renal failure.

Parathyroid surgical failures with sufficient decline of intraoperative parathyroid hormone levels: unobserved multiple endocrine neoplasia as an explanation.

PubMed

Westerdahl, Johan; Bergenfelz, Anders

2006-06-01

A sufficient decline in levels of parathyroid hormone measured intraoperatively (ioPTH) precludes early and late surgical failures. A case series of consecutive patients undergoing parathyroidectomy with ioPTH measurement. A university hospital. Two hundred sixty-nine consecutive patients with sporadic primary hyperparathyroidism who underwent first-time parathyroid surgery with ioPTH measurement were followed up for as long as 10 years after surgery. Data on all patients have been collected in a prospective database. Surgical failures up to 10 years after parathyroid surgery. With an average follow-up of 3.6 years (range, 6-120 months), the overall cure rate was 96%. The ioPTH level correctly predicted long-term outcome in 248 (92%) of 269 patients. Six patients had a false-positive ioPTH finding. Five of these patients were found to have germline mutations in the gene for multiple endocrine neoplasia. The remaining patient has not undergone genetic testing. The mutations have rarely (n = 1) or never (n = 4) been described before, to our knowledge. Intraoperative measurement of PTH level has a high overall accuracy with a mean follow-up of 3.6 years. However, among the late surgical failures with false-positive ioPTH findings, overlooked mutations in the multiple endocrine neoplasia gene should be suspected, and therefore genetic analyses in these patients are of great importance.

New anabolic therapies in osteoporosis.

PubMed

Rubin, Mishaela R; Bilezikian, John P

2003-03-01

Anabolic agents represent an important new advance in the therapy of osteoporosis. Their potential might be substantially greater than the anti-resorptives. Because the anti-resorptives and anabolic agents work by completely distinct mechanisms of action, it is possible that the combination of agents could be significantly more potent than either agent alone. Recent evidence suggests that a plateau in BMD might occur after prolonged exposure to PTH. Anti-resorptive therapy during or after anabolic therapy might prevent this skeletal adaptation. Protocols to consider anabolic agents as intermittent recycling therapy would be of interest. Of all the anabolics, PTH is the most promising. However, there are unanswered questions about PTH. More studies are needed to document an anabolic effect on cortical bone. More large-scale studies are needed to further determine the reduction in nonvertebral fractures with PTH, especially at the hip. In the future, PTH is likely to be modified for easier and more targeted delivery. Oral or transdermal delivery systems may become available. Recently, Gowen et al have described an oral calcilytic molecule that antagonizes the parathyroid cell calcium receptor, thus stimulating the endogenous release of PTH. This approach could represent a novel endogenous delivery system for intermittent PTH administration. Rising expectations that anabolic therapies for osteoporosis will soon play a major role in treating this disease are likely to fuel further studies and the development of even more novel approaches to therapy.

PTH promotes allograft integration in a calvarial bone defect

PubMed Central

Sheyn, Dmitriy; Yakubovich, Doron Cohn; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M.; Gazit, Dan; Gazit, Zulma

2013-01-01

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and micro–computed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in Allograft + PTH–treated mice comparing to Allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the Allograft + PTH–treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment. PMID:24131143

Vitamin D and its relationship with markers of bone metabolism in healthy Asian women.

PubMed

Tan, Karen M L; Saw, Sharon; Sethi, Sunil K

2013-07-01

In this study, we aimed to determine the normal ranges of 25-hydroxy-vitamin D(3) (25-OHD(3)), parathyroid hormone (PTH), and the markers of bone turnover, procollagen type 1 N propeptide (P1NP) and C-terminal cross-linked telopeptide of type 1 collagen (CTX), in normal healthy women in Singapore, and to explore the relationship between vitamin D, PTH, and these markers of bone turnover in the women. One hundred and ninety-seven healthy women, aged 25 to 60, were selected from a hospital staff health screening program; 68% were Chinese, 18% Malay, and 14% Indian. P1NP, CTX, and 25-OHD(3) were measured using the Roche Cobas® electrochemiluminescence immunoassay. Serum PTH was measured using the Siemens ADVIA Centaur® immunoassay. Sixty-five percent had 25-OHD(3) concentrations <50 nmol/l. Vitamin D insufficiency (25-OHD(3) < 50 nmol/l) was more prevalent in Malays (89%) and Indians (82%) compared to Chinese (56%). There was no correlation between vitamin D and age. PTH positively correlated with age, and Malays and Indians had higher PTH concentrations than Chinese. There was an inverse correlation between PTH and 25-OHD(3), but no threshold of 25-OHD(3) concentrations at which PTH plateaued. The bone turnover markers P1NP and CTX inversely correlated with age but were not different between ethnic groups. CTX and P1NP exhibited good correlation, however, there was no significant correlation between 25-OHD(3) or PTH concentrations and the bone turnover markers P1NP and CTX. Healthy women in Singapore have a high prevalence of vitamin D insufficiency. Vitamin D insufficiency was more prevalent in Malays and Indians compared to Chinese. © 2013 Wiley Periodicals, Inc.

PTH (parathyroid hormone) elevates inositol polyphosphates and diacylglycerol in a rat osteoblast-like cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Civitelli, R.; Reid, I.R.; Westbrook, S.

1988-11-01

Parathyroid hormone (PTH)-stimulated signal transduction through mechanisms alternate to adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) production were studied in UMR 106-01 cells, a cell line with an osteoblastic phenotype. PTH produced transient, dose-related increases in cytosolic calcium ((Ca{sup 2+}){sub i}), inositol trisphosphates, and diacylglycerol (DAG). Both inositol 1,4,5-trisphosphate (Ins-1,4,5P{sub 3}) and inositol 1,3,4-trisphosphate (Ins-1,3,4P{sub 3}) production were rapidly stimulated by PTH. Consistent with the production of Ins-1,3,4P{sub 3}, rapid stimulation of late eluting inositol tetrakisphosphate was observed. The effects on the inositol phosphates were induced rapidly, consistent with roles as signals for changes in (Ca{sup 2+}){sub i}. In saponin-permeabilized UMR 106-01 cells,more » Ins-1,4,5P{sub 3} stimulated {sup 45}Ca release from a nonmitochondrial intracellular pool. Thus the hypothesis that PTH-stimulated Ins-1,4,5P{sub 3} production initiates Ca{sup 2+} release and contributes to transient elevations of (Ca{sup 2+}){sub i} is supported. These data suggest that stimulation of cAMP production during PTH stimulation may negatively affect production of rises in (Ca{sup 2+}){sub i} during PTH stimulation. The inactivation of the inhibitory G protein of adenylate cyclase by pertussis toxin could explain its action similar to cAMP analogues. Cyclci nucleotides diminish the effects of PTH on (Ca{sup 2+}){sub i}, probably interacting on a biochemical step subsequent to or independent of Ins-1,4,5P{sub 3} release.« less

Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor.

PubMed

Panda, Dibyendu Kumar; Goltzman, David; Karaplis, Andrew C

2012-12-15

The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and β-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition.

Parathyroid hormone enhances fluid shear-induced [Ca2+]i signaling in osteoblastic cells through activation of mechanosensitive and voltage-sensitive Ca2+ channels

NASA Technical Reports Server (NTRS)

Ryder, K. D.; Duncan, R. L.

2001-01-01

Osteoblasts respond to both fluid shear and parathyroid hormone (PTH) with a rapid increase in intracellular calcium concentration ([Ca2+]i). Because both stimuli modulate the kinetics of the mechanosensitive cation channel (MSCC), we postulated PTH would enhance the [Ca2+]i response to fluid shear by increasing the sensitivity of MSCCs. After a 3-minute preflow at 1 dyne/cm2, MC3T3-E1 cells were subjected to various levels of shear and changes in [Ca2+]i were assessed using Fura-2. Pretreatment with 50 nM bovine PTH(1-34) [bPTH(1-34)] significantly enhanced the shear magnitude-dependent increase in [Ca2+]i. Gadolinium (Gd3+), an MSCC blocker, significantly inhibited the mean peak [Ca2+]i response to shear and shear + bPTH(1-34). Nifedipine (Nif), an L-type voltage-sensitive Ca2+ channel (VSCC) blocker, also significantly reduced the [Ca2+]i response to shear + bPTH(1-34), but not to shear alone, suggesting VSCC activation plays an interactive role in the action of these stimuli together. Activation of either the protein kinase C (PKC) or protein kinase A (PKA) pathways with specific agonists indicated that PKC activation did not alter the Ca2+ response to shear, whereas PKA activation significantly increased the [Ca2+]i response to lower magnitudes of shear. bPTH(1-34), which activates both pathways, induced the greatest [Ca2+]i response at each level of shear, suggesting an interaction of these pathways in this response. These data indicate that PTH significantly enhances the [Ca2+]i response to shear primarily via PKA modulation of the MSCC and VSCC.

Impact of Different Levels of iPTH on All-Cause Mortality in Dialysis Patients with Secondary Hyperparathyroidism after Parathyroidectomy

PubMed Central

Xie, Xi Sheng; Zhang, Rui; Xiao, Yue Fei; Jin, Cheng Gang; Li, Yan Bo; Wang, Lin; Zhang, Xiao Xuan; Du, Shu Tong

2017-01-01

Background Secondary hyperparathyroidism (SHPT) usually required parathyroidectomy (PTX) when drugs treatment is invalid. Analysis was done on the impact of different intact parathyroid hormone (iPTH) after the PTX on all-cause mortality. Methods An open, retrospective, multicenter cohort design was conducted. The sample included 525 dialysis patients with SHPT who had undergone PTX. Results 404 patients conformed to the standard, with 36 (8.91%) deaths during the 11 years of follow-up. One week postoperatively, different levels of serum iPTH were divided into four groups: A: ≤20 pg/mL; B: 21–150 pg/mL; C: 151–600 pg/mL; and D: >600 pg/mL. All-cause mortality in groups with different iPTH levels appeared as follows: A (8.29%), B (3.54%), C (10.91%), and D (29.03%). The all-cause mortality of B was the lowest, with D the highest. We used group A as reference (hazard ratio (HR) = 1) compared with the other groups, and HRs on groups B, C, and D appeared as 0.57, 1.43, and 3.45, respectively. Conclusion The all-cause mortality was associated with different levels of iPTH after the PTX. We found that iPTH > 600 pg/mL appeared as a factor which increased the risk of all-cause mortality. When iPTH levels were positively and effectively reducing, the risk of all-cause mortality also decreased. The most appropriate level of postoperative iPTH seemed to be 21–150 pg/mL. PMID:28656147

Extracellular production of human parathyroid hormone as a thioredoxin fusion form in Escherichia coli by chemical permeabilization combined with heat treatment.

PubMed

Fu, Xiang-Yang; Tong, Wang-Yu; Wei, Dong-Zhi

2005-01-01

A pET system encoding the fusion protein gene of thioredoxin (Trx) and human parathyroid hormone (hPTH) was introduced into Escherichia coli BL21 (DE3). Recombinant Trx-hPTH fusion protein was expressed in soluble form in the cytoplasm of the E. coli transformant. To recover Trx-hPTH from the E. coli culture efficiently, a novel tactic was developed by adding Triton X-100 into the fermentation culture at the exponential growth phase of E. coli and by heat treatment of the culture at the end of the fermentation. A concentration of 1% (v/v) Triton X-100 was added into the culture at the same time as IPTG addition after optimization. Under these conditions, addition of Triton X-100 had little effect on the cell growth, but more than 75% of the total recombinant Trx-hPTH was released into the fermentation broth. Also, a much higher volumetric yield of recombinant Trx-hPTH could be obtained with protein release compared to yield without protein release. Simultaneously, owing to the highly thermal stability of Trx-hPTH fusion protein, heat treatment of the fermentation broth at 80 degrees C for 15 min at the end of fermentation was employed for primary purification. Results demonstrated that heat treatment not only boosted further release of the recombinant Trx-hPTH fusion protein into the fermentation broth but also precipitated/denatured most of the nontarget proteins released in the broth. The tactics described herein integrated the fermentation process with subsequent recovery steps and thus provided a valuable and economical method for the production of Trx-hPTH and maybe some other Trx fusions in E. coli.

The Results of Neuroendoscopic Surgery in Patients with Posttraumatic and Posthemorrhagic Hydrocephalus.

PubMed

Chrastina, Jan; Novák, Zdeněk; Zeman, Tomáš; Feitová, Věra; Hrabovský, Dušan; Říha, Ivo

2018-05-01

Posttraumatic hydrocephalus (PTH) and posthemorrhagic hydrocephalus (PHH) were previously considered not suitable for neuroendoscopic treatment. New hydrocephalus theories support possible successful neuroendoscopy in such patients. This study presents the results of neuroendoscopy in PTH and PHH with a background analysis. From 130 hydrocephalic patients after neuroendoscopic surgeries, 35 cases with PTH (n = 11) or PHH (n = 24; acute: n = 9, subacute: n = 10, chronic: n = 5) were found. The success rate (Glasgow Outcome Scale [GOS] score 4 or 5 without shunt) and clinical outcome (GOS score) of endoscopic third ventriculostomy (ETV) were analyzed. During the study period, 34 patients had ventriculoperitoneal shunts implanted, including 2 PTH and 5 PHH patients (all chronic). The success rate of ETV in PTH was 54.5%. In acute PHH, the success rate was 33.3%, 42.8% after excluding devastating hematomas. A post-ETV shunt was implanted in 1 patient (massive subarachnoid hemorrhage [SAH]) with final GOS score of 5. In subacute cases, the ETV success rate was 40% (no post-ETV shunts). In chronic PHH, only 1 patient with a GOS score of 5 was shunt-free (20%). The cause of ETV failure was massive SAH. Low final GOS score was caused by the extent of intracerebral bleeding or extracranial problems. The main indications for primary shunt implantation in PTH and PHH were infectious complications. The rate of good outcomes was 0% in PTH and 40% in PHH. The best results of neuroendoscopy were achieved in PTH and acute PHH. ETV failures were associated with massive SAH; arachnoid cistern blockage and scarring precludes ETV success. Copyright © 2018 Elsevier Inc. All rights reserved.

Evaluation of prevalence, biochemical profile, and drugs associated with chronic kidney disease-mineral and bone disorder in 11 dialysis centers.

PubMed

Abrita, Rodrigo Reis; Pereira, Beatriz Dos Santos; Fernandes, Neimar da Silva; Abrita, Renata; Huaira, Rosalia Maria Nunes Henriques; Bastos, Marcus Gomes; Fernandes, Natália Maria da Silva

2018-01-01

The diagnosis and treatment of mineral and bone disorder of chronic kidney disease (CKD-MBD) is a challenge for nephrologists and health managers. The aim of this study was to evaluate the prevalence, biochemical profile, and drugs associated with CKD-MBD. Cross-sectional study between July and November 2013, with 1134 patients on dialysis. Sociodemographic, clinical, and laboratory data were compared between groups based on levels of intact parathyroid hormone (iPTH) (< 150, 150-300, 301-600, 601-1000, and > 1001 pg/mL). The mean age was 57.3 ± 14.4 years. The prevalence of iPTH < 150 pg/mL was 23.4% and iPTH > 601 pg/mL was 27.1%. The comparison between the groups showed that the level of iPTH decreased with increasing age. Diabetic patients had a higher prevalence of iPTH < 150 pg/mL (27.6%). Hyperphosphatemia (> 5.5 mg/dL) was observed in 35.8%. Calcium carbonate was used by 50.5%, sevelamer by 14.7%, 40% of patients had used some form of vitamin D and 3.5% used cinacalcet. Linear regression analysis showed a significant negative association between iPTH, age, and diabetes mellitus and a significant positive association between iPTH and dialysis time. The prevalence of patients outside the target for iPTH was 50.5%. There was a high prevalence of hyperphosphatemia (35.8%), and the minority of patients were using active vitamin D, vitamin D analogs, selective vitamin D receptor activators, and cinacalcet. These data indicate the need for better compliance with clinical guidelines and public policies on the supply of drugs associated with CKD-MBD.

Evaluation of prevalence, biochemical profile, and drugs associated with chronic kidney disease-mineral and bone disorder in 11 dialysis centers.

PubMed

Abrita, Rodrigo Reis; Pereira, Beatriz Dos Santos; Fernandes, Neimar da Silva; Abrita, Renata; Huaira, Rosalia Maria Nunes Henriques; Bastos, Marcus Gomes; Fernandes, Natália Maria da Silva

2018-05-07

The diagnosis and treatment of mineral and bone disorder of chronic kidney disease (CKD-MBD) is a challenge for nephrologists and health managers. The aim of this study was to evaluate the prevalence, biochemical profile, and drugs associated with CKD-MBD. Cross-sectional study between July and November 2013, with 1134 patients on dialysis. Sociodemographic, clinical, and laboratory data were compared between groups based on levels of intact parathyroid hormone (iPTH) (< 150, 150-300, 301-600, 601-1000, and > 1001 pg/mL). The mean age was 57.3 ± 14.4 years. The prevalence of iPTH < 150 pg/mL was 23.4% and iPTH > 601 pg/mL was 27.1%. The comparison between the groups showed that the level of iPTH decreased with increasing age. Diabetic patients had a higher prevalence of iPTH < 150 pg/mL (27.6%). Hyperphosphatemia (> 5.5 mg/dL) was observed in 35.8%. Calcium carbonate was used by 50.5%, sevelamer by 14.7%, 40% of patients had used some form of vitamin D and 3.5% used cinacalcet. Linear regression analysis showed a significant negative association between iPTH, age, and diabetes mellitus and a significant positive association between iPTH and dialysis time. The prevalence of patients outside the target for iPTH was 50.5%. There was a high prevalence of hyperphosphatemia (35.8%), and the minority of patients were using active vitamin D, vitamin D analogs, selective vitamin D receptor activators, and cinacalcet. These data indicate the need for better compliance with clinical guidelines and public policies on the supply of drugs associated with CKD-MBD.

Enhanced human bone marrow mesenchymal stem cell functions on cathodic arc plasma-treated titanium.

PubMed

Zhu, Wei; Teel, George; O'Brien, Christopher M; Zhuang, Taisen; Keidar, Michael; Zhang, Lijie Grace

2015-01-01

Surface modification of titanium for use in orthopedics has been explored for years; however, an ideal method of integrating titanium with native bone is still required to this day. Since human bone cells directly interact with nanostructured extracellular matrices, one of the most promising methods of improving titanium's osseointegration involves inducing bio-mimetic nanotopography to enhance cell-implant interaction. In this regard, we explored an approach to functionalize the surface of titanium by depositing a thin film of textured titanium nanoparticles via a cathodic arc discharge plasma. The aim is to improve human bone marrow mesenchymal stem cell (MSC) attachment and differentiation and to reduce deleterious effects of more complex surface modification methods. Surface functionalization was analyzed by scanning electron microscopy, atomic force microscopy, contact angle testing, and specific protein adsorption. Scanning electron microscopy and atomic force microscopy examination demonstrate the deposition of titanium nanoparticles and the surface roughness change after coating. The specific fibronectin adsorption was enhanced on the modified titanium surface that associates with the improved hydrophilicity. MSC adhesion and proliferation were significantly promoted on the nanocoated surface. More importantly, compared to bare titanium, greater production of total protein, deposition of calcium mineral, and synthesis of alkaline phosphatase were observed from MSCs on nanocoated titanium after 21 days. The method described herein presents a promising alternative method for inducing more cell favorable nanosurface for improved orthopedic applications.

Disability from posttraumatic headache is compounded by coexisting posttraumatic stress disorder.

PubMed

Roper, Louise S; Nightingale, Peter; Su, Zhangjie; Mitchell, James L; Belli, Antonio; Sinclair, Alexandra J

2017-01-01

Posttraumatic headache (PTH) occurs in up to 82% of patients with traumatic brain injury (TBI). Posttraumatic stress disorder (PTSD) occurs in 39% of those with PTH. This study evaluates whether PTSD affects PTH disability. Eighty-six patients with TBI were prospectively evaluated in a secondary care trauma center. Headache disability was assessed using the Headache Impact Test version 6 and signs indicative of PTSD using the PTSD Check List Civilian version. Increased PTSD-type symptoms were significantly associated with increased headache disability ( p <0.001), as were employment status and loss of consciousness ( p =0.049 and 0.016, respectively). Age was negatively correlated with headache disability (Spearman's correlation rho=0.361, p =0.001). Increased severity of PTSD-type symptoms is significantly associated with increased headache disability in patients with chronic PTH. Managing PTSD symptoms in patients with chronic PTH may facilitate headache management.

Postoperative day 1 levels of parathyroid as predictor of occurrence and severity of hypocalcaemia after total thyroidectomy.

PubMed

Karatzanis, Alexander D; Ierodiakonou, Despo P; Fountakis, Emmanuel S; Velegrakis, Stylianos G; Doulaptsi, Maria V; Prokopakis, Emmanuel P; Daraki, Vasiliki N; Velegrakis, George A

2018-05-01

Hypocalcaemia is a common and serious complication after thyroidectomy. The purpose of this study is to assess the effectiveness of first postoperative day parathyroid hormone (PTH) measurement in order to predict the presence and severity of postthyroidectomy hypocalcaemia. One hundred consecutive cases undergoing total thyroidectomy in a tertiary referral center were prospectively assessed. Preoperative measurements of PTH were compared with postoperative levels in the first morning after surgery. All cases of hypocalcaemia were recorded and evaluated with regard to preoperative and postoperative levels of PTH. A decrease of 56% of PTH levels on the first postoperative day could accurately predict postoperative hypocalcaemia with a sensitivity and specificity of 80%. Serum PTH levels on the first postoperative day may be used as a reliable predictive marker for calcium supplementation need and even prolonged hospitalization in cases undergoing total thyroidectomy. © 2018 Wiley Periodicals, Inc.

Effect of exercise and exogenous glucocorticoid on serum level of intact parathyroid hormone.

PubMed

Tsai, K S; Lin, J C; Chen, C K; Cheng, W C; Yang, C H

1997-11-01

Most previous studies suggest that physical exercise, or physiological response to exercise such as cortisol and adrenaline secretion regulate parathyroid hormone (PTH) secretion in humans. To investigate the effects and possible interaction of exercise and excessive glucocorticoid on PTH secretion, we examined the serum of levels of intact-PTH, cortisol, adrenocorticotrophic hormone (ACTH), calcium, magnesium and phosphorus before and during one-hour of bicycle-ergometric exercise at 60% of maximal oxygen uptake. These exercise tests were performed on eight Chinese male volunteers aged between 20 and 25 years, once with and once without pretreatment with 0.5 mg of dexamethasone taken orally 9.5 hours in advance. The results showed that dexamethasone pretreatment significantly lowered basal levels of cortisol and ACTH, but intact PTH did not change. After 60 minutes of bicycling, intact PTH level increases by 50% of baseline both with and without dexamethasone pretreatment. Serum levels of calcium, corrected for changes in serum albumin concentration, phosphorus and magnesium also increased in both cases. This study demonstrated an increase of intact-PTH with exercise which was not associated with hypocalcemia or hypomagnesemia, and was not altered in the presence of mild exogenous glucocorticoid excess and suppressed endogenous cortisol secretion.

Hip fracture type: important role of parathyroid hormone (PTH) response to hypovitaminosis D.

PubMed

Fisher, Alexander; Srikusalanukul, Wichat; Davis, Michael; Smith, Paul

2010-08-01

To investigate whether clinical and laboratory characteristics, including serum 25-hydroxyvitamin D (25(OH) D), PTH and parameters of mineral and bone metabolism, differ by hip fracture (HF) type. We studied prospectively 761 consecutively admitted older patients (mean age 82.3+8.8(SD) years; 74.9% women) with low trauma non-pathological HF. A detailed clinical examination was performed, haematologic, renal, liver and thyroid function tests, serum 25(OH)D, PTH, calcium, phosphate, magnesium, C-reactive protein (CRP) and cardiac troponin I (cTnI) measured. In a subset of 294 patients' markers of bone formation (serum osteocalcin, OC; bone specific alkaline phosphatase, BAP) and bone resorption (urinary deoxypyridinoline, DPD/Cr; N-terminal cross-linked telopeptide of type 1 collagen, NTx/Cr; both corrected to urinary creatinine, Cr) were also measured. In the trochanteric compared to the cervical group, females were older than males and the prevalence of Parkinson's disease, mean haemoglobin and albumin levels were lower. Incidence and degree of myocardial injury (cTnl rise) and inflammatory reaction (CRP elevation) as well as length of hospital stay, need of institutionalisation or in-hospital mortality were similar in both groups. Hypovitaminosis D (25(OH)D <50 mmol/L) was present in 77.8% of patients with cervical and in 82.1% with trochanteric HF, elevated PTH (>6.8 pmol/L) in 30.2% and 41.3%, respectively. The associations between 25(OH)D, PTH, and parameters of mineral metabolism and bone turnover were site-specific. In multivariate analyses, PTH (both as a continuous or categorical variable) response to hypovitaminosis D was a strong independent predictor of HF type. Coexistence of vitamin D deficiency (25(OH) D< 25 nmol/L) and elevated PTH predicts trochanteric HF while blunted PTH response predicts cervical HF (OR=3.5; 95% CI 1.5-80; p=0.005). PTH response and phosphate status (above or below median level) correctly discriminated HF type in 73.8% of patients with vitamin D deficiency. HF type is significantly associated with PTH response to hypovitaminosis D and impaired phosphate homeostasis. We detected only minor differences between two main HF types with regard to a wide range of clinical and routine laboratory variables as well as short-term outcomes. Copyright 2010 Elsevier Inc. All rights reserved.

Accentuated Osteoclastic Response to Parathyroid Hormone Undermines Bone Mass Acquisition in Osteonectin-null Mice

PubMed Central

do Reis, Luciene Machado; Kessler, Catherine B.; Adams, Douglas J.; Lorenzo, Joseph; Jorgetti, Vanda; Delany, Anne M.

2008-01-01

Matricellular proteins play a unique role in the skeleton as regulators of bone remodeling, and the matricellular protein osteonectin (SPARC, BM-40) is the most abundant non-collagenous protein in bone. In the absence of osteonectin, mice develop progressive low turnover osteopenia, particularly affecting trabecular bone. Polymorphisms in a regulatory region of the osteonectin gene are associated with bone mass in a subset of idiopathic osteoporosis patients, and these polymorphisms likely regulate osteonectin expression. Thus it is important to determine how osteonectin gene dosage affects skeletal function. Moreover, intermittent administration of parathyroid hormone (PTH) (1-34) is the only anabolic therapy approved for the treatment of osteoporosis, and it is critical to understand how modulators of bone remodeling, such as osteonectin, affect skeletal response to anabolic agents. In this study, 10 week old female wild type, osteonectin-haploinsufficient, and osteonectin-null mice (C57Bl/6 genetic background) were given 80 μg/kg body weight/day PTH(1-34) for 4 weeks. Osteonectin gene dosage had a profound effect on bone microarchitecture. The connectivity density of trabecular bone in osteonectin-haploinsufficient mice was substantially decreased compared with that of wild type mice, suggesting compromised mechanical properties. Whereas mice of each genotype had a similar osteoblastic response to PTH treatment, the osteoclastic response was accentuated in osteonectin-haploinsufficient and osteonectin-null mice. Eroded surface and osteoclast number were significantly higher in PTH-treated osteonectin-null mice, as was endosteal area. In vitro studies confirmed that PTH induced the formation of more osteoclast-like cells in marrow from osteonectin-null mice compared with wild type. PTH treated osteonectin-null bone marrow cells expressed more RANKL mRNA compared with wild type. However, the ratio of RANKL:OPG mRNA was somewhat lower in PTH treated osteonectin-null cultures. Increased expression of RANKL in response to PTH could contribute to the accentuated osteoclastic response in osteonectin-/- mice, but other mechanisms are also likely to be involved. The molecular mechanisms by which PTH elicits bone anabolic vs. bone catabolic effects remain poorly understood. Our results imply that osteonectin levels may play a role in modulating the balance of bone formation and resorption in response to PTH. PMID:18499553

Drug-releasing nano-engineered titanium implants: therapeutic efficacy in 3D cell culture model, controlled release and stability.

PubMed

Gulati, Karan; Kogawa, Masakazu; Prideaux, Matthew; Findlay, David M; Atkins, Gerald J; Losic, Dusan

2016-12-01

There is an ongoing demand for new approaches for treating localized bone pathologies. Here we propose a new strategy for treatment of such conditions, via local delivery of hormones/drugs to the trauma site using drug releasing nano-engineered implants. The proposed implants were prepared in the form of small Ti wires/needles with a nano-engineered oxide layer composed of array of titania nanotubes (TNTs). TNTs implants were inserted into a 3D collagen gel matrix containing human osteoblast-like, and the results confirmed cell migration onto the implants and their attachment and spread. To investigate therapeutic efficacy, TNTs/Ti wires loaded with parathyroid hormone (PTH), an approved anabolic therapeutic for the treatment of severe bone fractures, were inserted into 3D gels containing osteoblast-like cells. Gene expression studies revealed a suppression of SOST (sclerostin) and an increase in RANKL (receptor activator of nuclear factor kappa-B ligand) mRNA expression, confirming the release of PTH from TNTs at concentrations sufficient to alter cell function. The performance of the TNTs wire implants using an example of a drug needed at relatively higher concentrations, the anti-inflammatory drug indomethacin, is also demonstrated. Finally, the mechanical stability of the prepared implants was tested by their insertion into bovine trabecular bone cores ex vivo followed by retrieval, which confirmed the robustness of the TNT structures. This study provides proof of principle for the suitability of the TNT/Ti wire implants for localized bone therapy, which can be customized to cater for specific therapeutic requirements. Copyright © 2016 Elsevier B.V. All rights reserved.

Novel, selective vitamin D analog suppresses parathyroid hormone in uremic animals and postmenopausal women.

PubMed

Zella, Julia B; Plum, Lori A; Plowchalk, David R; Potochoiba, Michael; Clagett-Dame, Margaret; DeLuca, Hector F

2014-01-01

The use of 1α-hydroxylated vitamin D therapy to control secondary hyperparathyroidism in renal failure patients has been a success story, culminating with the demonstration of increased life expectancy in patients treated with these compounds. However, hypercalcemic episodes have been a recurrent problem with these therapies and have resulted in the added use of calcium mimetics. Clearly there is good reason to search for improved vitamin D therapy. In our inventory of vitamin D compounds, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) surfaced as a potential candidate. This was based on its preferential localization in the parathyroid gland and a clear suppression of serum parathyroid hormone (PTH) levels without a change in serum calcium in a clinical trial in postmenopausal women. 2MD has now been tested in the rat 5/6-nephrectomy model of renal failure, and in postmenopausal women to determine if it can suppress serum PTH at doses that do not elevate serum calcium and serum phosphorus concentrations. Daily oral treatment of uremic rats on 2.5 ng/bw/day of 2MD dramatically suppressed PTH without a change in serum calcium or serum phosphorus. Further, PTH was suppressed in postmenopausal women after only 3 daily oral doses of 2MD that continued for 4 weeks with no change in serum calcium or serum phosphorus. These results coupled with a pharmacokinetic half-life of ~24 h suggest that 2MD given either daily or at the time of dialysis may be a superior therapy for secondary hyperparathyroidism in chronic renal failure patients.

The Use of Calcimimetics for the Treatment of Secondary Hyperparathyroidism: A 10 Year Evidence Review.

PubMed

Rodríguez, Mariano; Goodman, William G; Liakopoulos, Vassilios; Messa, Piergiorgio; Wiecek, Andrzej; Cunningham, John

2015-01-01

Until the discovery of calcimimetics, the management of secondary hyperparathyroidism (SHPT) relied exclusively on treatment with phosphate binders, vitamin D derivatives or surgical parathyroidectomy with limited success. The therapeutic use of calcimimetic agents, together with a better understanding of the pivotal role of the calcium-sensing receptor (CaSR) in the physiological regulation of parathyroid gland function, substantially advanced the management of hyperparathyroidism in dialysis practice. Calcimimetics bind selectively to the CaSR receptor in parathyroid tissue and enhance the inhibitory effect of extracellular calcium ions on parathyroid hormone (PTH) secretion, thereby reducing PTH levels even when serum calcium concentrations are normal or low. The availability of calcimimetic agents for clinical use has opened a new era in the management of patients with SHPT. Indeed, calcimimetic compounds have been shown to reduce PTH levels and to lower serum calcium concentrations in all forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Such findings underscore the critical importance of the CaSR as a therapeutic target in this family of clinical disorders. New calcimimetic agents are being developed that have the potential to offer improved efficacy and safety compared with currently available calcimimetic compounds. © 2015 Wiley Periodicals, Inc.

Phosphate Binder Pill Burden, Patient-Reported Non-Adherence, and Mineral Bone Disorder Markers: Findings from the DOPPS

PubMed Central

Fissell, Rachel B.; Karaboyas, Angelo; Bieber, Brian A.; Sen, Ananda; Li, Yun; Lopes, Antonio A.; Akiba, Takashi; Bommer, Jürgen; Ethier, Jean; Jadoul, Michel; Pisoni, Ronald L.; Robinson, Bruce M.; Tentori, Francesca

2015-01-01

Background Due to multiple comorbidities, hemodialysis (HD) patients are prescribed many oral medications, including phosphate binders (PBs), often resulting in a high “pill burden”. Methods Using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS), we assessed associations between PB pill burden, patient-reported PB non-adherence, and levels of serum phosphorus (SPhos) and parathyroid hormone (PTH), using standard regression analyses. The study included data collected from 5,262 HD patients from dialysis units participating in the DOPPS in 12 countries. Results PB prescription ranged from a mean of 7.4 pills/day in the United States (US) to 3.9 pills/day in France. About half of the patients were prescribed at least 6 PB pills/day, and 13% were prescribed at least 12 PB pills/day. Overall, the proportion of patients who reported skipping PBs at least once in the past month was 45% overall, ranging from 33% in Belgium to 57% in the US. There was a trend toward greater PB non-adherence and a higher number of prescribed PB pills/day. Non-adherence to PB prescription was associated with high SPhos (>5.5 mg/dL) and PTH (> 600 pg/mL). Conclusions Adherence to PB is a challenge for many hemodialysis patients and may be related to the number of PB pills prescribed. Prescription of a simplified PB regimen could improve patient adherence and perhaps improve SPhos and PTH levels. PMID:25975222

Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression

NASA Technical Reports Server (NTRS)

Partridge, N. C.; Bloch, S. R.; Pearman, A. T.

1994-01-01

Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopontin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post-transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level.

Aldosterone and parathyroid hormone: a precarious couple for cardiovascular disease.

PubMed

Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Fahrleitner-Pammer, Astrid; Kienreich, Katharina; Horina, Jörg H; Drechsler, Christiane; März, Winfried; Ofner, Michael; Pieber, Thomas R; Pilz, Stefan

2012-04-01

Animal and human studies support a clinically relevant interaction between aldosterone and parathyroid hormone (PTH) levels and suggest an impact of the interaction on cardiovascular (CV) health. This review focuses on mechanisms behind the bidirectional interactions between aldosterone and PTH and their potential impact on the CV system. There is evidence that PTH increases the secretion of aldosterone from the adrenals directly as well as indirectly by activating the renin-angiotensin system. Upregulation of aldosterone synthesis might contribute to the higher risk of arterial hypertension and of CV damage in patients with primary hyperparathyroidism. Furthermore, parathyroidectomy is followed by decreased blood pressure levels and reduced CV morbidity as well as lower renin and aldosterone levels. In chronic heart failure, the aldosterone activity is inappropriately elevated, causing salt retention; it has been argued that the resulting calcium wasting causes secondary hyperparathyroidism. The ensuing intracellular calcium overload and oxidative stress, caused by PTH and amplified by the relative aldosterone excess, may increase the risk of CV events. In the setting of primary aldosteronism, renal and faecal calcium loss triggers increased PTH secretion which in turn aggravates aldosterone secretion and CV damage. This sequence explains why adrenalectomy and blockade of the mineralocorticoid receptor tend to decrease PTH levels in patients with primary aldosteronism. In view of the reciprocal interaction between aldosterone and PTH and the potentially ensuing CV damage, studies are urgently needed to evaluate diagnostic and therapeutic strategies addressing the interaction between the two hormones.

Association between Decreased Serum Parathyroid Hormone after Total Thyroidectomy and Persistent Hypoparathyroidism

PubMed Central

Wang, Jian-Biao; Sun, Hai-Li; Song, Chun-Yi; Gao, Li

2015-01-01

Background Postoperative hypocalcemia caused by hypoparathyroidism is one of the most common morbidities of total thyroidectomy. The aim of this study was to analyze the kinetics and factors affecting PTH levels after total thyroidectomy and central neck dissection (CND). Material/Methods We performed a retrospective study in 438 consecutive patients who underwent total thyroidectomy between January 2007 and December 2010. No patient had a history of thyroid or neck surgery. PTH and calcium levels were recorded 1 day before the operation, during the first 5 days, and during follow-up (2 weeks and 2, 6, and 12 months). Results PTH levels declined to 41.90% of its initial value on the first day after the operation. After surgery, PTH was correlated positively with calcium and inversely with phosphate levels from postoperative day 1 to 14. Based on clinical observation, using a PTH threshold of <7 ng/L on postoperative day 1 was predictive of persistent hypoparathyroidism, with sensitivity and negative predictive value 100%, but poor specificity (70.19%). CND increased the risk of transient hypoparathyroidism compared with total thyroidectomy alone. Patients with thyroiditis had an increased risk of permanent hypoparathyroidism compared with those without thyroiditis. Iatrogenic removal of the parathyroid glands increased the risk of permanent hypoparathyroidism compared with those without iatrogenic parathyroidectomy. Conclusions PTH declined on the first day after thyroidectomy. PTH levels <7 ng/L on the first day after surgery might be associated with persistent hypoparathyroidism. CND, thyroiditis, and iatrogenic parathyroidectomy increased the risk of hypoparathyroidism. PMID:25923249

Low parathyroid hormone levels in bedridden geriatric patients with vitamin D deficiency.

PubMed

Björkman, Mikko P; Sorva, Antti J; Risteli, Juha; Tilvis, Reijo S

2009-06-01

To identify the clinical conditions associated with low parathyroid hormone (PTH) in patients with vitamin D deficiency and to evaluate the stability of the blunted PTH response to vitamin D deficiency over 6 months. Secondary analysis of a randomized double-blind controlled vitamin D supplementation trial. Four long-term care hospitals in Helsinki, Finland. Two hundred eighteen chronically bedridden patients. Plasma 25-hydroxyvitamin D (25-OHD), intact PTH, amino-terminal propeptide of type I procollagen (PINP), carboxy-terminal telopeptide of type I collagen (ICTP), activities of daily living (ADLs), and body mass index (BMI) were measured at baseline and at 6 months. Patient records were reviewed for demographic data. PTH was within reference values (8-73 ng/L) despite low 25-OHD level (<50 nmol/L) in 74.8% (n=163) of patients (mean age 84.5+/-7.5). Patients in the lowest PTH quartile (<38 ng/L) were characterized by a history of hip fractures (OR=2.9, P=0.01), low BMI (OR=0.9, P=.02), and high ICTP (OR=1.1, P=.03). PTH remained within reference values even after 6 months in 76.2% of the patients with persistent vitamin D deficiency in the placebo group. The absence of secondary hyperparathyroidism seems to be common and persistent in frail chronically bedridden patients with vitamin D deficiency. Attenuated parathyroid function appears to be associated with immobilization that causes accelerated bone resorption. Further studies addressing the possible adverse effects of low PTH are warranted.

A micropuncture study of the effect of parathyroid hormone on renal bicarbonate reabsorption.

PubMed Central

Bank, N; Aynediian, H S

1976-01-01

Renal micropuncture and clearance experiments were carried out in rats to study the effect of parathyroid hormone (PTH) on renal tubular HCO-/3 reabsorption. The rats were studied during an initial period of parathyroid deficiency (acute thyroidparathyroidectomy, TPTX) and during infusion of large amounts of bovine PTH. Under normal acid-base conditions, PTH administration to TPTX rats caused a significant rise in proximal tubular fluid HCO-/3 concentration (TFHCO-/3), a decrease in fluid reabsorption, and a fall in proximal HCO-/3 reabsorption from 94.0 to 88.2% (P less than 0.01). In control experiments with mannitol infusion, a comparable reduction in proximal fluid reabsorption occurred without any significant effect on intraluminal HCO-/3 concentration. During acute intravenous HCO-/3 loading, PTH inhibited proximal HCO-/3 reabsorption. However, no change in whole kidney HCO-/3 reabsorption was observed in these experiments or in the animals studied under normal acid-base conditions. The findings are consistent with the view that PTH inhibits proximal tubular HCO-/3 reabsorption with normal or high filtered loads of HCO-/3, but distal segments of the nephron are able to reabsorb the excess delivered from the proximal tubule. Measurements of urinary ammonium and titratable acid indicate that net acid excretion (NH+/4 + TA -- HCO-/3) increases significantly after PTH administration. These results do not provide support for the view that PTH excess causes metabolic acidosis by reducing renal acid excretion. PMID:956369

Vitamin D, parathyroid hormone and cardiovascular risk: the good, the bad and the ugly.

PubMed

Pascale, Antonietta V; Finelli, Rosa; Giannotti, Rocco; Visco, Valeria; Fabbricatore, Davide; Matula, Ida; Mazzeo, Pietro; Ragosa, Nicola; Massari, Angelo; Izzo, Raffaele; Coscioni, Enrico; Illario, Maddalena; Ciccarelli, Michele; Trimarco, Bruno; Iaccarino, Guido

2018-02-01

: 25-Hydroxyvitamin D insufficiency and increased cardiovascular risk (CVR) association is still debated. The vitamin D (VitD)-dependent parathyroid hormone (PTH) is considered as the possible actuator of VitD effects on CVR. To investigate the association of CVR, PTH and VitD, we carried out blood pressure measurements and blood samples and collected information on dietary habits, anamnestic, clinical and metabolic data of 451 participants in the Salerno area (Southern Italy) during the World Hypertension Day (17 May). CVR was calculated according to the Framingham CVR charts. The overall population mean age was 51.6 ± 0.7 years, and female sex was slightly prevalent (55%). VitD deficiency (<20 ng/ml) was most frequent (59.7%). In this population, VitD and CVR did not correlate. VitD and PTH inversely correlated (r = -0.265, P < 0.001) as expected. PTH was in direct correlation (r = 0.225, P < 0.001) with CVR. Elevated PTH (75 percentile; ≥49.5 pg/ml) levels identify a population with higher CVR (11.8 ± 0.5 vs. 8.5 ± 0.3, P < 0.001). In a multivariate analysis, both age and PTH correlate to CVR, but not VitD. In conclusion, VitD does not directly affect CVR in the overall population. Rather, increased PTH might be a better predictor of CVR.

Biofunctionalization of Titanium Granules with Simvastatin for Improving Osteogenic Activity and Antibacterial Properties (Ex Vivo Study).

PubMed

Karaji, Zahra Gorgin; Houshmand, Behzad; Abbasi, Shahsanam; Shafiei, Sara; Faghihi, Shahab

Titanium-based biomaterials present good biocompatibility, while their osseointegration and antibacterial properties need to be improved. This study aimed to enhance the bone-bonding ability of titanium-based granules, which are intended to be used as bone graft. The titanium granules were anodized in ethylene glycol-based electrolyte and subsequently annealed to be loaded separately with simvastatin. The samples were then inspected with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) for drug loading. The release of simvastatin from titanium granule samples was measured after soaking samples in phosphate-buffered saline (PBS) for 30 days using ultraviolet-visible (UV/Vis) spectroscopy. The alkaline phosphatase (ALP) activity of MG63 osteosarcoma-loaded samples was measured, and microbroth dilution assay was performed to evaluate the antibacterial potential of drug-loaded and nonloaded titanium granule samples for bacterial growth. The results expressed the gradual and constant release of simvastatin within the duration of the examination. ALP of the samples showed improved activity of anodized and annealed granules, while the antibacterial test illustrated no significant improvement in their bactericidal effects. However, the simvastatin-loaded samples showed an improved antibacterial effect compared with nonloaded samples. It is assumed that anodizing, annealing, and subsequent simvastatin loading of titanium granules could be used as surface modification to improve osseointegration and restrain bacterial growth and adhesion. It is fair to believe that the results of this study could be used to treat titanium granules as bone graft substitute materials for dental and orthopedic applications.

Disruption of Calcium Homeostasis During Exercise as a Mediator of Bone Metabolism

DTIC Science & Technology

2015-10-01

Meeting of the American College of Sports Medicine (Appendix A). 15. SUBJECT TERMS calcium homeostasis, exercise, bone resorption, parathyroid hormone ... hormone (PTH). PTH can defend serum Ca by reducing urinary Ca excretion, increasing intestinal Ca absorption, and increasing mobilization of skeletal Ca...certain conditions. It is our contention that disruptions in calcium homeostasis during exercise lead to increases in parathyroid hormone (PTH) and

Human parathyroid hormone-(1-38) restores cancellous bone to the immobilized, osteopenic proximal tibial metaphysis in rats

NASA Technical Reports Server (NTRS)

Ma, Y. F.; Jee, W. S. S.; Ke, H. Z.; Lin, B. Y.; Liang, X. G.; Li, M.; Yamamoto, N.

1994-01-01

The purpose of this study was to determine if human parathyroid hormone-(1-38) (PTH) can restore cancellous bone mass to the established osteopenic, immobilized proximal tibial metaphyses (PTM) of female rats. The right hindlimbs of six-month-old female Sprague-Dawley rats were immobilized by bandaging the right hindlimbs to the abdomen. After 30 days of right hindlimb immobilization (RHLI), the rats were subcutaneously injected with 200 microgram hPTH(1-38)/kg/day for 15 (short-term) or 75 (longer-term) days. Static bone histomorphometry was performed on the primary spongiosa, while both static and dynamic histomorphometry were performed on the secondary spongiosa of the right PTM. Immobilization for 30 days without treatment decreased trabecular bone area, number and thickness in both primary and secondary spongiosa, and induced an increase in eroded perimeter and a decrease in tissue referent-bone formation rate (BFR/TV) in the secondary spongios. These changes reached a new steady state thereafter. Treatment with 200 microgram hPTH(1-38)/kg/day for 15 days, beginning at 30 days post immobilization (IM), significantly increased trabecular bone area, thickness and number in both primary and secondary spongiosa despite continuous IM when compared to the age-related and IM controls. The short-term (15 days) PTH treatment significantly increased labeling perimeter, mineral apposition rate and BFR/TV in the secondary spongiosa and stimulated longitudinal bone growth as compared to the age-related and IM controls. PTH treatment for longer-term (75 days) further increased trabecular bone area, thickness and number as compared to aging and IM controls and short-term (15 days) PTH treated groups. The bone formation indices in the secondary spongiosa of these longer-term treated rats were lower than that of short-term (15 days) PTH treated group, but they were still higher than those of IM and age-related controls. Our findings indicate that PTH treatment stimulates cancellous bone formation, restores and adds extra cancellous bone to the established, disuse-osteopenic proximal tibial metaphysis of continuously RHLI female rats. These results suggest that PTH may be a useful agent in treatment disuse-induced osteoporosis in humans.

Early prediction of post-thyroidectomy hypocalcemia by early parathyroid hormone measurement.

PubMed

Yetkin, Gurkan; Citgez, Bulent; Yazici, Pinar; Mihmanli, Mehmet; Sit, Erhan; Uludag, Mehmet

2016-01-01

Hypoparathyroidism is the most common complication of total thyroidectomy (TT). Postthyroidectomy hypocalcemia occurs 24 to 48 hours after the operation. It prolongs the length of hospital stay, even though transient in most cases. The aim of this study was to predetermine the patients who may develop postthyroidectomy hypocalcemia by using early postoperative serum intact parathormone (iPTH) and calcium (Ca2+) measurements, and to investigate the effects of early initiated oral calcium and vitamin D treatments on the development of transient hypocalcemia. Patients who underwent TT after initiation of the early iPTH measurement protocol in January 2013 were included into the study group (Group 1, n=202). The control group (Group 2) was composed of 72 patients who underwent TT before the protocol. Prior to the initiation of the protocol, Ca2+ was measured instead of iPTH. In the study group, the serum Ca2+ and iPTH levels were measured before surgery, and 1 and 24-hours after. A calcium level below 8 mg/dL was accepted as biochemical hypocalcaemia, and a iPTH level under 15pg/mL was accepted as hypoparathyroidism. In the study group, patients with below normal iPTH levels were treated with prophylactic oral calcium and vitamin D. In Group 1, 15.8% (n=32) of the patients had hypoparathyroidism on the 1h and 24 h iPTH measurements. There was no statistically difference with regard to PTH levels measured in the postoperative 1st hour and at the 24th hour (p= 0.078). Biochemical hypocalcaemia developed in 16 (7.9%) and 13 (18%) patients in Groups 1 and 2, respectively, 24 hours after thyroidectomy (p<0.05). Mean length of hospital stay was 2.17 and 3.26 days in the study and control groups (p<0.001). We believe that the measurement of iPTH levels one hour after thyroidectomy, when compared to levels at 24 hours after procedure, is a safe, reliable, and adequate method for the effective management of plausible postthyroidectomic hypocalcemia. It yields significantly shorter hospital stay periods. Calcium, Hypoparathyroidism, Postoperative complication, Total thyroidectomy.

Study of Red Cell Fragility in Different Stages of Chronic Kidney Disease in Relation to Parathyroid Hormone.

PubMed

Panda, Suchismita; Mishra, Anuva; Jena, Manoranjan; Rout, Sashi Bhusan; Mohapatra, Srikrushna

2017-08-01

Anaemia is one of the common complications associated with Chronic Kidney Disease (CKD) responsible for the increase in the morbidity and mortality in such patients. Several factors have been attributed to cause renal anaemia, amongst which hyperparathyroidism is one of the less recognised reasons. Most studies have been conducted in this regard in CKD patients undergoing haemodialysis. The level of PTH in early stages of chronic kidney disease has not been much studied. The excess amount of Parathyroid Hormone (PTH) secondary to CKD has been suggested to be a causative factor for anaemia. To evaluate the serum PTH level in CKD patients before haemodialysis and to study the association of the haemoglobin status with the parathyroid hormone. Forty CKD patients above 18 years of age before haemodialysis and 25 age and sex matched healthy controls were included in the study. Routine biochemical and haematological parameters such as Routine Blood Sugar (RBS), urea, creatinine, Na + , K + , Ca 2+ , PTH and Hb% were perfomed. Red cell osmotic fragility was measured by serial dilutions of whole blood with varying concentrations of sodium chloride ranging from 0.1% to 0.9%. The study revealed a significant fall in Hb%, along with a rise in Median Osmotic Fragility (MOF) and PTH in the CKD patients when compared to the control group. Linear regression of PTH with Hb% revealed significant negative association between both the parameters with a R 2 value of 0.677. Multilinear regression analysis of MOF and other independent variables such as Hb%, Na + , K + , Ca 2+ , urea, PTH and creatinine highlighted the variance of MOF by 72%, maximal variance contributed by PTH. Receiver Operating Curve (ROC) analysis revealed an area under the curve of 0.980 with a sensitivity of 100% and specificity of 87% in detecting osmotic fragility at a cut off value of PTH ≥100 pg/ml. The underlying cause of anaemia should be identified early in the CKD patients before haemodialysis. Secondary hyperparathyroidism should be ruled out as a causative factor of anaemia to slow down the progression of the disease process.

Threshold levels of 25-hydroxyvitamin D and parathyroid hormone for impaired bone health in children with congenital ichthyosis and type IV and V skin.

PubMed

Sethuraman, G; Sreenivas, V; Yenamandra, V K; Gupta, N; Sharma, V K; Marwaha, R K; Bhari, N; Irshad, M; Kabra, M; Thulkar, S

2015-01-01

Patients with congenital ichthyosis, especially those with darker skin types, are at increased risk of developing vitamin D deficiency and rickets. The relationships between 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH) and bone health have not been studied previously, in ichthyosis. To determine the threshold levels of 25(OH)D and PTH for impaired bone health in children with congenital ichthyosis. In this cross-sectional study, 119 children with ichthyosis and 168 controls were recruited. Serum 25(OH)D, PTH, calcium, phosphate and alkaline phosphatase (ALP) were measured. Radiological screening for rickets was carried out only in children with ichthyosis. Forty-seven children with ichthyosis had either clinical or radiological evidence of rickets. The correlation between serum 25(OH)D and PTH showed that a serum level of 25(OH)D 8 ng mL(-1) was associated with a significant increase in PTH. The correlation between PTH and ALP showed that a serum PTH level of 75 pg mL(-1) was associated with a significant increase in ALP levels. Of the different clinical phenotypes of ichthyosis, both autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis (EI) were found to have significantly increased PTH, ALP and radiological rickets scores compared with common ichthyosis. Serum levels of 25(OH)D ≤ 8 ng mL(-1) and PTH ≥ 75 pg mL(-1) significantly increases the risk for development of rickets [odds ratio (OR) 2·8; 95% confidence interval (CI) 1·05-7·40; P = 0·04] in ichthyosis. Among the different types, patients with ARCI (OR 4·83; 95% CI 1·74-13·45; P < 0·01) and EI (OR 5·71; 95% CI 1·74-18·79; P < 0·01) are at an increased risk of developing rickets. © 2014 British Association of Dermatologists.

Translating in vitro ligand bias into in vivo efficacy.

PubMed

Luttrell, Louis M; Maudsley, Stuart; Gesty-Palmer, Diane

2018-01-01

It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the manner in which they are activated. Thus, 'biased' agonists, synthetic ligands whose intrinsic efficacy differs from the native ligand, afford a strategy for manipulating GPCR signaling in ways that promote beneficial signals while blocking potentially deleterious ones. Still, there are significant challenges in relating in vitro ligand efficacy, which is typically measured in heterologous expression systems, to the biological response in vivo, where the ligand is acting on natively expressed receptors and in the presence of the endogenous ligand. This is particularly true of arrestin pathway-selective 'biased' agonists. The type 1 parathyroid hormone receptor (PTH 1 R) is a case in point. Parathyroid hormone (PTH) is the principal physiological regulator of calcium homeostasis, and PTH 1 R expressed on cells of the osteoblast lineage are an established therapeutic target in osteoporosis. In vitro, PTH 1 R signaling is highly sensitive to ligand structure, and PTH analogs that affect the selectivity/kinetics of G protein coupling or that engage arrestin-dependent signaling mechanisms without activating heterotrimeric G proteins have been identified. In vivo, intermittent administration of conventional PTH analogs accelerates the rate of osteoblastic bone formation, largely through known cAMP-dependent mechanisms. Paradoxically, both intermittent and continuous administration of an arrestin pathway-selective PTH analog, which in vivo would be expected to antagonize endogenous PTH 1 R-cAMP signaling, also increases bone mass. Transcriptomic analysis of tissue from treated animals suggests that conventional and arrestin pathway-selective PTH1R ligands act in largely different ways, with the latter principally affecting pathways involved in the regulation of cell cycle, survival, and migration/cytoskeletal dynamics. Such multi-dimensional in vitro and in vivo analyses of ligand bias may provide insights into the physiological roles of non-canonical arrestin-mediated signaling pathways in vivo, and provide a conceptual framework for translating arrestin pathway-selective ligands into viable therapeutics. Copyright © 2017 Elsevier Inc. All rights reserved.

Recombinant human parathyroid hormone (PTH 1-34) and low-intensity pulsed ultrasound have contrasting additive effects during fracture healing.

PubMed

Warden, Stuart J; Komatsu, David E; Rydberg, Johanna; Bond, Julie L; Hassett, Sean M

2009-03-01

Fracture healing is thought to be naturally optimized; however, recent evidence indicates that it may be manipulated to occur at a faster rate. This has implications for the duration of morbidity associated with bone injuries. Two interventions found to accelerate fracture healing processes are recombinant human parathyroid hormone [1-34] (PTH) and low-intensity pulsed ultrasound (LIPUS). This study aimed to investigate the individual and combined effects of PTH and LIPUS on fracture healing. Bilateral midshaft femur fractures were created in Sprague-Dawley rats, and the animals treated 7 days/week with PTH (10 microg/kg) or a vehicle solution. Each animal also had one fracture treated for 20 min/day with active-LIPUS (spatial-averaged, temporal-averaged intensity [I(SATA)]=100 mW/cm(2)) and the contralateral fracture treated with inactive-LIPUS (placebo). Femurs were harvested 35 days following injury to permit micro-computed tomography, mechanical property and histological assessments of the fracture calluses. There were no interactions between PTH and LIPUS indicating that their effects were additive rather than synergistic. These additive effects were contrasting with LIPUS primarily increasing total callus volume (TV) without influencing bone mineral content (BMC), and PTH having the opposite effect of increasing BMC without influencing TV. As a consequence of the effect of LIPUS on TV but not BMC, it decreased volumetric bone mineral density (vBMD) resulting in a less mature callus. The decreased maturity and persistence of cartilage at the fracture site when harvested offset any beneficial mechanical effects of the increased callus size with LIPUS. In contrast, the effect of PTH on callus BMC but not TV resulted in increased callus vBMD and a more mature callus. This resulted in PTH increasing fracture site mechanical strength and stiffness. These data suggest that PTH may have utility in the treatment of acute bone fractures, whereas LIPUS at an I(SATA) of 100 mW/cm(2) does not appear to be indicated in the management of closed, diaphyseal fractures.

A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-dose IL-2

PubMed Central

Correale, P; Micheli, L; Vecchio, M T Del; Sabatino, M; Petrioli, R; Pozzessere, D; Marsili, S; Giorgi, G; Lozzi, L; Neri, P; Francini, G

2001-01-01

Bone metastases are one of the most common events in patients with prostate carcinoma. PTH-rP, a protein produced by prostate carcinoma and other epithelial cancers, is a key agent for the development of bone metastases. A PTH-rP-derived peptide, designated PTR-4 was identified, which is capable to bind HLA-A2.1 molecules and to generate PTH-rP-specific cytotoxic T cell (CTL) lines from healthy HLA-A2.1+ individual peripheral-blood-mononuclear-cells (PBMC). In this model, we investigated the in vitro possibility of generating an efficient PTH-rP specific CTL response by cyclical stimulations with IL-2 and PTR-4 peptide-pulsed autologous dendritic cells (DC), of HLA-A2.1+ tumour infiltrating lymphocytes (TIL) derived from a patient with metastatic prostate carcinoma. A T cell line generated in this way (called TM-PTR-4) had a CD3+, CD5+, CD4−, CD8+, CD45Ro+, CD56− immunophenotype and a HLA-A2.1 restricted cytotoxic activity to PTR-4-peptide pulsed CIR-A2 (HLA-A2.1+) target cells, PTH-rP+/HLA-A2.1+ CIR-A2 transfected with PTH-rP gene, prostate carcinoma LNCaP cells, and autologous metastatic prostate cancer cells (M-CaP). These lymphocytes were not cytotoxic to HLA-A2.1+ targets not producing PTH-rP, such as peptide-unpulsed CIR-A2 and colon carcinoma SW-1463, cell lines. Our results provide evidence that PTR-4 peptide-pulsed autologous DC may break the tolerance of human TIL against the autologous tumour by inducing a PTH-rP-specific CTL immune reaction. In conclusion PTR-4 peptide-pulsed autologous DC may be a promising approach for vaccine-therapy and antigen-specific CTL adoptive immunotherapy of hormone-resistant prostrate cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11742494

Enhanced human bone marrow mesenchymal stem cell functions on cathodic arc plasma-treated titanium

PubMed Central

Zhu, Wei; Teel, George; O’Brien, Christopher M; Zhuang, Taisen; Keidar, Michael; Zhang, Lijie Grace

2015-01-01

Surface modification of titanium for use in orthopedics has been explored for years; however, an ideal method of integrating titanium with native bone is still required to this day. Since human bone cells directly interact with nanostructured extracellular matrices, one of the most promising methods of improving titanium’s osseointegration involves inducing bio-mimetic nanotopography to enhance cell–implant interaction. In this regard, we explored an approach to functionalize the surface of titanium by depositing a thin film of textured titanium nanoparticles via a cathodic arc discharge plasma. The aim is to improve human bone marrow mesenchymal stem cell (MSC) attachment and differentiation and to reduce deleterious effects of more complex surface modification methods. Surface functionalization was analyzed by scanning electron microscopy, atomic force microscopy, contact angle testing, and specific protein adsorption. Scanning electron microscopy and atomic force microscopy examination demonstrate the deposition of titanium nanoparticles and the surface roughness change after coating. The specific fibronectin adsorption was enhanced on the modified titanium surface that associates with the improved hydrophilicity. MSC adhesion and proliferation were significantly promoted on the nanocoated surface. More importantly, compared to bare titanium, greater production of total protein, deposition of calcium mineral, and synthesis of alkaline phosphatase were observed from MSCs on nanocoated titanium after 21 days. The method described herein presents a promising alternative method for inducing more cell favorable nanosurface for improved orthopedic applications. PMID:26677327

Hypocalcemic stimulation and nonselective venous sampling for localizing parathyroid adenomas: work in progress.

PubMed

Doppman, J L; Skarulis, M C; Chang, R; Alexander, H R; Bartlett, D; Libutti, S K; Marx, S J; Spiegel, A M

1998-07-01

To evaluate whether the release of parathyroid hormone (PTH) from parathyroid tumors during selective parathyroid arteriography can help localize the tumors. In 20 patients (six men, 14 women; age range, 24-72 years) with parathyroid tumors undergoing parathyroid arteriography after failed surgery, serial measurements of PTH were obtained during selective arteriography with nonionic contrast material. PTH levels were measured in the superior vena cava (SVC) before and at varying times from 20 to 120 seconds after arteriography. A 1.4-fold increase in the PTH level of the postarteriographic SVC samples enabled correct prediction of the site of adenoma in 13 of the 20 patients (65%). Of nine patients with positive arteriograms, eight had positive results of postarteriographic sampling. Of 11 patients with negative arteriograms, five had positive results of postarteriographic sampling. Sampling the SVC for PTH gradients after selective parathyroid arteriography correctly indicated the site of the adenoma in 13 of 20 patients (65%).

Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism

NASA Technical Reports Server (NTRS)

Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

2003-01-01

Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.

Regional responsiveness of the tibia to intermittent administration of parathyroid hormone as affected by skeletal unloading

NASA Technical Reports Server (NTRS)

Halloran, B. P.; Bikle, D. D.; Harris, J.; Tanner, S.; Curren, T.; Morey-Holton, E.

1997-01-01

To determine whether the acute inhibition of bone formation and deficit in bone mineral induced by skeletal unloading can be prevented, we studied the effects of intermittent parathyroid hormone (PTH) administration (8 micrograms/100 g/day) on growing rats submitted to 8 days of skeletal unloading. Loss of weight bearing decreased periosteal bone formation by 34 and 51% at the tibiofibular junction and tibial midshaft, respectively, and reduced the normal gain in tibial mass by 35%. Treatment with PTH of normally loaded and unloaded animals increased mRNA for osteocalcin (+58 and +148%, respectively), cancellous bone volume in the proximal tibia (+41 and +42%, respectively), and bone formation at the tibiofibular junction (+27 and +27%, respectively). Formation was also stimulated at the midshaft in unloaded (+47%, p < 0.05), but not loaded animals (-3%, NS). Although cancellous bone volume was preserved in PTH-treated, unloaded animals, PTH did not restore periosteal bone formation to normal nor prevent the deficit in overall tibial mass induced by unloading. We conclude that the effects of PTH on bone formation are region specific and load dependent. PTH can prevent the decrease in cancellous bone volume and reduce the decrement in cortical bone formation induced by loss of weight bearing.

Intraoperative serum parathyroid hormone level is an indicator of hypocalcaemia in total thyroidectomy patients.

PubMed

Islam, M S; Sultana, T; Paul, D; Huq, A H M Z; Chowdhury, A A; Ferdous, C; Ahmed, A N N

2012-12-01

Postoperative hypocalcaemia is the most frequent and common complication after total thyroidectomy. It is necessary to diagnose or to predict hypocalcaemia immediately after total thyroidectomy for minimizing complications. A prospective observational study was carried out in the Department of Clinical Pathology in collaboration with Department of Microbiology & Immunology, Department of Surgery, Department of Otolaryngology, Bangabandhu Sheikh Mujib Medical University (BSMMU) and Department of Otolaryngology, Dhaka Medical College & Hospital (DMC&H), Dhaka, during the period of September 2010 to August 2011 to evaluate intraoperative (20 minutes after total thyroidectomy) parathyroid hormone (PTH) measurement as a predictor of post thyroidectomy hypocalcaemia. Total 65 patients were enrolled in this study those came for total thyroidectomy. Postoperative hypocalcaemia developed in 25 cases. Intraoperative PTH was assessed and significant correlation was found between intraoperative PTH level and development of hypocalcaemia. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value of intraoperative serum PTH for prediction of post total thyroidectomy hypocalcaemia were 84.0%, 85.0%, 84.6%, 77.8%, and 89.5% respectively. Because of the high sensitivity, specificity and accuracy of intraoperative serum PTH of this study, the early prediction of hypocalcaemia could be made by single assay of intraoperative serum PTH level at 20 minutes after total thyroidectomy.

Phosphate homeostasis in Bartter syndrome: a case-control study.

PubMed

Bettinelli, Alberto; Viganò, Cristina; Provero, Maria Cristina; Barretta, Francesco; Albisetti, Alessandra; Tedeschi, Silvana; Scicchitano, Barbara; Bianchetti, Mario G

2014-11-01

Bartter patients may be hypercalciuric. Additional abnormalities in the metabolism of calcium, phosphate, and calciotropic hormones have occasionally been reported. The metabolism of calcium, phosphate, and calciotropic hormones was investigated in 15 patients with Bartter syndrome and 15 healthy subjects. Compared to the controls, Bartter patients had significantly reduced plasma phosphate {mean [interquartile range]:1.29 [1.16-1.46] vs. 1.61 [1.54-1.67] mmol/L} and maximal tubular phosphate reabsorption (1.16 [1.00-1.35] vs. 1.41 [1.37-1.47] mmol/L) and significantly increased parathyroid hormone (PTH) level (6.1 [4.5-7.7] vs. 2.8 [2.2-4.4] pmol/L). However, patients and controls did not differ in blood calcium, 25-hydroxyvitamin D, alkaline phosphatase, and osteocalcin levels. In patients, an inverse correlation (P < 0.05) was noted between total plasma calcium or glomerular filtration rate and PTH concentration. A positive correlation was also noted between PTH and osteocalcin concentrations (P < 0.005), as well as between chloriduria or natriuria and phosphaturia (P < 0.001). No correlation was noted between calciuria and PTH concentration or between urinary or circulating phosphate and PTH. The results of this study demonstrate a tendency towards renal phosphate wasting and elevated circulating PTH levels in Bartter patients.

Parathyroid hormone modulates the response of osteoblast-like cells to mechanical stimulation

NASA Technical Reports Server (NTRS)

Ryder, K. D.; Duncan, R. L.

2000-01-01

Mechanical loading stimulates many responses in bone and osteoblasts associated with osteogenesis. Since loading and parathyroid hormone (PTH) activate similar signaling pathways in osteoblasts, we postulate that PTH can potentiate the effects of mechanical stimulation. Using an in vitro four-point bending device, we found that expression of COX-2, the inducible isoform of cyclooxygenase, was dependent on fluid forces generated across the culture plate, but not physiologic levels of strain in MC3T3-E1 osteoblast-like cells. Addition of 50 nM PTH during loading increased COX-2 expression at both subthreshold and threshold levels of fluid forces compared with either stimuli alone. We also demonstrated that application of fluid shear to MC3T3-E1 cells induced a rapid increase in [Ca(2+)](i). Although PTH did not significantly change [Ca(2+)](i) levels, flow and PTH did produce a significantly greater [Ca(2+)](i) response and increased the number of responding cells than is found in fluid shear alone. The [Ca(2+)](i) response to these stimuli was significantly decreased when the mechanosensitive channel inhibitor, gadolinium, was present. These studies indicate that PTH increases the cellular responses of osteoblasts to mechanical loading. Furthermore, this response may be mediated by alterations in [Ca(2+)](i) by modulating the mechanosensitive channel.

The effect of cryotherapy on nerve conduction velocity, pain threshold and pain tolerance.

PubMed

Algafly, Amin A; George, Keith P

2007-06-01

To determine the impact of the application of cryotherapy on nerve conduction velocity (NCV), pain threshold (PTH) and pain tolerance (PTO). A within-subject experimental design; treatment ankle (cryotherapy) and control ankle (no cryotherapy). Hospital-based physiotherapy laboratory. A convenience sample of adult male sports players (n = 23). NCV of the tibial nerve via electromyogram as well as PTH and PTO via pressure algometer. All outcome measures were assessed at two sites served by the tibial nerve: one receiving cryotherapy and one not receiving cryotherapy. In the control ankle, NCV, PTH and PTO did not alter when reassessed. In the ankle receiving cryotherapy, NCV was significantly and progressively reduced as ankle skin temperature was reduced to 10 degrees C by a cumulative total of 32.8% (p<0.05). Cryotherapy led to an increased PTH and PTO at both assessment sites (p<0.05). The changes in PTH (89% and 71%) and PTO (76% and 56%) were not different between the iced and non-iced sites. The data suggest that cryotherapy can increase PTH and PTO at the ankle and this was associated with a significant decrease in NCV. Reduced NCV at the ankle may be a mechanism by which cryotherapy achieves its clinical goals.

The effect of cryotherapy on nerve conduction velocity, pain threshold and pain tolerance

PubMed Central

Algafly, Amin A; George, Keith P

2007-01-01

Objectives To determine the impact of the application of cryotherapy on nerve conduction velocity (NCV), pain threshold (PTH) and pain tolerance (PTO). Design A within‐subject experimental design; treatment ankle (cryotherapy) and control ankle (no cryotherapy). Setting Hospital‐based physiotherapy laboratory. Participants A convenience sample of adult male sports players (n = 23). Main outcome measures NCV of the tibial nerve via electromyogram as well as PTH and PTO via pressure algometer. All outcome measures were assessed at two sites served by the tibial nerve: one receiving cryotherapy and one not receiving cryotherapy. Results In the control ankle, NCV, PTH and PTO did not alter when reassessed. In the ankle receiving cryotherapy, NCV was significantly and progressively reduced as ankle skin temperature was reduced to 10°C by a cumulative total of 32.8% (p<0.05). Cryotherapy led to an increased PTH and PTO at both assessment sites (p<0.05). The changes in PTH (89% and 71%) and PTO (76% and 56%) were not different between the iced and non‐iced sites. Conclusions The data suggest that cryotherapy can increase PTH and PTO at the ankle and this was associated with a significant decrease in NCV. Reduced NCV at the ankle may be a mechanism by which cryotherapy achieves its clinical goals. PMID:17224445

Frequency of papillary tubal hyperplasia (PTH), salpingoliths and transition from adenoma to borderline ovarian tumors (BOT): A systematic analysis of 74 BOT with different histologic types.

PubMed

Horn, Lars-Christian; Angermann, Karolin; Hentschel, Bettina; Einenkel, Jens; Höhn, Anne Kathrin

2017-04-01

Borderline ovarian tumors (BOT) arise from cystadenomas and represent a transition step within the development of low-grade ovarian carcinomas (Type I tumors). That pathway mirrors the adenoma-to-carcinoma sequence known for colorectal cancer. It has been suggested that papillary tubal hyperplasia (PTH) and salpingoliths may be associated with the development of BOT. To evaluate the frequency of the presence of benign cystadenoma and its transition to BOT in a given patient as well as the presence of PTH and salpingoliths we re-valuated in 74 consecutive cases of BOT with different histologic types. The majority of cases represented serous-BOT (60.8%), followed by mucinous BOT (25.7%), other histologic types were rare. 86.5% showed an adenoma-BOT sequence, which was seen in all mucinous BOT but was missed in 15.6% of serous BOT. Two cases had salpingoliths without associated PTH. PTH was seen in four out of the 74 (5.4%) BOT and occurred only in cases with serous histology. The vast majority of BOT represent a transition from benign cystadenoma to BOT in cases with mucinous and serous histology. Salpingoliths are rarely seen in association with BOT and occurred exclusively in BOT with serous histology. PTH may represent a distinct lesion but is rarely seen in association with BOT, especially in those with non-serous histology. Further studies are needed to evaluate the frequency and pathogenetic association of PTH with BOT. Copyright © 2017 Elsevier GmbH. All rights reserved.

[Diagnostic value of PTH total kit for estimation of bone turnover in children with chronic renal failure].

PubMed

Ziółkowska, Helena; Roszkowska-Blaim, Maria

2006-01-01

The aim of the study was to estimate the usefulness of total PTH and 1-84 molecule (CAP) assay in clinical practice. 118 children with chronic renal failure aged 13.8 +/- 4.5 years were examined: 69 on conservative treatment with creatinine clearance 40.7 +/- 20 ml/min/1.73 m2, 31 on peritoneal dialysis and 16 on hemodialysis. In all patients the following parameters were assessed: serum levels of calcium (sCa), phosphorus (sP), PTH intact (PTHs) by chemiluminescence method (Immulite analyzer), total PTH (PTHc) and CAP with Duo PTH Assay (Scantibodies Laboratories, USA). The value of CIP as the difference between total PTH and CAP was calculated. For the evaluation of bone turnover the serum level of osteocalcin (OC) with IRMA, (OsteoRiact, CIS, F) and activity of serum alkaline phosphatase (AP) were determined. The correlations between parameters were calculated by Pearson's correlation coefficient (r). Significant correlation were found between PTHs and PTHc (r=0.84, p=0.0000), CAP (r=0.79, p=0.0000) and CIP. The increase of PTHs, PTHc, CAP, CIP, sP, OC and percentage of CIP were noticed, when parallel increase of creatinine level was found. The negative correlation between creatinine level and CAP/CIP was observed. The similar correlations between level of PTHs, PTHc, CAP and OC level were observed (r=0.55, 0.49 and 0.50 respectively). The assay of total PTH and CAP fragment is not usefull in clinical practice for estimation of bone turnover in children with chronic renal failure.

The role of cyclase activating (CAP) and cyclase inhibiting (CIP) parathormone fractions in the assessment of bone metabolism disturbances in women with hyperprolactinemia of various origin.

PubMed

Zadrozna-Sliwka, Beata; Bolanowski, Marek; Jawiarczyk, Aleksandra; Kaluzny, Marcin; Syrycka, Joanna

2008-02-01

Hyperprolactinemia could be one of possible causes of bone loss. The reason is thought to be connected with hypogonadism due to PRL excess and the role of other hormones like PTH and PTH-rP. There is no data on the influence of PTH fractions (CAP and CIP) on bone turnover and density in hyperprolactinemia. The aim of the study was to assess the influence of PTH and its fractions on bone metabolism in hyperprolactinemia of various origin. The study was carried out in 75 women. Group I consisted of 32 women with prolactinoma, group II consisted of 43 women with functional hyperprolactinemia. Both groups were subdivided in patients with hypogonadism and normal gonadal function. The control group consisted of 29 healthy women. In all subjects PRL, PTH and its fractions (CAP, CIP), and bone turnover markers (BAP, ICTP) were studied. BMD measurement was carried out using DXA. In patients with functional hyperprolactinemia i-PTH and CAP levels were lower than in controls. CIP concentrations were lower in patients than in controls. CAP/CIP ratio was higher in patients with prolactinoma than in patients with functional hyperprolactinemia and controls. Higher values of bone turnover markers (BAP, ICTP) in patients groups and subgroups were shown as compared to controls. Some correlations between PTH and its fractions, and BMD and bone turnover were observed. There is no direct benefit from the assessment of parathormone fractions and CAP/CIP ratio in the prognosis of bone metabolism changes in hyperprolactinemia of various origin.

Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial.

PubMed

Havens, Peter L; Stephensen, Charles B; Hazra, Rohan; Flynn, Patricia M; Wilson, Craig M; Rutledge, Brandy; Bethel, James; Pan, Cynthia G; Woodhouse, Leslie R; Van Loan, Marta D; Liu, Nancy; Lujan-Zilbermann, Jorge; Baker, Alyne; Kapogiannis, Bill G; Mulligan, Kathleen

2012-04-01

The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. NCT00490412.

The role of intraoperative parathyroid hormone testing in patients with tertiary hyperparathyroidism after renal transplantation.

PubMed

Haustein, Silke V; Mack, Eberhard; Starling, James R; Chen, Herbert

2005-12-01

Intraoperative parathyroid hormone (PTH) testing has been shown to accurately define adequacy of parathyroid resection in patients with primary hyperparathyroidism (HPT) and alters the operative management in 10% to 15% of cases. However, the benefit of this technique in patients with tertiary HPT after renal transplantation undergoing parathyroidectomy is unclear. Intraoperative PTH was measured in 32 consecutive patients undergoing parathyroidectomy for tertiary HPT after renal transplantation between March 2001 and November 2004 by using the Elecsys assay at baseline and, subsequently, 5, 10, and 15 minutes after curative resection. The outcomes of these patients were evaluated. All patients were cured after surgery. Of the 32 patients, 29 were found to have parathyroid hyperplasia, while 1 had a single adenoma and 2 had double adenomas. The average drop in intraoperative PTH levels after curative resection was 69 +/- 3.5% at 5 min., 77 +/- 2.3% at 10 minutes, and 83 +/- 3.4% at 15 minutes. PTH testing changed the intraoperative management in 5 (16%) patients. One patient with a single adenoma and 2 patients with double adenomas had a >50% drop at 10 minutes. after excision; therefore, the operation was terminated without further resection. Two patients did not have a >50% drop at 10 minutes after 3.5 gland resection. These patients were explored further, and additional supernumerary parathyroid glands were identified and resected. After resection of these additional glands, the PTH fell by >50%, indicating cure. In patients undergoing parathyroidectomy for tertiary HPT after renal transplantation, a decrease in intraoperative PTH levels >50% at 10 minutes after completion of the operation indicated adequate resection. Furthermore, intraoperative PTH testing altered the operative management in 16% of patients. Therefore, similar to its role in patients with primary HPT, intraoperative PTH testing appears to play an equally important role in the management of patients with tertiary HPT undergoing parathyroidectomy.

Expression of parathyroid hormone/parathyroid hormone-related peptide receptor 1 in normal and diseased bladder detrusor muscles: a clinico-pathological study.

PubMed

Nishikawa, Nobuyuki; Yago, Rie; Yamazaki, Yuichiro; Negoro, Hiromitsu; Suzuki, Mari; Imamura, Masaaki; Toda, Yoshinobu; Tanabe, Kazunari; Ogawa, Osamu; Kanematsu, Akihiro

2015-01-21

To investigate the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor 1 (PTH1R) in clinical specimens of normal and diseased bladders. PTHrP is a unique stretch-induced endogenous detrusor relaxant that functions via PTH1R. We hypothesized that suppression of this axis could be involved in the pathogenesis of bladder disease. PTH1R expression in clinical samples was examined by immunohistochemistry. Normal kidney tissue from a patient with renal cancer and bladder specimens from patients undergoing ureteral reimplantation for vesicoureteral reflux or partial cystectomy for urachal cyst were examined as normal control organs. These were compared with 13 diseased bladder specimens from patients undergoing bladder augmentation. The augmentation patients ranged from 8 to 31 years old (median 15 years), including 9 males and 4 females. Seven patients had spinal disorders, 3 had posterior urethral valves and 3 non-neurogenic neurogenic bladders (Hinman syndrome). Renal tubules, detrusor muscle and blood vessels in normal control bladders stained positive for PTH1R. According to preoperative urodynamic studies of augmentation patients, the median percent bladder capacity compared with the age-standard was 43.6% (range 1.5-86.6%), median intravesical pressure at maximal capacity was 30 cmH2O (range 10-107 cmH2O), and median compliance was 3.93 ml/cmH2O (range 0.05-30.3 ml/cmH2O). Detrusor overactivity was observed in five cases (38.5%). All augmented bladders showed negative stainings in PTH1R expression in the detrusor tissue, but positive staining of blood vessels in majority of the cases. Downregulation of PTH1R may be involved in the pathogenesis of human end-stage bladder disease requiring augmentation.

Increasing dietary phosphorus intake from food additives: potential for negative impact on bone health.

PubMed

Takeda, Eiji; Yamamoto, Hironori; Yamanaka-Okumura, Hisami; Taketani, Yutaka

2014-01-01

It is important to consider whether habitual high phosphorus intake adversely affects bone health, because phosphorus intake has been increasing, whereas calcium intake has been decreasing in dietary patterns. A higher total habitual dietary phosphorus intake has been associated with higher serum parathyroid hormone (PTH) and lower serum calcium concentrations in healthy individuals. Higher serum PTH concentrations have been shown in those who consume foods with phosphorus additives. These findings suggest that long-term dietary phosphorus loads and long-term hyperphosphatemia may have important negative effects on bone health. In contrast, PTH concentrations did not increase as a result of high dietary phosphorus intake when phosphorus was provided with adequate amounts of calcium. Intake of foods with a ratio of calcium to phosphorus close to that found in dairy products led to positive effects on bone health. Several randomized controlled trials have shown positive relations between dairy intake and bone mineral density. In our loading test with a low-calcium, high-phosphorus lunch provided to healthy young men, serum PTH concentrations showed peaks at 1 and 6 h, and serum fibroblast growth factor 23 (FGF23) concentrations increased significantly at 8 h after the meal. In contrast, the high-calcium, high-phosphorus meal suppressed the second PTH and FGF23 elevations until 8 h after the meal. This implies that adequate dietary calcium intake is needed to overcome the interfering effects of high phosphorus intake on PTH and FGF23 secretion. FGF23 acts on the parathyroid gland to decrease PTH mRNA and PTH secretion in rats with normal kidney function. However, increased serum FGF23 is an early alteration of mineral metabolism in chronic kidney disease, causing secondary hyperthyroidism, and implying resistance of the parathyroid gland to the action of FGF23 in chronic kidney disease. These findings suggest that long-term high-phosphorus diets may impair bone health mediated by FGF23 resistance both in chronic kidney disease patients and in the healthy population.

Changes in Vitamin D-Related Mineral Metabolism After Induction With Anti-Tumor Necrosis Factor-α Therapy in Crohn's Disease

PubMed Central

Augustine, Marianne V.; Leonard, Mary B.; Thayu, Meena; Baldassano, Robert N.; de Boer, Ian H.; Shults, Justine; Denson, Lee A.; DeBoer, Mark D.; Herskovitz, Rita

2014-01-01

Context: Preclinical studies suggest that TNF-α suppresses PTH synthesis, inhibits renal 1α-hydroxylase activity, and impairs fibroblast growth factor 23 (FGF23) degradation. The impact of inflammation on vitamin D and mineral metabolism has not been well-characterized in Crohn's disease (CD). Objective: The objective of the study was to assess short-term changes in vitamin D-related mineral metabolism in CD after anti-TNF-α induction therapy. Design/Participants: Eighty-seven CD participants, aged 5–39 years, were assessed at the initiation of anti-TNF-α therapy and 10 weeks later. Outcomes: Indices of clinical disease activity and serum concentrations of vitamin D metabolites, vitamin D-binding protein (DBP), calcium, PTH, FGF23, IL-6, and TNF-α were measured at each visit. A multivariable generalized estimating equation (GEE) regression analysis was used to examine the correlates of PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations at each visit. Results: After anti-TNF-α therapy, cytokines and inflammatory markers [IL-6, TNF-α, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)] concentrations decreased (all P < .0001), and PTH and 1,25(OH)2D concentrations increased (median 21 vs 30 pg/mL, P < .0001, and median 41.7 vs 48.1 pg/mL, P = .014, respectively). Levels of 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D, DBP, and FGF23 did not change. In GEE analyses, higher IL-6, TNF-α, ESR, and CRP were associated with lower PTH concentrations (all P < .001), adjusted for corrected calcium and 25(OH)D levels. Higher PTH was associated with higher 1,25(OH)2D concentrations (P < .001) at each visit, independent of 25(OH)D concentrations. Higher levels of all inflammatory markers were associated with lower 1,25(OH)2D concentrations (all P < .05). However, when PTH was added to these models, the inflammatory markers (with the exception of CRP) were no longer significantly associated with 1,25(OH)2D. Conclusions: Greater inflammation was associated with lower PTH and 1,25(OH)2D concentrations. After anti-TNF-α induction, PTH and 1,25(OH)2D concentrations increased without concomitant changes in 25(OH)D and FGF23, consistent with effects of inflammation on PTH and thereby renal conversion of 25(OH)D to 1,25(OH)2D. PMID:24617709

A comparative study of the bone metabolic response to dried plum supplementation and PTH treatment in adult, osteopenic ovariectomized rat.

PubMed

Smith, Brenda J; Bu, So Young; Wang, Yan; Rendina, Elizabeth; Lim, Yin F; Marlow, Denver; Clarke, Stephen L; Cullen, Diane M; Lucas, Edralin A

2014-01-01

Dried plum has been reported to have potent effects on bone in osteopenic animal models, but the mechanisms through which bone metabolism is altered in vivo remain unclear. To address this issue, a study comparing the metabolic response of dried plum to the anabolic agent, parathyroid hormone (PTH), was undertaken. Six month-old female Sprague Dawley rats (n=84) were sham-operated (SHAM) or ovariectomized (OVX) and maintained on a control diet for 6wks until osteopenia was confirmed. Treatments were initiated consisting of a control diet (AIN-93M) supplemented with dried plum (0, 5, 15 or 25%; w/w) or a positive control group receiving PTH. At the end of 6wks of treatment, whole body and femoral bone mineral density (BMD) were restored by the two higher doses of dried plum to the level of the SHAM group. Trabecular bone volume and cortical thickness were also improved with these two doses of dried plum. Dried plum suppressed the OVX-induced increase in bone turnover as indicated by systemic biomarkers of bone metabolism, N-terminal procollagen type 1 (P1NP) and deoxypyridinoline (DPD). Dynamic bone histomorphometric analysis of the tibial metaphysis revealed that dried plum restored the OVX-induced increase in cancellous bone formation rate (BFR) and mineralizing surface (MS/BS) to the SHAM group, but some doses of dried plum increased endocortical mineral apposition rate (MAR). As expected, PTH significantly increased endocortical MAR and BFR, periosteal BFR, and trabecular MAR and BFR beyond that of the OVX and maintained the accelerated rate of bone resorption associated with OVX. Dried plum up-regulated bone morphogenetic protein 4 (Bmp4) and insulin-like growth factor 1 (Igf1) while down-regulating nuclear factor T cell activator 1 (Nfatc1). These findings demonstrate that in the adult osteopenic OVX animal, the effects of dried plum differ from that of PTH in that dried plum primarily suppressed bone turnover with the exception of the indices of bone formation at the endocortical surface. © 2013.

Low vitamin D levels have become less common in primary hyperparathyroidism.

PubMed

Walker, M D; Cong, E; Lee, J A; Kepley, A; Zhang, C; McMahon, D J; Bilezikian, J P; Silverberg, S J

2015-12-01

We compared temporal trends in serum 25-hydroxyvitamin D and parathyroid hormone (PTH) in two primary hyperparathyroidism (PHPT) cohorts recruited 20 years apart. The prevalence of 25-hydroxyvitamin D levels <20 and <30 ng/mL declined by 30-50 %, respectively, and was accompanied by lower PTH. In the older cohort, higher PTH may be due to lower 25-hydroxyvitamin D. Vitamin D deficiency may exacerbate PHPT. Whether there have been temporal trends in 25-hydroxyvitamin D (25OHD) levels in PHPT is unclear. The prevalence of low vitamin D levels (25OHD <20 and <30 ng/mL) and associated biochemical and bone mineral density (BMD) profiles were assessed in two PHPT cohorts recruited over 20 years apart. This is a cross-sectional comparison of serum 25OHD levels, calciotropic hormones, and BMD between two PHPT cohorts recruited at the same hospital: the "old" (N = 103) and "new" (N = 100) cohorts were enrolled between 1984 and 1991 and between 2010 and 2014, respectively. Mean 25OHD levels were 26 % higher in the new cohort (23 ± 10 vs. 29 ± 10 ng/mL, p < 0.0001). Levels of 25OHD <20 and <30 ng/mL declined from 46 and 82 %, respectively, to 19 and 54 % (both p < 0.0001). Supplemental vitamin D use was common in the new (64 %) but not the old cohort (0 %). The new cohort demonstrated 33 % lower serum PTH levels (p < 0.0001). Neither serum nor urine calcium differed. BMD was higher in the new cohort at all skeletal sites (all p < 0.001). With the rise in vitamin D supplementation over the last two decades, low 25OHD levels are no longer common in PHPT patients in the New York area. Those with 25OHD <20 and <30 ng/mL have declined by over 50 and 30 %, respectively. The lower mean PTH levels in the new cohort are most likely accounted for by higher vitamin D intake. Whether improved vitamin D status also underlies the relatively higher BMD in the more vitamin D replete cohort of PHPT patients is unknown.

Titanium aluminide intermetallic alloys with improved wear resistance

DOEpatents

Qu, Jun; Lin, Hua-Tay; Blau, Peter J.; Sikka, Vinod K.

2014-07-08

The invention is directed to a method for producing a titanium aluminide intermetallic alloy composition having an improved wear resistance, the method comprising heating a titanium aluminide intermetallic alloy material in an oxygen-containing environment at a temperature and for a time sufficient to produce a top oxide layer and underlying oxygen-diffused layer, followed by removal of the top oxide layer such that the oxygen-diffused layer is exposed. The invention is also directed to the resulting oxygen-diffused titanium aluminide intermetallic alloy, as well as mechanical components or devices containing the improved alloy composition.

Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanaka, Ken-ichiro, E-mail: ken1nai@med.shimane-u.ac.jp; Yamaguchi, Toru, E-mail: yamaguch@med.shimane-u.ac.jp; Kanazawa, Ippei, E-mail: ippei.k@med.shimane-u.ac.jp

In diabetes mellitus (DM), high glucose (HG) and advanced glycation end products (AGEs) are involved in bone quality deterioration. Osteocytes produce sclerostin and receptor activator of nuclear factor-kB ligand (RANKL) and regulate osteoblast and osteoclast function. However, whether HG or AGEs directly affect osteocytes and regulate sclerostin and RANKL production is unknown. Here, we examined the effects of HG, AGE2, and AGE3 on the expression of sclerostin and RANKL and on apoptosis in osteocyte-like MLO-Y4-A2 cells. Treatment of the cells with 22 mM glucose, 100 μg/mL either AGE2 or AGE3 significantly increased the expression of sclerostin protein and mRNA; however, both AGEs,more » but not glucose, significantly decreased the expression of RANKL protein and mRNA. Moreover, treatment of the cells with HG, AGE2, or AGE3 for 72 h induced significant apoptosis. These detrimental effects of HG, AGE2, and AGE3 on sclerostin and RANKL expressions and on apoptosis were antagonized by pretreatment of the cells with 10{sup −8} M human parathyroid hormone (PTH)-(1–34). Thus, HG and AGEs likely suppress bone formation by increasing sclerostin expression in osteocytes, whereas AGEs suppress bone resorption by decreasing RANKL expression. Together, these processes may cause low bone turnover in DM. In addition, HG and AGEs may cause cortical bone deterioration by inducing osteocyte apoptosis. PTH may effectively treat these pathological processes and improve osteocyte function. - Highlights: • AGEs are involved in bone quality deterioration in diabetes mellitus (DM). • AGEs increased sclerostin as well as apoptosis, and decreased RANKL in osteocytes. • The effects of AGEs on osteocyte function were antagonized by human PTH-(1–34). • AGEs may cause low bone turnover and cortical porosity in DM. • PTH may be effective in bone quality deterioration by improving osteocyte function.« less

Parathyroid Hormone Activates Phospholipase C (PLC)-Independent Protein Kinase C Signaling Pathway via Protein Kinase A (PKA)-Dependent Mechanism: A New Defined Signaling Route Would Induce Alternative Consideration to Previous Conceptions

PubMed Central

Tong, Guojun; Meng, Yue; Hao, Song; Hu, Shaoyu; He, Youhua; Yan, Wenjuan; Yang, Dehong

2017-01-01

Background Parathyroid hormone (PTH) is an effective anti-osteoporosis agent, after binding to its receptor PTHR1, several signaling pathways, including cAMP/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC), are initiated through G proteins; with the cAMP/PKA pathway as the major pathway. Earlier studies have reported that PTHR1 might also activate PKC via a PLC-independent mechanism, but this pathway remains unclear. Material/Methods In HEK293 cells, cAMP accumulation was measured with ELISA and PKC was measured with fluorescence resonance energy transfer (FRET) analysis using CKAR plasmid. In MC3T3-E1 cells, real-time PCR was performed to examine gene expressions. Then assays for cell apoptosis, cell differentiation, alkaline phosphatase activity, and mineralization were performed. Results The FRET analysis found that PTH(1–34), [G1,R19]PTH(1–34) (GR(1–34), and [G1,R19]PTH(1–28) (GR(1–28) were all activated by PKC. The PKC activation ability of GR(1–28) was blocked by cAMP inhibitor (Rp-cAMP) and rescued with the addition of active PKA-α and PKA-β. The PKC activation ability of GR(1–34) was partially inhibited by Rp-cAMP. In MC3T3-E1 cells, gene expressions of ALP, CITED1, NR4a2, and OSX that was regulated by GR(1–28) were significantly changed by the pan-PKC inhibitor Go6983. After pretreatment with Rp-cAMP, the gene expressions of ALP, CITED1, and OPG were differentially regulated by GR(1–28) or GR(1–34), and the difference was blunted by Go6983. PTH(1–34), GR(1–28), and GR(1–34) significantly decreased early apoptosis and augmented osteoblastic differentiation in accordance with the activities of PKA and PKC. Conclusions PLC-independent PKC activation induced by PTH could be divided into two potential mechanisms: one was PKA-dependent and associated with PTH(1–28); the other was PKA-independent and associated with PTH(29–34). We also found that PTH could activate PLC-independent PKC via PKA-dependent mechanisms. PMID:28424452

Hypocalcaemia after total thyroidectomy: could intact parathyroid hormone be a predictive factor for transient postoperative hypocalcemia?

PubMed

Puzziello, Alessandro; Gervasi, Rita; Orlando, Giulio; Innaro, Nadia; Vitale, Mario; Sacco, Rosario

2015-02-01

Hypocalcemia, the most common complication of thyroidectomy, is a transient condition in up to 27% of patients and a permanent condition approximately 1% of patients. The aim of this prospective study was to evaluate reliability of postoperative intact parathyroid hormone (iPTH) assessment for predicting clinically relevant postthyroidectomy hypocalcemia for a safe early discharge of patients with no overtreatment. Seventy-five consecutive patients (age 51 ± 13 years [mean ± SD]) undergoing total or completion thyroidectomy with no concomitant parathyroid diseases or renal failure were included in the present study. Serum iPTH level was determined before and 2 hours after thyroidectomy. Serum calcium concentration was determined 1 day before and 2 days postoperatively. The occurrence of postoperative hypocalcemia was correlated both with the absolute and relative iPTH decrease, determined as a ratio of the preoperative value (P < .0001). There was a greater difference in relative decrease in iPTH between patients remaining normocalcemic and those with hypocalcemia present on the second postoperative day. Hypocalcemic patients on the second postoperative day had a 62% relative decrease in iPTH 2 hours after thyroidectomy. The relative decrease in serum iPTH was greater in patients with hypocalcemia arising on the second postoperative day rather than in patients who remained normocalcemic. The relative decrease in iPTH determined 2 hours after total thyroidectomy together with the serum calcium concentration 24 hours after thyroidectomy proved to be useful predictors of sustained hypocalcemia and might change the clinical management of patients after thyroid surgery to support a longer hospitalization in these selected patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Influence of the autonomic nervous system on calcium homeostasis in the rat.

PubMed

Stern, J E; Cardinali, D P

1994-01-01

The local surgical manipulation of sympathetic and parasympathetic nerves innervating the thyroid-parathyroid territory was employed to search for the existence of a peripheral neuroendocrine link controlling parathyroid hormone (PTH) and calcitonin (CT) release. From 8 to 24 h after superior cervical ganglionectomy (SCGx), at the time of wallerian degeneration of thyroid-parathyroid sympathetic nerve terminals, an alpha-adrenergic inhibition, together with a minor beta-adrenergic stimulation, of hypercalcemia-induced CT release, and an alpha-adrenoceptor inhibition of hypocalcemia-induced PTH release were found. In chronically SCGx rats PTH response to EDTA was slower, and after CaCl2 injection, serum calcium attained higher levels in face of normal CT levels. SCGx blocked the PTH increase found in sham-operated rats stressed by a subcutaneous injection of turpentine oil, but did not affect the greater response to EDTA. The higher hypocalcemia seen after turpentine oil was no longer observed in SCGx rats. The effects of turpentine oil stress on calcium and CT responses to a bolus injection of CaCl2 persisted in rats subjected to SCGx 14 days earlier. Interruption of thyroid-parathyroid parasympathetic input conveyed by the thyroid nerves (TN) and the inferior laryngeal nerves (ILN) caused a fall in total serum calcium, an increase of PTH levels and a decrease of CT levels, when measured 10 days after surgery. Greater responses of serum CT and PTH were detected in TN-sectioned, and in TN- or ILN-sectioned rats, respectively. Physiological concentrations of CT decreased, and those of PTH increased, in vitro cholinergic activity in rat SCG, measured as specific choline uptake, and acetylcholine synthesis and release. The results indicate that cervical autonomic nerves constitute a pathway through which the brain modulates calcium homeostasis.

The effect of cinacalcet on bone remodeling and renal function in transplant patients with persistent hyperparathyroidism.

PubMed

Schwarz, Anke; Merkel, Saskia; Leitolf, Holger; Haller, Hermann

2011-03-15

Parathyroidectomy is associated with renal functional losses in transplant patients; cinacalcet offers an attractive alternative. We performed a prospective observational study in 58 patients with persisting hyperparathyroidism after renal transplantation (Ca≥2.6 mmol/L) and impaired renal transplant function (estimated glomerular filtration rate [eGFR] <50 mL/min). The patients received 30 to 90 mg cinacalcet for 12 months with the target to normalize serum Ca. We measured parathyroid hormone (PTH), serum Ca, serum phosphorus, alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, and telopeptide at 0, 1, 2, 3, 6, 9, and 12 months of cinacalcet treatment. Fractional excretion of calcium and phosphorus (n=24) were monitored at 0 and 1 month. At inclusion, creatinine was 181±70 μmol/L, eGFR 43±19 mL/min, PTH 371±279 pg/mL, and Ca 2.73±0.22 mmol/L. We observed nephrocalcinosis in 58% of biopsied patients at enrollment. After cinacalcet, Ca decreased significantly and normalized at nearly any measurement. Phosphorus increased significantly at months 1, 9, and 12. PTH decreased significantly, but only at months 9 and 12 and did not normalize. Bone-specific alkaline phosphatase increased significantly (>normal) by month 12. eGFR decreased and serum creatinine increased at all time points. The Δ(creatinine) % increase correlated significantly with the Δ(PTH) % decrease at month 1 and 12. Telopeptide and alkaline phosphatase correlated with PTH and telopeptide also correlated with serum creatinine. Calcium-phosphorus homeostasis in hypercalcemic renal transplant patients normalizes under cinacalcet and PTH decreases, albeit not to normal. The renal functional decline could be PTH mediated, analogous to the effects observed after parathyroidectomy.

Necessity of therapy for post-thyroidectomy hypocalcaemia: a multi-centre experience.

PubMed

De Pasquale, L; Sartori, P V; Vicentini, L; Beretta, E; Boniardi, M; Leopaldi, E; Gini, P; La Manna, L; Cozzaglio, L; Steffano, G B; Andreani, S; Badiali, S; Cantoni, G M; Galimberti, A; Ghilardi, G; Gusmeroli, M; Maggiore, R; Morenghi, E; Pauna, J; Poggi, L; Testa, V

2015-04-01

Hypoparathyroidism is one of the most common and most feared complications of total thyroidectomy (TT). The aim of this study is to detect possible markers that may facilitate early tracing of hypocalcaemia-prone patients in order to reduce clinical cost by optimizing patient discharge and to avoid unnecessary treatment. Over an 18-month period, 995 patients, 23 % male and 77 % female, aged 52.9 ± 13.4 years, underwent TT in ten Lombardy hospitals. The following parameters were analyzed: calcaemia before and 12-24 and 48 h after surgery, pre- and post-operative parathyroid hormone (PTH) at 24 h and pre-operative 25OH vitamin D. Mortality was nil and morbidity was 22.4 %. Mean 24-h calcaemia and PTH were 2.17 ± 0.15 mmol/l and 31.81 ± 20.35 pg/ml, respectively; mean 24-h PTH decay was 36.7 ± 34.12 %. Four hundred seventy-three (47.5 %) patients were hypocalcaemic at discharge; 142 of whom had transient hypoparathyroidism that became permanent in 27. Patients developing hypocalcaemia had significantly higher values of PTH and calcium decay. At multiple logistic regression, only 24-h calcium decay, PTH drop and the presence of symptoms and parathyroid auto-grafting were significantly related to hypoparathyroidism. The association of these factors had a 99.2 % negative predictive value (NPV) for the development of hypoparathyroidism. A 70 % PTH drop had a 93.75 NPV for transient hypoparathyroidism. A 12 % calcaemia decay had a 95.7 NPV for hypoparathyroidism. Hypocalcaemic asymptomatic patients with less than 70 % PTH and 12 % calcaemia decay may be safely discharged without treatment. Symptomatic patients and those with parathyroid grafting should receive calcium and vitamin D.

Parathyroid hormone and its analogues--molecular mechanisms of action and efficacy in osteoporosis therapy.

PubMed

Misiorowski, Waldemar

2011-01-01

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.

[Parathyroid hormone and its analogues - molecular mechanisms of action and efficacy of osteoporosis therapy].

PubMed

Misiorowski, Waldemar

2011-01-01

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.

Vitamin D supplementation has minor effects on parathyroid hormone and bone turnover markers in vitamin D-deficient bedridden older patients.

PubMed

Björkman, Mikko; Sorva, Antti; Risteli, Juha; Tilvis, Reijo

2008-01-01

to evaluate the effects of vitamin D supplementation on parathyroid function and bone turnover in aged, chronically immobile patients. a randomised double-blind controlled trial. two hundred and eighteen long-term inpatients aged over 65 years. the patients were randomised into treatment groups of I-III, each receiving 0 IU, 400 IU and 1200 IU cholecalciferol per day, respectively. In case of inadequate consumption of dairy products, patients received a daily calcium substitution of 500 mg. plasma concentrations of 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone (PTH), amino-terminal propeptide of type I procollagen (PINP), a marker of bone formation, and carboxy-terminal telopeptide of type I collagen (ICTP), a marker of bone resorption, were measured at baseline and after 6 months. the patients (age 84.5 years) were chronically bedridden. The baseline 25-OHD was low (23 nmol/l), correlated inversely with PINP, and tended to associate inversely with PTH. The prevalence of vitamin D deficiency (VDD) (25-OHD < 50 nmol/l) was 98% and PTH was elevated in 23% of the patients. Vitamin D supplementation significantly increased 25-OHD concentrations (124% group II, 204% group III) and decreased PTH (-7% group II, -8% group III). PINP tended to decrease, but ICTP tended to increase, and only their ratio decreased significantly. The tendency of ICTP to increase was inconsistent. Changes in 25-OHD correlated inversely with those in PTH and PINP. vitamin D supplementation has minor effects on PTH and bone turnover in chronically immobilised aged patients with VDD. Further comparative studies and meta-analyses are warranted to elucidate the confounding effects of different mobility levels on the benefits of vitamin D supplementation in patients with differing baseline PTH levels.

Regulation Of Hypothalamic Signaling By Tuberoinfundibular Peptide Of 39 Residues Is Critical For The Response To Cold: A Novel Peptidergic Mechanism Of Thermoregulation

PubMed Central

Dimitrov, Eugene L.; Kim, Yoon Yi; Usdin, Ted B.

2012-01-01

Euthermia is critical for mammalian homeostasis. Circuits within the preoptic hypothalamus regulate temperature, with fine control exerted via descending GABAergic inhibition of presympathetic motor neurons that control brown adipose tissue (BAT) thermogenesis and cutaneous vascular tone. The thermoregulatory role of hypothalamic excitatory neurons is less clear. Here we report peptidergic regulation of preoptic glutamatergic neurons that contributes to temperature regulation. Tuberoinfundibular peptide of 39 residues (TIP39) is a ligand for the parathyroid hormone 2 receptor (PTH2R). Both peptide and receptor are abundant in the preoptic hypothalamus. Based on PTH2R and vesicular glutamate transporter 2 (VGlut2) immunolabeling in animals with retrograde tracer injection, PTH2R containing glutamatergic fibers are presynaptic to neurons projecting from the median preoptic nucleus (MnPO) to the dorsomedial hypothalamus. Transneuronal retrograde pathway tracing with pseudorabies virus revealed connectivity between MnPO VGlut2 and PTH2R neurons and BAT. MnPO injection of TIP39 increased body temperature by 2° C for several hours. Mice lacking TIP39 signaling, either because of PTH2R null mutation or brain delivery of a PTH2R antagonist had impaired heat production upon cold exposure, but no change in basal temperature and no impairment in response to a hot environment. Thus, TIP39 appears to act on PTH2Rs present on MnPO glutamatergic terminals to regulate their activation of projection neurons and subsequent sympathetic BAT activation. This excitatory mechanism of heat production appears to be activated on demand, during cold exposure, and parallels the tonic inhibitory GABAergic control of body temperature. PMID:22159128

Simultaneous Control of PTH and Ca×P Is Sustained over Three Years of Treatment with Cinacalcet HCl

PubMed Central

Evenepoel, Pieter; Curzi, Mario P.; González, Maria Teresa; Husserl, Fred E.; Kopyt, Nelson; Sterling, Lulu Ren; Mix, Chris; Wong, Gordon

2009-01-01

Background & objectives: Chronic kidney disease (CKD) is commonly complicated by secondary hyperparathyroidism (SHPT), leading to increased risk of morbidity and mortality. SHPT is a progressive disease often requiring long-term therapy to control parathyroid hormone (PTH) and mineral imbalances. Vitamin D sterols and phosphate binders, used as traditional therapies to lower PTH and phosphorus, may provide inadequate long-term control for many dialysis patients. Cinacalcet, by simultaneously lowering PTH, calcium, phosphorus, and calcium-phosphorus levels, may maintain PTH and mineral balance in these individuals. However, as with traditional therapies, long-term data are limited. Design, setting, participants, & measurement: Dialysis subjects from at least one of five lead-in studies (double-blind placebo-controlled, including one extension trial) completing up to 52 wk of either cinacalcet or placebo were eligible for this open-label extension study, including an 8-wk dose titration (initiated at 30 mg/d), followed by 24-wk maintenance and up to 132 wk of follow-up. Final efficacy analysis was at week 180. Results: Three hundred thirty-four of 589 enrolled subjects received cinacalcet from the beginning of the lead-in study. Weekly median PTH values were ≤300 pg/ml (weeks 16 through 180) and median Ca×P values were ≤55 mg2/dl2 (weeks 4 through 180). Similar results were exhibited in the 255 subjects who initially received placebo. Among the patients exposed to cinacalcet from the beginning of the lead-in study, 3% of subjects exhibited treatment-related serious adverse events. Conclusions: Cinacalcet effectively maintained PTH, Ca and P reductions in dialysis subjects for up to 180 wk. PMID:19696213

Independent and Synergistic Associations of Biomarkers of Vitamin D Status With Risk of Coronary Heart Disease.

PubMed

Qi, Lu; Ma, Wenjie; Heianza, Yoriko; Zheng, Yan; Wang, Tiange; Sun, Dianjianyi; Rimm, Eric B; Hu, Frank B; Giovannucci, Edward; Albert, Christine M; Rexrode, Kathryn M; Manson, JoAnn E

2017-11-01

To comprehensively evaluate the independent associations and potential interactions of vitamin D-related biomarkers including total and bioavailable 25-hydroxyvitamin D (25OHD), VDBP (vitamin D binding protein), and parathyroid hormone (PTH) with risk of coronary heart disease (CHD). We prospectively identified incident cases of nonfatal myocardial infarction and fatal CHD among women in the Nurses' Health Study during 20 years of follow-up (1990-2010). Using risk-set sampling, 1 to 2 matched controls were selected for each case. The analysis of 25OHD and PTH included 382 cases and 575 controls; the analysis of VDBP included 396 cases and 398 controls. After multivariate adjustment, plasma levels of total 25OHD, bioavailable 25OHD, and PTH were not significantly associated with CHD risk. VDBP was associated with a lower CHD risk with an extreme-quartile odds ratio of 0.60 (95% confidence interval, 0.39-0.92; P trend=0.02). When examining the biomarkers jointly, a significant, inverse association between 25OHD and CHD was observed among participants with higher PTH levels ( P for interaction=0.02). The odds ratio (95% confidence interval) comparing the highest quartile of 25OHD to lowest was 0.43 (0.23-0.82; P trend=0.003) when PTH levels were above population median (35.3 pg/mL), whereas among the rest of participants the corresponding odds ratio (95% confidence interval) was 1.28 (0.70-2.36; P trend=0.43). Our data suggest that higher 25OHD levels were associated with a lower CHD risk when PTH levels were high, whereas no association was observed for participants with low PTH levels. VDBP but not bioavailable 25OHD was independently associated with lower CHD risk. © 2017 American Heart Association, Inc.

Parathyroid hormone response to severe vitamin D deficiency is associated with femoral neck bone mineral density: an observational study of 405 women with hip-fracture.

PubMed

Di Monaco, Marco; Castiglioni, Carlotta; Tappero, Rosa

2016-10-01

Hip-fracture patients with vitamin D deficiency can have either secondary hyperparathyroidism or normal levels of parathyroid hormone (PTH). We hypothesized that bone mineral density (BMD) could be lower in patients with high PTH levels than in those with normal levels of PTH, irrespectively of the severity of vitamin D depletion. In this cross-sectional study, we examined 405 women who had serum 25-hydroxyvitamin D below 12ng/ml 20.0 ± 5.9 (mean ± SD) days after a hip-fracture. PTH was assessed by a chemiluminescent immunometric assay and BMD by dual-energy x-ray absorptiometry at the unfractured femoral neck. BMD was significantly lower in the 148 women with secondary hyperparathyroidism than in the 257 with normal PTH levels: the mean T-score (SD) was -2.88 (0.93) and -2.65 (0.83), respectively, in the two groups (mean difference 0.23; 95% CI 0.05 - 0.41; P = 0.010). The association between PTH status and BMD persisted after adjustment for age, body mass index, phosphate, albumin-adjusted total calcium, 25-hydroxyvitamin D, estimated glomerular filtration rate, and magnesium (P=0.01). The presence of secondary hyperparathyroidism was significantly associated with a femoral neck T-score lower than -2.5. The adjusted odds ratio was 1.81 (95% CI 1.11 - 2.95; P=0.017). Our results show that PTH levels in the presence of severe vitamin D deficiency were significantly associated with femoral BMD in women with hip-fracture. Prevention and treatment of vitamin D deficiency may be particularly relevant in women who develop secondary hyperparathyroidism.

Surfactant-assisted synthesis of polythiophene/Ni0.5Zn0.5Fe2-xCexO4 ferrite composites: study of structural, dielectric and magnetic properties for EMI-shielding applications.

PubMed

Dar, M Abdullah; Majid, Kowsar; Hanief Najar, Mohd; Kotnala, R K; Shah, Jyoti; Dhawan, S K; Farukh, M

2017-04-19

This work reports the exploitation of nanocrystalline Ni 0.5 Zn 0.5 Fe 2-x Ce x O 4 ferrite for potential application by designing quasi-spherical shaped polythiophene (PTH) composites via in situ emulsion polymerization. The structural, electronic, dielectric, magnetic, and electromagnetic interference (EMI) shielding properties of PTH/Ni 0.5 Zn 0.5 Fe 2-x Ce x O 4 composites were investigated. Our results suggest that these properties could be optimized by modulating the concentration of x (composition) in the polymer matrix. Higher values of ε' and ε'' were obtained on composite formation, and could be due to the heterogeneity developed in the material. An enhancement in the value of saturation magnetization (123 emu g -1 for x = 0.04) and Curie temperature was obtained with Ce concentration, which is useful for high density recording purposes. A low value of saturation magnetization was obtained for the PTH/Ni 0.5 Zn 0.5 Fe 2-x Ce x O 4 composite (36 emu g -1 for x = 0.04). This could be attributed to the non-magnetic nature of the polymer. A total shielding effectiveness (SE T = SE A + SE R ) up to 34 dB (≈99.9% attenuation) was recorded for PTH/Ni 0.5 Zn 0.5 Fe 2-x Ce x O 4 composites (x = 0.04) in a frequency range of 8.2-12.4 GHz (X-band), which surpasses the shielding criteria of SE T > 30 dB for commercial purposes. Such a material with high SE identifies its potential for making electromagnetic shields. The effect of Ce substitution on the microstructure, dielectric, impedance and magnetic properties of PTH/Ni 0.5 Zn 0.5 Fe 2-x Ce x O 4 ferrite composites was also investigated. X-ray diffraction analysis confirmed cubic spinel phase formation, and the broad reflection peaks indicated the formation of smaller sized particles. The smaller energy band gap (2.53 eV) of the composite indicated that this material could be used for photocatalysis in the visible region. Dielectric and impedance measurements were carried out in a frequency range of 8.2-12.4 GHz. Dielectric properties were improved considerably by the substitution of Ce 3+ ions in PTH/Ni 0.5 Zn 0.5 Fe 2-x Ce x O 4 composites. Impedance spectroscopy was used to study the effect of grain and grain boundaries on the electrical properties of PTH/Ni 0.5 Zn 0.5 Fe 2-x Ce x O 4 composites. Cole-Cole plots showed the formation of single semi-circles for all samples in the measured frequency range. This showed that the composite material was composed of good conducting grains and poorly conducting grain boundaries.

Avionics Integrity Issues Presented during NAECON (National Aerospace and Electronics Convention) 1984.

DTIC Science & Technology

1984-12-01

PLASTIC ABOVE BOOC 2. PTH COPPER SHOULD BE ABOVE 62 ELONGATION, 5OKPSI 3. PTH LIFE IS INCREAS-D WITH LARGER PTH AND POLYIMIDE PWB’S 4. SOLDER JOINT DEFO M...34XTION IS PREDOMINANTLY PLASTIC , THEREFORE HIGH SOLDER DUCTILITY IS IMPORTANT - AVOID SOLDER CONTAMINANTS - AVOID HOT STORAGE OR SLOW COOLDOWN SUMMARY...UTILIZATION OF STEP-STRESS TECHNIQUE o MANAGEMENT CONSIDERATIONS * PLASTIC PARTS AFAILURE ANALYSIS/DPA 0SHELF TIME VS RESCREEN *USE OF ACCELERATED

Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy

PubMed Central

Kuroshima, Shinichiro; Mecano, Rodan B.; Tanoue, Ryuichiro; Koi, Kiyono; Yamashita, Junro

2014-01-01

Background Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies. Methods Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting. Results Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition. Conclusion Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss. PMID:23688101

Parathyroid hormone levels 1 hour after thyroidectomy: an early predictor of postoperative hypocalcemia

PubMed Central

AlQahtani, Awad; Parsyan, Armen; Payne, Richard; Tabah, Roger

2014-01-01

Background Parathyroid dysfunction leading to symptomatic hypocalcemia is not uncommon following a total or completion thyroidectomy and is often associated with significant patient morbidity and a prolonged hospital stay. A simple, reliable indicator to identify patients at risk would permit earlier pharmacologic prophylaxis to avoid these adverse outcomes. We examined the role of intact parathormone (PTH) levels 1 hour after surgery as a predictor of post-thyroidectomy hypocalcemia. Methods We prospectively reviewed the cases of consecutive patients undergoing total or completion thyroidectomy. Ionized calcium (Ca2+) and intact PTH levels were measured preoperatively and at 1-, 6- and 24-hour intervals postoperatively. The specificity, sensitivity, negative and positive predictive values of the 1-hour PTH serum levels (PTH-1) in predicting 24-hour post-thyroidectomy hypocalcemia and eucalcemia were determined. Results We reviewed the cases of 149 patients. Biochemical hypocalcaemia (Ca2+ < 1.1 mmol/L) developed in 38 of 149 (25.7%) patients 24 hours after thyroidectomy. The sensitivity, specificity, positive and negative predictive values of a low PTH-1 were 89%, 100%, 97% and 100%, respectively. Conclusion We found that PTH-1 levels were predictive of symptomatic hypocalcemia 24 hours after thyroidectomy. Routine use of this assay should be considered, as it could prompt the early administration of calcitriol in patients at risk of hypocalcemia and allow for the safe and timely discharge of patients expected to remain eucalcemic. PMID:25078927

Provocative tests of parathyroid and C cell function in adrenalectomized and chemically sympathectomized rats.

PubMed

Heath, H

1980-10-01

Recent in vitro and in vivo evidence shows that secretion of parathyroid hormone (PTH) and calcitonin (CT) is stimulated by beta-adrenergic agonists and inhibited by beta-adrenergic antagonists. To assess the possible roles of adrenal medullary or adrenergic nerve terminal catecholamines in calcium homeostasis, we have examined serum calcium (Ca), immunoreactive PTH (iPTH), and immunoreactive CT (iCT) in control, adrenalectomized (ADRX), and chemically sympathectomized [6-hydroxydopamine (6-OHDA)] rats. Animals were studied in the fed and fasted states, after ip injection of CA and after ip injection of EDTA. In comparison with fasted rats, fed control rats tended to have increased serum Ca and iCT, but decreased or unchanged iPTH. Neither adrenalectomy nor 6-OHDA treatment notably altered this pattern. Serum iCT concentrations rose markedly after ip Ca, and peak iCT responses remained normal in ADRX and 6-OHDA-treated rats. Similarly, rises of iPTH levels after EDTA-induced hypocalcemia were normal in ADRX and 6-OHDA-treated rats. The only possible abnormality concerned basal serum iCT levels after 6-OHDA treatment, which were lower than control in five of six experiments, albeit not always significantly. We conclude that deprivation of either adrenal medullary or adrenergic nerve terminal catecholamines does not interfere with plasma Ca regulation or the homeostatic responses of PTH and CT in the rat.

First-in-human testing of a wirelessly controlled drug delivery microchip.

PubMed

Farra, Robert; Sheppard, Norman F; McCabe, Laura; Neer, Robert M; Anderson, James M; Santini, John T; Cima, Michael J; Langer, Robert

2012-02-22

The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) [hPTH(1-34)] was delivered from the device in vivo. hPTH(1-34) is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life.

Parathyroid hormone levels 1 hour after thyroidectomy: an early predictor of postoperative hypocalcemia.

PubMed

AlQahtani, Awad; Parsyan, Armen; Payne, Richard; Tabah, Roger

2014-08-01

Parathyroid dysfunction leading to symptomatic hypocalcemia is not uncommon following a total or completion thyroidectomy and is often associated with significant patient morbidity and a prolonged hospital stay. A simple, reliable indicator to identify patients at risk would permit earlier pharmacologic prophylaxis to avoid these adverse outcomes. We examined the role of intact parathormone (PTH) levels 1 hour after surgery as a predictor of post-thyroidectomy hypocalcemia. We prospectively reviewed the cases of consecutive patients undergoing total or completion thyroidectomy. Ionized calcium (Ca(2+)) and intact PTH levels were measured preoperatively and at 1-, 6- and 24-hour intervals postoperatively. The specificity, sensitivity, negative and positive predictive values of the 1-hour PTH serum levels (PTH-1) in predicting 24-hour post-thyroidectomy hypocalcemia and eucalcemia were determined. We reviewed the cases of 149 patients. Biochemical hypocalcaemia (Ca(2+) < 1.1 mmol/L) developed in 38 of 149 (25.7%) patients 24 hours after thyroidectomy. The sensitivity, specificity, positive and negative predictive values of a low PTH-1 were 89%, 100%, 97% and 100%, respectively. We found that PTH-1 levels were predictive of symptomatic hypocalcemia 24 hours after thyroidectomy. Routine use of this assay should be considered, as it could prompt the early administration of calcitriol in patients at risk of hypocalcemia and allow for the safe and timely discharge of patients expected to remain eucalcemic.

Systemic delivery of parathyroid hormone (1-34) using inhalation dry powders in rats.

PubMed

Codrons, Valérie; Vanderbist, Francis; Verbeeck, Roger K; Arras, Mohammed; Lison, Dominique; Préat, Véronique; Vanbever, Rita

2003-05-01

The aim of this work was to prepare and characterize inhalation dry powders of human parathyroid hormone (PTH), as well as to assess their efficacy for systemic delivery of the peptide and safety in rats. The powders were prepared by spray-drying using PTH, sugars, dipalmitoylphosphatidylcholine, and/or albumin. They presented an average primary particle diameter of 4.5 microm and tap density of 0.06 g/cm(3), a mass median aerodynamic diameter between 3.9 and 5.9 microm, and reached up to 98% emitted dose and up to 61% fine particle fraction in the multi-stage liquid impinger using a Spinhaler inhaler device. Varying the airflow rate from 30 to 100 L/min had limited influence on the aerodynamic behavior of the aerosols. The absolute PTH bioavailability was 21% after intratracheal administration of the powder formed of PTH/albumin/lactose/dipalmitoylphosphatidylcholine and 18% after subcutaneous injection in rats. Equilibrium dialysis revealed a 78% binding of PTH to albumin and the withdrawal of albumin from the powder increased absolute bioavailability after inhalation from 21 to 34%. No acute inflammation appeared in the lung up to 48 h after a single inhalation. The increased bioavailability of the optimized powder aerosol of PTH makes it a promising alternative to subcutaneous injection. Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:938-950, 2003

Parathyroid hormone gene expression in hypophosphatemic rats.

PubMed Central

Kilav, R; Silver, J; Naveh-Many, T

1995-01-01

Phosphate is central to bone metabolism and we have therefore studied whether parathyroid hormone (PTH) is regulated by dietary phosphate in vivo. Weanling rats were fed diets with different phosphate contents for 3 wk: low phosphate (0.02%), normal calcium (0.6%), normal phosphate (0.3%), and calcium (0.6%); high phosphate (1.2%), high calcium (1.2%). The low phosphate diet led to hypophosphatemia, hypercalcemia, and increased serum 1,25(OH)2D3 together with decreased PTH mRNA levels (25 +/- 8% of controls, P < 0.01) and serum immunoreactive PTH (4.7 +/- 0.8: 22.1 +/- 3.7 pg/ml; low phosphate: control, P < 0.05). A high phosphate diet led to increased PTH mRNA levels. In situ hybridization showed that hypophosphatemia decreased PTH mRNA in all the parathyroid cells. To separate the effect of low phosphate from changes in calcium and vitamin D rats were fed diets to maintain them as vitamin D-deficient and normocalcemic despite the hypophosphatemia. Hypophosphatemic, normocalemic rats with normal serum 1,25(OH)2D3 levels still had decreased PTH mRNAs. Nuclear transcript run-ons showed that the effect of low phosphate was posttranscriptional. Calcium and 1,25(OH)2D3 regulate the parathyroid and we now show that dietary phosphate also regulates the parathyroid by a mechanism which remains to be defined. Images PMID:7615802

Selected wheat seed defense proteins exhibit competitive binding to model microbial lipid interfaces.

PubMed

Sanders, Michael R; Clifton, Luke A; Neylon, Cameron; Frazier, Richard A; Green, Rebecca J

2013-07-17

Puroindolines (Pins) and purothionins (Pths) are basic, amphiphilic, cysteine-rich wheat proteins that play a role in plant defense against microbial pathogens. This study examined the co-adsorption and sequential addition of Pins (Pin-a, Pin-b, and a mutant form of Pin-b with Trp-44 to Arg-44 substitution) and β-purothionin (β-Pth) model anionic lipid layers using a combination of surface pressure measurements, external reflection FTIR spectroscopy, and neutron reflectometry. Results highlighted differences in the protein binding mechanisms and in the competitive binding and penetration of lipid layers between respective Pins and β-Pth. Pin-a formed a blanket-like layer of protein below the lipid surface that resulted in the reduction or inhibition of β-Pth penetration of the lipid layer. Wild-type Pin-b participated in co-operative binding with β-Pth, whereas the mutant Pin-b did not bind to the lipid layer in the presence of β-Pth. The results provide further insight into the role of hydrophobic and cationic amino acid residues in antimicrobial activity.

Plasma nanocoating of thiophene onto MoS2 nanotubes

NASA Astrophysics Data System (ADS)

Türkaslan, Banu Esencan; Dikmen, Sibel; Öksüz, Lütfi; Öksüz, Aysegul Uygun

2015-12-01

MoS2 nanotubes were coated with conductive polymer thiophene by atmospheric pressure radio-frequency (RF) glow discharge. MoS2 nanotubes were prepared by thermal decomposition of hexadecylamine (HDA) intercalated laminar MoS2 precursor on anodized aluminum oxide template and the thiophene was polymerized directly on surface of these nanotubes as in situ by plasma method. The effect of plasma power on PTh/MoS2 nanocomposite properties has been investigated by means of Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM and EDX), and X-ray diffraction spectroscopy (XRD). The presence of PTh bands in the FTIR spectra of PTh/MoS2 nanotube nanocomposites corresponding XRD results indicates that the polythiophene coating onto MoS2 nanotube. The chemical structure of PTh is not changed when the plasma power of discharge differ from 117 to 360 W. SEM images of nanocomposites show that when the discharge power is increased between 117 and 360 W the average diameter of PTh/MoS2 nanotube nanocomposites are changed and the structure become more uniformly.

Effect of Annealing on the Passive Film Stability and Corrosion Resistance of New Families of Iron-Based Amorphous Metals

DTIC Science & Technology

2011-06-01

metallic glass easier to create and more stable once formed, thus improving the corrosion resistance. Adding titanium will enable the formation of...glass easier to create and more stable once formed, thus improving the corrosion resistance. Adding titanium will enable the formation of an extremely...research, it was hypothesized that additions of titanium could enable the formation of a protective titanium oxide film on the surface of the alloy

pth moment exponential stability of stochastic memristor-based bidirectional associative memory (BAM) neural networks with time delays.

PubMed

Wang, Fen; Chen, Yuanlong; Liu, Meichun

2018-02-01

Stochastic memristor-based bidirectional associative memory (BAM) neural networks with time delays play an increasingly important role in the design and implementation of neural network systems. Under the framework of Filippov solutions, the issues of the pth moment exponential stability of stochastic memristor-based BAM neural networks are investigated. By using the stochastic stability theory, Itô's differential formula and Young inequality, the criteria are derived. Meanwhile, with Lyapunov approach and Cauchy-Schwarz inequality, we derive some sufficient conditions for the mean square exponential stability of the above systems. The obtained results improve and extend previous works on memristor-based or usual neural networks dynamical systems. Four numerical examples are provided to illustrate the effectiveness of the proposed results. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hypercalcemia with renal failure.

PubMed

Bhavani, Nisha; Praveen, Valiyaparambil Pavithran; Jayakumar, Rohinivilasam Vasukutty; Nair, Vasantha; Muraleedharan, Mangath; Kuma, Harish; Unnikrishnan, Ambika Gopalakrishnan; Menon, Vadayath Usha

2012-06-01

We report a cse of nephrocalcinosis with renal failure which on evaluation was found to have hypercalcemia. Further investigations showed an inappropriately normal intact parathormone (iPTH) and 1,25 dihydroxy-vitamin D level in the setting of renal failure. Probing for a cause of non-PTH mediated hypercalcemia led to the diagnosis of sarcoidosis. Treatment with glucocorticoids could partially reverse the renal failure and control the hypercalcemia. This case illustrates the importance of careful interpretation of laboratory parameters especially levels of iPTH and vitamin D metabolites in renal failure.

Human parathyroid hormone-(1-38) restores cancellous bone to the immobilized, osteopenic proximal tibial metaphysis in rats

NASA Technical Reports Server (NTRS)

Ma, Y. F.; Jee, W. S.; Ke, H. Z.; Lin, B. Y.; Liang, X. G.; Li, M.; Yamamoto, N.

1995-01-01

The purpose of this study was to determine if human parathyroid hormone-(1-38) (hPTH(1-38)) can restore cancellous bone mass to the established osteopenic, immobilized proximal tibial metaphyses of female rats. The right hindlimbs of 6-month-old female Sprague-Dawley rats were immobilized by bandaging the right hindlimbs to the abdomen. After 30 days of right hindlimb immobilization, the rats were subcutaneously injected with 200 micrograms hPTH(1-38)/kg/day for 15 days (short-term treatment) or 75 days (longer-term treatment). Static bone histomorphometry was performed on the primary spongiosa, and both static and dynamic histomorphometry were performed on the secondary spongiosa of the right proximal tibial metaphyses. Immobilization for 30 days without treatment decreased trabecular bone area, number, and thickness in both primary and secondary spongiosa, and induced an increase in eroded perimeter and a decrease in tissue referent-bone formation rate in the secondary spongiosa. These changes reached a new steady state thereafter. Treatment with 200 micrograms hPTH(1-38)/kg/day for 15 days, beginning 30 days after immobilization, significantly increased trabecular bone area, thickness, and number in both primary and secondary spongiosa despite continuous immobilization when compared with controls. The short-term PTH treatment (15 days) significantly increased labeling perimeter, mineral apposition rate, and tissue referent-bone formation rate in the secondary spongiosa and stimulated longitudinal bone growth as compared with the controls. Longer PTH treatment (75 days) further increased trabecular bone area, thickness, and number as compared with controls and groups given short-term PTH treatment (15 days). The bone formation indices in the secondary spongiosa of the longer-term treated rats were lower than those of the short-term treated group, but they were still higher than those of controls. Our findings indicate that PTH treatment stimulates cancellous bone formation, and restores and adds extra cancellous bone to the established, disuse-osteopenic proximal tibial metaphysis of female rats with continuously immobilized right hindlimbs. These results suggest that PTH may be useful in treating disuse-induced osteoporosis in humans.

A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover.

PubMed

Horwitz, Mara J; Tedesco, Mary Beth; Sereika, Susan M; Prebehala, Linda; Gundberg, Caren M; Hollis, Bruce W; Bisello, Alessandro; Garcia-Ocaña, Adolfo; Carneiro, Raquel M; Stewart, Andrew F

2011-09-01

Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7-day continuous-infusion models using human parathyroid hormone(1-34) [hPTH(1-34)] and human parathyroid hormone-related protein(1-36) [hPTHrP(1-36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1-84). The maximal tolerated infused doses over a 7-day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone-formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone-resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT. Copyright © 2011 American Society for Bone and Mineral Research.

Increasing Dietary Phosphorus Intake from Food Additives: Potential for Negative Impact on Bone Health123

PubMed Central

Takeda, Eiji; Yamamoto, Hironori; Yamanaka-Okumura, Hisami; Taketani, Yutaka

2014-01-01

It is important to consider whether habitual high phosphorus intake adversely affects bone health, because phosphorus intake has been increasing, whereas calcium intake has been decreasing in dietary patterns. A higher total habitual dietary phosphorus intake has been associated with higher serum parathyroid hormone (PTH) and lower serum calcium concentrations in healthy individuals. Higher serum PTH concentrations have been shown in those who consume foods with phosphorus additives. These findings suggest that long-term dietary phosphorus loads and long-term hyperphosphatemia may have important negative effects on bone health. In contrast, PTH concentrations did not increase as a result of high dietary phosphorus intake when phosphorus was provided with adequate amounts of calcium. Intake of foods with a ratio of calcium to phosphorus close to that found in dairy products led to positive effects on bone health. Several randomized controlled trials have shown positive relations between dairy intake and bone mineral density. In our loading test with a low-calcium, high-phosphorus lunch provided to healthy young men, serum PTH concentrations showed peaks at 1 and 6 h, and serum fibroblast growth factor 23 (FGF23) concentrations increased significantly at 8 h after the meal. In contrast, the high-calcium, high-phosphorus meal suppressed the second PTH and FGF23 elevations until 8 h after the meal. This implies that adequate dietary calcium intake is needed to overcome the interfering effects of high phosphorus intake on PTH and FGF23 secretion. FGF23 acts on the parathyroid gland to decrease PTH mRNA and PTH secretion in rats with normal kidney function. However, increased serum FGF23 is an early alteration of mineral metabolism in chronic kidney disease, causing secondary hyperthyroidism, and implying resistance of the parathyroid gland to the action of FGF23 in chronic kidney disease. These findings suggest that long-term high-phosphorus diets may impair bone health mediated by FGF23 resistance both in chronic kidney disease patients and in the healthy population. PMID:24425727

Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms.

PubMed

Dorado, P; López-Torres, E; Peñas-Lledó, E M; Martínez-Antón, J; Llerena, A

2013-08-01

Pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzymes encoded by CYP2C9, CYP2C19 genes and by the transporter ABCB1 gene can influence phenytoin (PTH) plasma levels and toxicity. The patient reported here is a 2-year-old girl with a medical history of cryptogenic (probably symptomatic) epilepsy, who had her first focal seizure with secondary generalization at 13 months of age. She initially received oral valproate treatment and three months later, she was prescribed an oral oxcarbazepine treatment. At 20 months of age, she was admitted to the Emergency Department because of generalized convulsive Status Epilepticus needing to be immediately treated with rectal diazepam (0.5 mg kg(-1)), intravenous diazepam (0.3 mg kg(-1)), and intravenous phenytoin with an initial-loading dose of 15 mg kg(-1). However, two hours after the initial-loading dose of PTH, the patient developed dizziness, nystagmus, ataxia and excessive sedation. Other potential causes of PTH toxicity were excluded such as drug interactions, decreased albumin or lab error. Therefore, to explain the neurological toxicity, PTH plasma levels and CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms were analyzed. Initial plasma PTH levels were higher than expected (69 mg l(-1); normal range: 10-20 mg l(-1)), and the patient was homozygous for the CYP2C9*2 allele, heterozygous for the CYP2C19*4 allele and homozygous for the 3435C and 1236C ABCB1 alleles. Present findings support the previously established relationship between CYP2C9 and CYP2C19 genetic polymorphisms and the increased risk to develop PTH toxicity owing to high plasma concentrations. Nevertheless, although the association of these genes with PTH-induced adverse effects has been well-documented in adult populations, this is the first report examining the influence of these genetic polymorphisms on PTH plasma levels and toxicity in a pediatric patient.

The effect of parathyroid hormone on the uptake and retention of 25-hydroxyvitamin D in skeletal muscle cells.

PubMed

Abboud, M; Rybchyn, M S; Liu, J; Ning, Y; Gordon-Thomson, C; Brennan-Speranza, T C; Cole, L; Greenfield, H; Fraser, D R; Mason, R S

2017-10-01

Data from our studies, and those of others, support the proposal that there is a role for skeletal muscle in the maintenance of vitamin D status. We demonstrated that skeletal muscle is able to internalise extracellular vitamin D binding protein, which then binds to actin in the cytoplasm, to provide high affinity binding sites which accumulate 25-hydroxyvitamin D 3 (25(OH)D 3 ) [1]. This study investigated the concentration- and time-dependent effects of parathyroid hormone (PTH) on the capacity of muscle cells to take up and release 3 H-25(OH)D 3 . Uptake and retention studies for 3 H-25(OH)D 3 were carried out with C2C12 cells differentiated into myotubes and with primary mouse muscle fibers as described [1]. The presence of PTH receptors on mouse muscle fibers was demonstrated by immunohistochemistry and PTH receptors were detected in differentiated myotubes, but not myoblasts, and on muscle fibers by Western blot. Addition of low concentrations of vitamin D binding protein to the incubation media did not alter uptake of 25(OH)D 3 . Pre-incubation of C2 myotubes or primary mouse muscle fibers with PTH (0.1 to 100 pM) for 3h resulted in a concentration-dependent decrease in 25(OH)D 3 uptake after 4 or 16h. These effects were significant at 0.1 or 1pM PTH (p<0.001) and plateaued at 10pM, with 25(OH)D 3 uptake reduced by over 60% (p<0.001) in both cell types. In C2 myotubes, retention of 25(OH)D 3 was decreased after addition of PTH (0.1 to 100pM) in a concentration-dependent manner by up to 80% (p<0.001) compared to non-PTH treated-C2 myotubes. These data show that muscle uptake and retention of 25(OH)D 3 are modulated by PTH, a physiological regulator of mineral homeostasis, but the cell culture model may not be a comprehensive reflection of vitamin D homeostatic mechanisms in whole animals. Copyright © 2017 Elsevier Ltd. All rights reserved.

The parathyroid hormone circadian rhythm is truly endogenous--a general clinical research center study

NASA Technical Reports Server (NTRS)

el-Hajj Fuleihan, G.; Klerman, E. B.; Brown, E. N.; Choe, Y.; Brown, E. M.; Czeisler, C. A.

1997-01-01

While circulating levels of PTH follow a diurnal pattern, it has been unclear whether these changes are truly endogenous or are dictated by external factors that themselves follow a diurnal pattern, such as sleep-wake cycles, light-dark cycles, meals, or posture. We evaluated the diurnal rhythm of PTH in 11 normal healthy male volunteers in our Intensive Physiologic Monitoring Unit. The first 36 h spent under baseline conditions were followed by 28-40 h of constant routine conditions (CR; enforced wakefulness in the strict semirecumbent position, with the consumption of hourly snacks). During baseline conditions, PTH levels followed a bimodal diurnal rhythm with an average amplitude of 4.2 pg/mL. A primary peak (t1max) occurred at 0314 h, and the secondary peak (t2max) occurred at 1726 h, whereas the primary and secondary nadirs (t1min and t2min) took place, on the average, at 1041 and 2103 h, respectively. This rhythm was preserved under CR conditions, albeit with different characteristics, thus confirming its endogenous nature. The serum ionized calcium (Cai) demonstrated a rhythm in 3 of the 5 subjects studied that varied widely between individuals and did not have any apparent relation to PTH. Urinary calcium/creatinine (UCa/Cr), phosphate/Cr (UPO4/Cr), and sodium/Cr (UNa/Cr) ratios all followed a diurnal rhythm during the baseline day. These rhythms persisted during the CR, although with different characteristics for the first two parameters, whereas that of UNa/Cr was unchanged. In general, the temporal pattern for the UCa/Cr curve was a mirror image of the PTH curve, whereas the UPO4/Cr pattern moved in parallel with the PTH curve. In conclusion, PTH levels exhibit a diurnal rhythm that persists during a CR, thereby confirming that a large component of this rhythm is an endogenous circadian rhythm. The clinical relevance of this rhythm is reflected in the associated rhythms of biological markers of PTH effect at the kidney, namely UCa/Cr and UPO4/Cr.

Are PTH levels related to oxidative stress and inflammation in chronic kidney disease patients on hemodialysis?

PubMed

Jaqueto, Marcel; Delfino, Vinicius Daher Alvares; Bortolasci, Chiara Cristina; Barbosa, Decio Sabbatini; Morimoto, Helena Kaminami; Frange, Raquel Ferreira Nassar; Ferreira, Larissa França Fontoura; Guimarães, Fernanda Burle Dos Santos

2016-01-01

Patients at end stage renal disease have higher levels of inflammation and oxidative stress than the general population. Many factors contribute to these issues, and the parathyroid hormone (PTH) is also implicated. The study was conducted in order to assess the relationship between PTH levels and inflammation and oxidative stress in hemodialysis patients. Cross-sectional study with patients of two hemodialysis facilities in Londrina, Brazil. Patients with other conditions known to generate oxidative stress and inflammation were excluded. Blood levels of PTH and biochemical parameters of inflammation (interleukins 1 and 6, tumor necrosis factor-alpha) and oxidative stress (total plasma antioxidant capacity, malonic dialdehyde, lipid hydroperoxidation, advanced oxidation protein products, quantification of nitric oxide metabolites, and 8-isoprostane) were measured before a dialysis session. Then, we made correlation analyses between PTH levels - either as the continuous variable or categorized into tertiles-, and inflammatory and oxidative stress biomarkers. PTH did not show any correlation with the tested inflammation and oxidative stress parameters, nor as continuous variable neither as categorical variable. In this descriptive study, the results suggest that the inflammation and oxidative stress of hemodialysis patients probably arise from mechanisms other than secondary hyperparathyroidism. Pacientes com doença renal em estágio terminal têm níveis de inflamação e estresse oxidativo maiores do que a população geral. Muitos fatores contribuem para isso, e o hormônio paratireoidiano (PTH) é um deles. Estudo foi realizado para avaliar a relação entre os níveis de PTH e níveis de inflamação e estresse oxidativo em pacientes em hemodiálise. estudo transversal com pacientes de duas unidades de hemodiálise de Londrina, Brasil. Pacientes com condições causadoras de inflamação e estresse oxidativo foram exclusos. Níveis plasmáticos de PTH e parâmetros bioquímicos de inflamação (interleucina 1 e 6, fator de necrose tumoral alfa) e estresse oxidativo (capacidade antioxidante plasmática total, dialdeído malônico, hidroperoxidação lipídica, produtos avançados da degradação proteica, quantificação de metabólitos de óxido nítrico e 8-isoprostano) foram dosados antes da sessão de hemodiálise. Realizou-se análise de correlação entre os níveis de PTH - tanto como variável continua como variável categórica em tercis - e os parâmetros de inflamação e estresse oxidativo. Não houve correlação do PTH com nenhum dos parâmetros testados, nem como variável contínua, nem como categórica. Neste estudo descritivo, os resultados sugerem que a inflamação e o estresse oxidativo em pacientes em hemodiálise provavelmente tem origem em mecanismos que não incluem o hiperparatireoidismo secundário.

[Calciotropic actions of parathyroid hormone and vitamin D-endocrine system].

PubMed

Avila, Euclides; Barrera, David; Díaz, Lorenza

2007-01-01

Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)zD] participate in systemic regulation of calcium homeostasis through endocrine effects mediated via the specific receptors PTHR1 and VDR, expressed in bone, kidney, intestine and parathyroid glands. In bone, both hormones PTH and 1,25-(OH)2D promote calcium release into the circulation; however, they also have anabolic effects in this tissue. In kidney, PTH controls 1,25-(OH)2D synthesis, and together both hormones stimulate calcium reabsorption. The most important calciotropic action of 1,25-(OH)2D is stimulation of intestinal calcium absorption. In the parathyroid glands, 1,25-(OH)2D regulates PTH synthesis through a negative feedback mechanism, while modulating the gland growth. Finally, a general overview of the maternal adaptations regarding calcium homeostasis during pregnancy and lactation is presented.

Age-related changes in the response of intestinal cells to parathyroid hormone.

PubMed

Russo de Boland, Ana

2004-12-01

The concept of the role(s) of parathyroid hormone (PTH), has expanded from that on acting on the classical target tissues, bone and kidney, to the intestine where its actions are of regulatory and developmental importance: regulation of intracellular calcium through modulation of second messengers and, activation of mitogenic cascades leading to cell proliferation. Several causes have been postulated to modify the hormone response in intestinal cells with ageing, among them, alterations of PTH receptor (PTHR1) binding sites, reduced expression of G proteins and hormone signal transduction changes. The current review summarizes the actual knowledge regarding the molecular and biochemical basis of age-impaired PTH receptor-mediated signaling in intestinal cells. A fundamental understanding of why PTH functions are impaired with age will enhance our understanding of its importance in intestinal cell physiology.

Pathophysiological links between traumatic brain injury and post-traumatic headaches

PubMed Central

Ruff, Robert L.; Blake, Kayla

2016-01-01

This article reviews possible ways that traumatic brain injury (TBI) can induce migraine-type post-traumatic headaches (PTHs) in children, adults, civilians, and military personnel. Several cerebral alterations resulting from TBI can foster the development of PTH, including neuroinflammation that can activate neural systems associated with migraine. TBI can also compromise the intrinsic pain modulation system and this would increase the level of perceived pain associated with PTH. Depression and anxiety disorders, especially post-traumatic stress disorder (PTSD), are associated with TBI and these psychological conditions can directly intensify PTH. Additionally, depression and PTSD alter sleep and this will increase headache severity and foster the genesis of PTH. This article also reviews the anatomic loci of injury associated with TBI and notes the overlap between areas of injury associated with TBI and PTSD. PMID:27635228

The local administration of parathyroid hormone encourages the healing of bone defects in the rat calvaria: Micro-computed tomography, histological and histomorphometric evaluation.

PubMed

Auersvald, Caroline Moreira; Santos, Felipe Rychuv; Nakano, Mayara Mytie; Leoni, Graziela Bianchi; de Sousa Neto, Manoel Damião; Scariot, Rafaela; Giovanini, Allan Fernando; Deliberador, Tatiana Miranda

2017-07-01

To evaluate the effect of a single-dose local administration of PTH on bone healing in rat calvarial bone defects by means of micro-computed tomography, histological and histomorphometric analysis. Critical-size cranial osteotomy defects were created in 42 male rats. The animals were randomly divided into 3 groups. In the C Group, the bone defect was only filled with a blood clot. In the S Group, it was filled with a collagen sponge and covered with bovine cortical membrane. In the PTH Group, the defect was filled with a collagen sponge soaked with PTH and covered with bovine cortical membrane. The groups were further split in two for euthanasia 15 and 60days post-surgery. Data was statistically analyzed with t-tests for independent samples or the nonparametric Mann-Whitney test when applicable. Intragroup comparisons were analyzed with paired t-tests (p<0.05). Micro-CT analysis results did not demonstrate statistically significant intergroup differences. At 15days post-surgery, the histomorphometric analysis showed that the PTH Group exhibited a significantly higher percentage of bone formation compared with the S Group. At 60days post-surgery, a higher percentage of new bone was observed in the PTH group. The results suggest that the local administration of PTH encouraged the bone healing in critical-size calvarial defects in rats. Copyright © 2017 Elsevier Ltd. All rights reserved.

Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia.

PubMed

Rosol, T J; Nagode, L A; Couto, C G; Hammer, A S; Chew, D J; Peterson, J L; Ayl, R D; Steinmeyer, C L; Capen, C C

1992-09-01

Circulating N-terminal PTH-related protein (PTHrP), N-terminal PTH, and 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations were measured in normal dogs and dogs with cancer-associated hypercalcemia (CAH), parathyroid adenomas, and miscellaneous tumors. PTHrP was undetectable (less than 1.8 pM) in normal dogs and increased in dogs with CAH due to adenocarcinomas derived from apocrine glands of the anal sac (44.9 +/- 27 pM), lymphoma (8.3 +/- 4.4 pM), and miscellaneous carcinomas (13.3 +/- 11.4 pM). The PTHrP concentration decreased in dogs with lymphoma and anal sac adenocarcinomas after successful treatment of CAH. The PTHrP concentration had a significant linear correlation with total serum calcium in dogs with anal sac adenocarcinomas and hypercalcemia, but not in dogs with lymphoma and hypercalcemia. Serum N-terminal PTH concentrations were usually in the normal range (12-34 pg/ml) for all groups of dogs except dogs with parathyroid adenomas (83 +/- 38 pg/ml). The serum PTH concentration increased after successful treatment of CAH. Serum 1,25-(OH)2D concentrations were decreased, normal, or increased in dogs with CAH, and 1,25-(OH)2D levels decreased after treatment of CAH. In summary, circulating concentrations of PTHrP are consistently increased in dogs with CAH, and PTHrP appears to play an important role in the induction of hypercalcemia.

Ratio of cyclase activating and cyclase inactive parathormone (CAP/CIP) in dialysis patients: correlations with other markers of bone disease.

PubMed

Grzegorzewska, A E; Młot, M

2004-01-01

We checked correlation of CAP/CIP with osteoprotegrin (OPG), its soluble ligand (OPGL) and routinely measured parameters of bone turnover in patients treated with peritoneal dialysis (PD) and hemodialysis (HD). In 30 patients (22 HD, 8 PD) we determined serum concentrations of intact parathormone (iPTH), CAP, OPG, OPGL, total Ca, inorganic phosphates (Pi), creatinine, urea, total alkaline phosphatase (AP) and blood pH. CIP was calculated by subtraction of CAP from iPTH. Controls (Cs) included 9 healthy persons in whom iPTH, CAP, OPG and OPGL were measured as well as CIP, CAP/CIP and OPGL/OPG were calculated. Differences between HD and PD patients included dialysis duration, OPGL, OPGL/OPG, AP, Pi, Ca and pH. After adjustment to dialysis duration differences in OPGL/OPG, Pi, Ca and pH remained significant. HD patients differed from Cs in terms of iPTH, CAP, CIP, OPGL, OPG and OPGL/OPG. In whole group of patients iPTH, CAP, CIP but not CAP/CIP correlated negatively with OPGL and OPGL/OPG as well as positively with dialysis duration, OPG and AP. Despite more advanced uremic bone disease in longer dialyzed HD patients than in shorter dialyzed PD ones, CAP/CIP is not different neither between these groups nor Cs persons. CAP/CIP does not seem to be more powerful tool in noninvasive diagnosis of bone disease than iPTH or CAP and CIP alone.

Parathyroid hormone plus alendronate in osteoporosis: a meta-analysis of randomized controlled trials.

PubMed

Zhang, Qinggang; Qian, Jing; Zhu, Yuchang

2015-01-01

Parathyroid hormone (PTH) increases both bone formation (BMD) and bone resorption, whereas alendronate reduces bone resorption. It is possible that the combination therapy of PTH with alendronate will enhance their effects on BMD. Therefore, we conducted this meta-analysis to evaluate the efficacy of the combination therapy of PTH with alendronate in the treatment of patients with osteoporosis. A comprehensive literature search of PubMed, Embase, and Web of Science was conducted to identify relative studies. Eligible studies were randomized controlled trials (RCT), which assessed the efficacy of combination therapy in patients with osteoporosis. The outcomes included the mean percent increases in BMD of lumbar spine, femoral neck, total hip, and distal radius. Weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using of random-effects or fixed-effects model, depending on the heterogeneity between the included studies. Six RCTs with a total number of 833 patients were included in this meta-analysis. The pooled estimates showed that, the combination therapy of PTH with alendronate resulted in a higher mean percent change of increased BMD in distal radius (WMD = 2.45, 95% CI: 1.58, 3.31; P = 0.000), but not in lumbar spine (WMD = -0.83, 95% CI: -3.48, 1.81; P = 0.538), femoral neck (WMD = -0.99, 95% CI: -2.04, 0.07; P = 0.068), and total hip (WMD = -0.06, 95% CI: -0.93, 0.81; P = 0.892). The subgroup analysis based on the dosage and schedule of PTH, study duration, gender of patients, and anabolic agents, were conducted. And results revealed that among the patients in the combination therapy group, greater increases in the spine BMD were observed when the PTH was administered with a dosage of 20 μg (WMD = 2.33, 95% CI: 1.24, 3.43; P = 0.000), or the treatment duration lasted more than 12 months (WMD = 2.23, 95% CI: 1.00, 3.47; P = 0.000), or the combination therapy was used in osteoporosis women (WMD = 1.58, 95% CI: 0.63, 2.53; P = 0.001). However, the combination of PTH of 40 μg with alendronate produced a decrease in the BMD at spine (WMD = -4.56, 95% CI: -7.56, -1.56; P = 0.003) and femoral neck (WMD = -5.82, 95% CI: -9.91, -1.72; P = 0.005). Our findings indicated that the addition of alendronate to PTH in the treatment of osteoporosis, reduced the ability of PTH therapy to increase the BMD at the lumbar spine, femoral neck, and total hip.

Calcium Metabolism in Newborn Infants THE INTERRELATIONSHIP OF PARATHYROID FUNCTION AND CALCIUM, MAGNESIUM, AND PHOSPHORUS METABOLISM IN NORMAL, “SICK,” AND HYPOCALCEMIC NEWBORNS

PubMed Central

David, Louis; Anast, Constantine S.

1974-01-01

Serum immunoreactive parathyroid hormone (iPTH) and plasma total calcium, ionized calcium, magnesium, and phosphorus levels were determined during the first 9 days of life in 137 normal term infants, 55 “sick” infants, and 43 hypocalcemic (Ca <7.5 mg/100 ml; Ca++<4.0 mg/100 ml) infants. In the cord blood, elevated levels of plasma Ca++ and Ca were observed, while levels of serum iPTH were either undetectable or low. In normal newborns during the first 48 h of life there was a decrease in plasma Ca and Ca++, while the serum iPTH level in most samples remained undetectable or low; after 48 h there were parallel increases in plasma Ca and Ca++ and serum iPTH levels. Plasma Mg and P levels increased progressively after birth in normal infants. In the sick infants, plasma Ca, Ca++ and P levels were significantly lower than in the normal newborns, while no significant differences were found in the plasma Mg levels. The general pattern of serum iPTH levels in the sick infants was similar to that observed in the normal group, though there was a tendency for the increase in serum iPTH to occur earlier and for the iPTH levels to be higher in the sick infants. In the hypocalcemic infants, plasma Mg levels were consistently lower than in the normal infants after 24 h of age, while no significant differences were found in the plasma P levels. Hyperphosphatemia was uncommon and did not appear to be a contributing factor in the pathogenesis of hypocalcemia in most infants. Most of the hypocalcemic infants, including those older than 48 h, had inappropriately low serum iPTH levels. Evidence obtained from these studies indicates that parathyroid secretion is normally low in the early new born period and impaired parathyroid function, characterized by undetectable or low serum iPTH, is present in most infants with neonatal hypocalcemia. Additional unknown factors appear to contribute to the lowering of plasma Ca in the neonatal period. The net effect of unknown plasma hypocalcemic factor(s) on the one hand and parathyroid activity on the other may account for differences in plasma Ca levels observed between normal, sick, and hypocalcemic infants. Depressed plasma Mg is frequently present in hypocalcemic infants. To what degree the hypomagnesemia reflects parathyroid insufficiency or the converse, to what degree parathyroid insufficiency and hypocalcemia are secondary to hypomagnesemia, is uncertain. PMID:4858778

Informatic deconvolution of biased GPCR signaling mechanisms from in vivo pharmacological experimentation.

PubMed

Maudsley, Stuart; Martin, Bronwen; Janssens, Jonathan; Etienne, Harmonie; Jushaj, Areta; van Gastel, Jaana; Willemsen, Ann; Chen, Hongyu; Gesty-Palmer, Diane; Luttrell, Louis M

2016-01-01

Ligands possessing different physico-chemical structures productively interact with G protein-coupled receptors generating distinct downstream signaling events due to their abilities to activate/select idiosyncratic receptor entities ('receptorsomes') from the full spectrum of potential receptor partners. We have employed multiple novel informatic approaches to identify and characterize the in vivo transcriptomic signature of an arrestin-signaling biased ligand, [D-Trp(12),Tyr(34)]-bPTH(7-34), acting at the parathyroid hormone type 1 receptor (PTH1R), across six different murine tissues after chronic drug exposure. We are able to demonstrate that [D-Trp(12),Tyr(34)]-bPTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated, in an arrestin signaling-dependent manner, across more tissues than that of the pluripotent endogenous PTH1R ligand, hPTH(1-34). This arrestin-focused response signature is strongly linked with the transcriptional regulation of cell growth and development. Our informatic deconvolution of a conserved arrestin-dependent transcriptomic signature from wild type mice demonstrates a conceptual framework within which the in vivo outcomes of biased receptor signaling may be further investigated or predicted. Published by Elsevier Inc.

A Novel Technology for Localization of Parathyroid Adenoma: Ultrasound-Guided Fine Needle Aspiration Combined With Rapid Parathyroid Hormone Detection and Nano-Carbon Technology.

PubMed

Yan, Shouyi; Zhao, Wenxin; Wang, Bo; Zhang, Liyong

2018-06-01

The study aims to evaluate the clinic feasibility of rapid parathyroid hormone (PTH) detection and nano-carbon technology in preoperative diagnosis and localization of parathyroid adenoma. With the guidance of ultrasound, the operator performed the parathyroid puncture and tested the PTH value by using a PTH test kit, and then injected nano-carbon into parathyroid adenoma as a marker to observe whether the parathyroid adenoma was stained black during the final operation. Meanwhile, a part of excised specimen was made into homogenate and detected rapidly again by using the PTH test kit. The remaining was confirmed by intraoperative frozen pathological examination. The sensitivity (12/12) of preoperative diagnosis was significantly higher than that of ultrasound (6/12), magnetic resonance imaging (7/12), and MIBI (9/12). During the operation, we found that the inner part of the parathyroid adenoma was stained black, and the PTH value of the specimen homogenate confirmed as parathyroid adenoma was more than 3000 pg/mL. This novel technology, as a very positive method for localization of parathyroid adenoma, plays an important role in guaranteeing the surgical reliability of parathyroid adenoma with help of nano-carbon technology.

Parathyroid diseases and animal models.

PubMed

Imanishi, Yasuo; Nagata, Yuki; Inaba, Masaaki

2012-01-01

CIRCULATING CALCIUM AND PHOSPHATE ARE TIGHTLY REGULATED BY THREE HORMONES: the active form of vitamin D (1,25-dihydroxyvitamin D), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). PTH acts to stimulate a rapid increment in serum calcium and has a crucial role in calcium homeostasis. Major target organs of PTH are kidney and bone. The oversecretion of the hormone results in hypercalcemia, caused by increased intestinal calcium absorption, reduced renal calcium clearance, and mobilization of calcium from bone in primary hyperparathyroidism. In chronic kidney disease, secondary hyperparathyroidism of uremia is observed in its early stages, and this finally develops into the autonomous secretion of PTH during maintenance hemodialysis. Receptors in parathyroid cells, such as the calcium-sensing receptor, vitamin D receptor, and FGF receptor (FGFR)-Klotho complex have crucial roles in the regulation of PTH secretion. Genes such as Cyclin D1, RET, MEN1, HRPT2, and CDKN1B have been identified in parathyroid diseases. Genetically engineered animals with these receptors and the associated genes have provided us with valuable information on the patho-physiology of parathyroid diseases. The application of these animal models is significant for the development of new therapies.

Hypoparathyroidism: clinical features, skeletal microstructure and parathyroid hormone replacement

PubMed Central

Rubin, Mishaela R.; Bilezikian, John P.

2013-01-01

Objective Hypoparathyroidism is a disorder in which parathyroid hormone is deficient in the circulation due most often to immunological destruction of the parathyroids or to their surgical removal. The objective of this work was to define the abnormalities in skeletal microstructure as well as to establish the potential efficacy of PTH(1-84) replacement in this disorder. Subjects and methods Standard histomorphometric and μCT analyses were performed on iliac crest bone biopsies obtained from patients with hypoparathyroidism. Participants were treated with PTH(1-84) for two years. Results Bone density was increased and skeletal features reflected the low turnover state with greater BV/TV, Tb. Wi and Ct. Wi as well as suppressed MS and BFR/BS as compared to controls. With PTH(1-84), bone turnover and bone mineral density increased in the lumbar spine. Requirements for calcium and vitamin D fell while serum and urinary calcium concentrations did not change. Conclusion Abnormal microstructure of the skeleton in hypoparathyroidism reflects the absence of PTH. Replacement therapy with PTH has the potential to correct these abnormalities as well as to reduce the requirements for calcium and vitamin D. PMID:20485912

Effects of anodizing parameters and heat treatment on nanotopographical features, bioactivity, and cell culture response of additively manufactured porous titanium.

PubMed

Amin Yavari, S; Chai, Y C; Böttger, A J; Wauthle, R; Schrooten, J; Weinans, H; Zadpoor, A A

2015-06-01

Anodizing could be used for bio-functionalization of the surfaces of titanium alloys. In this study, we use anodizing for creating nanotubes on the surface of porous titanium alloy bone substitutes manufactured using selective laser melting. Different sets of anodizing parameters (voltage: 10 or 20V anodizing time: 30min to 3h) are used for anodizing porous titanium structures that were later heat treated at 500°C. The nanotopographical features are examined using electron microscopy while the bioactivity of anodized surfaces is measured using immersion tests in the simulated body fluid (SBF). Moreover, the effects of anodizing and heat treatment on the performance of one representative anodized porous titanium structures are evaluated using in vitro cell culture assays using human periosteum-derived cells (hPDCs). It has been shown that while anodizing with different anodizing parameters results in very different nanotopographical features, i.e. nanotubes in the range of 20 to 55nm, anodized surfaces have limited apatite-forming ability regardless of the applied anodizing parameters. The results of in vitro cell culture show that both anodizing, and thus generation of regular nanotopographical feature, and heat treatment improve the cell culture response of porous titanium. In particular, cell proliferation measured using metabolic activity and DNA content was improved for anodized and heat treated as well as for anodized but not heat-treated specimens. Heat treatment additionally improved the cell attachment of porous titanium surfaces and upregulated expression of osteogenic markers. Anodized but not heat-treated specimens showed some limited signs of upregulated expression of osteogenic markers. In conclusion, while varying the anodizing parameters creates different nanotube structure, it does not improve apatite-forming ability of porous titanium. However, both anodizing and heat treatment at 500°C improve the cell culture response of porous titanium. Copyright © 2015 Elsevier B.V. All rights reserved.

A Home-Based Walking Program Improves Respiratory Endurance in Patients With Acute Myocardial Infarction: A Randomized Controlled Trial.

PubMed

Matos-Garcia, Bruna C; Rocco, Isadora S; Maiorano, Lara D; Peixoto, Thatiana C A; Moreira, Rita Simone L; Carvalho, Antonio C C; Catai, Aparecida Maria; Arena, Ross; Gomes, Walter J; Guizilini, Solange

2017-06-01

The purpose of this study was to evaluate respiratory muscle strength and endurance in the inpatient period in patients who recently experienced myocardial infarction (MI) and investigate the effects of a home-based walking program on respiratory strength and endurance in low-risk patients after MI. Patients were randomized into a usual-care group (UCG) entailing regular care (n = 23) and an intervention group (IG) entailing an outpatient home-based walking program (n = 31). Healthy sex- and age-matched participants served as a control group for respiratory endurance variables. Respiratory muscle strength was evaluated through maximal inspiratory pressure (MIP) and endurance during the inpatient period, at 15 days, and at 60 days after MI. Submaximal functional capacity was determined by a 6-minute walk test (6MWT) at hospital discharge and 60 days after MI. Both groups showed impaired inspiratory muscle strength at hospital discharge. When compared with healthy individuals, after MI, patients had worse respiratory muscle endurance pressure (PTH max  = 73.02 ± 8.40 vs 44.47 ± 16.32; P < 0.05) and time (Tlim = 324.1 ± 12.2 vs 58.7 ± 93.3; P < 0.05). Only the IG showed a significant improvement in MIP and PTH max at 15 days and 60 days after MI (P < 0.05). When comparing groups, the IG achieved higher values for MIP, PTH max , and Tlim 15 and 60 days after MI (P < 0.01). The 60-day assessment revealed that the 6MWT distance and level of physical activity was significantly higher in the IG compared with the UCG. Low-risk patients recently experiencing MI demonstrate impaired MIP and respiratory endurance compared with healthy participants. A home-based walking program improved respiratory endurance and functional capacity. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Calcium Regulates FGF-23 Expression in Bone

PubMed Central

David, Valentin; Dai, Bing; Martin, Aline; Huang, Jinsong; Han, Xiaobin

2013-01-01

Calcium has recently been shown to regulate fibroblast growth factor 23 (FGF-23), a bone-derived phosphate and vitamin D-regulating hormone. To better understand the regulation of FGF-23 by calcium, phosphorus, 1,25 dihydroxyvitamin D3 [1,25(OH)2D], and PTH, we examined FGF-23 expression under basal conditions and in response to PTH, doxercalciferol, or high-calcium diet treatment in Gcm2−/− and Cyp27b1−/− mutant mice. Gcm2−/− mice exhibited low serum PTH and 1,25(OH)2D concentrations, hypocalcemia, and hyperphosphatemia, whereas Cyp27b1−/− mice had high PTH, undetectable 1,25(OH)2D, hypocalcemia, and hypophosphatemia. Serum FGF-23 levels were decreased in both mutant models. Doxercalciferol administration increased serum FGF-23 levels in both mutant models. PTH administration to Gcm2−/− mice also increased serum FGF-23 levels, in association with an increase in both 1,25(OH)2D and calcium concentrations. Multiple regression analysis of pooled data indicated that changes in FGF-23 were positively correlated with serum calcium and 1,25(OH)2D but not related to changes in serum phosphate concentrations. A high-calcium diet also increased serum FGF-23 concentrations in Cyp27b1−/− mice in the absence of 1,25(OH)2D and in Gcm2−/− mice with low PTH. The addition of calcium to the culture media also stimulated FGF-23 message expression in MC3T3-E1 osteoblasts. In addition, FGF-23 promoter activity in cultured osteoblasts was inhibited by the L-calcium-channel inhibitor nifedipine and stimulated by calcium ionophores. The effects of chronic low calcium to prevent 1,25(OH)2D and PTH stimulation of FGF-23 in these mutant mouse models suggest that suppression of FGF-23 plays an important physiological adaptive response to hypocalcemia. PMID:24140714

Effects of FGF-23-mediated ERK/MAPK signaling pathway on parathyroid hormone secretion of parathyroid cells in rats with secondary hyperparathyroidism.

PubMed

Chen, Xiao-Jun; Chen, Xiong; Wu, Wen-Jun; Zhou, Qi; Gong, Xiao-Hua; Shi, Bi-Min

2018-04-10

This study is supposed to investigate the effect of FGF-23 on parathyroid hormone (PTH) secretion through ERK/MAPK signaling pathway in secondary hyperparathyroidism (SHPT) rat model. Thirty rats were equally served as the normal and SHPT groups. After transfection, parathyroid cells was assigned into blank, NC, pcDNA3.1-FGF-23, siRNA-FGF-23, U0126, and siRNA-FGF-23 + U0126 groups. The serum levels of Calcium (Ca), Phosphorus (P), alkaline phosphatase (ALP), and PTH were detected. HE and immunohistochemical (IHC) staining were used for the histopathological changes and the FGF-23, EKR1/2, and pEKR1/2 expressions. qRT-PCR and Western blotting were performed to determine the mRNA and protein expression of FGF-23, PTH, MAPK, EKR1/2, and Klotho. The proliferation, apoptosis, and cell cycle were all measured for parathyroid cells by CCK-8 assay, TUNEL staining and Flow cytometry. Compared with the normal group, the SHPT group showed increased serum levels PTH, P, ALP, and FGF-23 and mRNA and protein expressions of FGF-23 and PTH, whereas declined Ca and p-ERK1/2 expression, mRNA and protein expression of Klotho, cell apoptosis rate was reduced. Furthermore, compared to the blank and NC groups, the pcDNA3.1-FGF-23 and U0126 groups had a decreased mRNA expression of Klotho, protein expression of EKR1/2 and Klotho, and cell apoptosis rate was down-regulated, whereas the RNA and protein expressions of FGF-23 and PTH were up-regulated, and cell proliferation was elevated. The opposite results were observed in the siRNA-FGF-23 group. Our study demonstrated that FGF-23 could inhibit signaling transduction of ERK/MAPK pathway and accelerate the secretion of PTH in rats with SHPT. © 2018 Wiley Periodicals, Inc.

Elevated fibroblast growth factor 23 levels as a cause of early post-renal transplantation hypophosphatemia.

PubMed

Han, S Y; Hwang, E A; Park, S B; Kim, H C; Kim, H T

2012-04-01

Hypophosphatemia is a common complication after renal transplantation. Hyperparathyroidism has long been thought to be the cause, but hypophosphatemia can persist after high parathyroid hormone (PTH) levels normalize. Furthermore, calcitriol levels remain inappropriately low after transplantation, suggesting that mechanisms other than PTH contribute. Fibroblast growth factor 23 (FGF-23) induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. We performed prospective study to investigate if FGF-23 early after renal transplantation contributes to hypophosphatemia. We measured FGF-23 levels before and at 1, 2, 4, and 12 weeks after transplantation in 20 renal transplant recipients. Serum creatinine, calcium (Ca), phosphate (Pi), intact PTH (PTH), and 1,25-dihydroxy vitamin D (1,25(OH)(2)VitD) were measured at the same time. FGF-23 levels decreased by 97% at 4 weeks after renal transplantation (PRT) (7,471 ± 11,746 vs 225 ± 295 pg/mL; P < .05) but were still above normal. PTH and Pi levels also decreased significantly after renal transplantation, and Ca and 1,25(OH)(2)VitD slightly increased. PRT hypophosphatemia of <2.5 mg/dL developed in 15 (75%) and 12 (60%) patients at 4 weeks and 12 weeks respectively. Compared with nonhypophosphatemic patients, the levels of FGF-23 of hypophosphatemic patients were higher (303 ± 311 vs 10 ± 6.9 pg/mL; P = .02) at 4 weeks PRT. FGF-23 levels were inversely correlated with Pi (r(2) = 0.406; P = .011); PTH was not independently associated with Pi (r(2) = 0.132; P = .151). FGF-23 levels decrease dramatically after renal transplantation. During the early PRT period, Pi rapidly decreased, suggesting that FGF-23 is cleared by the kidney, but residual FGF-23 may contribute to the PRT hypophosphatemia. FGF-23, but not PTH levels, was independently associated with PRT hypophosphatemia. Copyright © 2012 Elsevier Inc. All rights reserved.

Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism.

PubMed

Campion, Katherine L; McCormick, Wanda D; Warwicker, Jim; Khayat, Mohd Ezuan Bin; Atkinson-Dell, Rebecca; Steward, Martin C; Delbridge, Leigh W; Mun, Hee-Chang; Conigrave, Arthur D; Ward, Donald T

2015-09-01

The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca(2+)i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca(2+)o). Similar pHo effects were observed for Ca(2+)o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca(2+)i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo. Copyright © 2015 by the American Society of Nephrology.

Bone Status Among Patients With Nonsurgical Hypoparathyroidism, Autosomal Dominant Hypocalcaemia, and Pseudohypoparathyroidism: A Cohort Study.

PubMed

Underbjerg, Line; Malmstroem, Sofie; Sikjaer, Tanja; Rejnmark, Lars

2018-03-01

Nonsurgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP) are both rare diseases, characterized by hypocalcemia. In Ns-HypoPT, PTH levels are low, whereas patients with PHP often have very high levels due to receptor-insensitivity to PTH (PTH-resistance). Accordingly, we hypothesized that indices of bone turnover and bone mineralization/architecture are similar in Ns-HypoPT and PHP despite marked differences in PTH levels. We studied 62 patients with Ns-HypoPT and 31 with PHP as well as a group of age- and sex-matched healthy controls. We found a significantly higher areal BMD (aBMD) by DXA among patients with Ns-HypoPT, both compared with PHP and the background population. Compared with Ns-HypoPT, PHP patients had significantly lower total and trabecular volumetric BMD (vBMD) assessed by quantitative computed tomography (QCT) scans at the spine and hip. High-resolution peripheral quantitative computed tomography (HRpQCT) scans showed a lower trabecular area and vBMD as well as a lower trabecular number at the tibia in PHP compared to Ns-HypoPT and matched controls. In PHP, PTH levels correlated with levels of markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, P1NP), and bone resorption (CTx). In adult males, levels of bone markers were significantly higher in PHP compared with Ns-HypoPT. Levels of procalcitonin and calcitonin were significantly higher in PHP compared with Ns-HypoPT. In conclusion, indices of bone turnover, density, and microarchitecture differ between patients with Ns-HypoPT and PHP. Our data suggest that patients with PHP do not have a complete skeletal resistance to PTH and that the effects of chronically high PTH levels in PHP are mostly confined to the trabecular tissue. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Anabolic action of parathyroid hormone (PTH) does not compromise bone matrix mineral composition or maturation.

PubMed

Vrahnas, Christina; Pearson, Thomas A; Brunt, Athena R; Forwood, Mark R; Bambery, Keith R; Tobin, Mark J; Martin, T John; Sims, Natalie A

2016-12-01

Intermittent administration of parathyroid hormone (PTH) is used to stimulate bone formation in patients with osteoporosis. A reduction in the degree of matrix mineralisation has been reported during treatment, which may reflect either production of undermineralised matrix or a greater proportion of new matrix within the bone samples assessed. To explore these alternatives, high resolution synchrotron-based Fourier Transform Infrared Microspectroscopy (sFTIRM) coupled with calcein labelling was used in a region of non-remodelling cortical bone to determine bone composition during anabolic PTH treatment compared with region-matched samples from controls. 8week old male C57BL/6 mice were treated with vehicle or 50μg/kg PTH, 5 times/week for 4weeks (n=7-9/group). Histomorphometry confirmed greater trabecular and periosteal bone formation and 3-point bending tests confirmed greater femoral strength in PTH-treated mice. Dual calcein labels were used to match bone regions by time-since-mineralisation (bone age) and composition was measured by sFTIRM in six 15μm 2 regions at increasing depth perpendicular to the most immature bone on the medial periosteal edge; this allowed in situ measurement of progressive changes in bone matrix during its maturation. The sFTIRM method was validated in vehicle-treated bones where the expected progressive increases in mineral:matrix ratio and collagen crosslink type ratio were detected with increasing bone maturity. We also observed a gradual increase in carbonate content that strongly correlated with an increase in longitudinal stretch of the collagen triple helix (amide I:amide II ratio). PTH treatment did not alter the progressive changes in any of these parameters from the periosteal edge through to the more mature bone. These data provide new information about how the bone matrix matures in situ and confirm that bone deposited during PTH treatment undergoes normal collagen maturation and normal mineral accrual. Copyright © 2016 Elsevier Inc. All rights reserved.

Longitudinal effects of Parathyroid Hormone treatment on morphological, densitometric and mechanical properties of mouse tibia.

PubMed

Lu, Yongtao; Boudiffa, Maya; Dall'Ara, Enrico; Liu, Yue; Bellantuono, Ilaria; Viceconti, Marco

2017-11-01

The use of Parathyroid Hormone (PTH) as bone anabolic is limited due to cost-benefit assessments. Preclinical studies evaluating the effects of PTH on bone have reported variable and often contradictory results. Here, we have applied a new approach using a combination of in-vivo longitudinal µCT, image processing techniques and finite element models to monitor early local changes in the whole tibia (divided in 40 compartments) and mechanical properties of female C57BL/6J mice treated with PTH 1-34, compared to controls. Compared with standard 3D bone morphometric analysis, our new approach allowed detection of much smaller and localised changes in bone mineral content (BMC) at very early time points (1 week vs 3 weeks with standard methods) and showed that changes do not occur uniformly over time and across the anatomical space. Indeed, in the PTH treated mice, significant changes in BMC were observed in the medial and posterior sectors of the proximal tibia, a week after treatment, and in the medial sector of the tibia midshaft region a week later (p < 0.05). By the third week, two thirds of the regions showed significantly higher values of BMC (p < 0.05). The effect of PTH on bone regional volume is similar to that on BMC, but there is almost no effect of PTH on bone tissue mineral density. The differences in estimated mechanical properties became significant after three weeks of treatment (p < 0.05). These results provide the first evidence of an early and localised PTH effect on murine bone, and show that our novel partitioning approach, compared to the standard evaluation protocol, allows a more precise quantification of bone changes following treatment, which would facilitate preclinical testing of novel mono- and/or combination therapies throughout the bone. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Vitamin D and parathyroid hormone are associated with gait instability and poor balance performance in mid-age to older aged women.

PubMed

Bird, Marie-Louise; El Haber, Natalie; Batchelor, Frances; Hill, Keith; Wark, John D

2018-01-01

Vitamin D status and parathyroid hormone (PTH) levels influence the risk of accidental falls in older people, but the mechanisms underlying this effect remain unclear. Investigate the relationship between circulating PTH and 25 hydroxyvitamin D (25-OHD) levels and clinical tests of gait stability and balance as physical fall risk factors. We hypothesized that high levels of PTH and low 25-OHD levels would be significantly associated with gait stability and decreased balance performance. Observational cohort study. Australian community. 119 healthy, ambulatory female twin adults aged 47-80 years residing in Victoria, Australia. Serum PTH and 25-OHD levels with clinical tests of gait stability [double support duration (DSD)] and dynamic balance (Step Test). Associations were investigated by regression analysis and by comparing groups divided by tertiles of PTH (<3.5, 3.5-4.9, >4.9pmol/L) and 25-OHD (<53, 53-75, >75 nmol/L) using analysis of variance. Serum PTH was associated positively with DSD, with an increase of 10.6-15.7% when the mid and highest PTH tertiles were compared to the lowest tertile (p <0.025) when 25-OHD was included in the regression analysis. 25-OHD was significantly associated with DSD (greater by 10.6-11.1% when lowest and mid-tertiles compared with the highest 25-OHD tertile) (p <0.025) and dynamic balance (better performance by 12.6% in the highest compared with the lowest 25OHD tertile) (p <0.025). These findings reveal an important new relationship between parathyroid hormone and gait stability parameters and add to understanding of the role of 25-OHD in motor control of gait and dynamic balance in community-dwelling women across a wide age span. Copyright © 2017 Elsevier B.V. All rights reserved.

Calcium regulates FGF-23 expression in bone.

PubMed

David, Valentin; Dai, Bing; Martin, Aline; Huang, Jinsong; Han, Xiaobin; Quarles, L Darryl

2013-12-01

Calcium has recently been shown to regulate fibroblast growth factor 23 (FGF-23), a bone-derived phosphate and vitamin D-regulating hormone. To better understand the regulation of FGF-23 by calcium, phosphorus, 1,25 dihydroxyvitamin D3 [1,25(OH)2D], and PTH, we examined FGF-23 expression under basal conditions and in response to PTH, doxercalciferol, or high-calcium diet treatment in Gcm2(-/-) and Cyp27b1(-/-) mutant mice. Gcm2(-/-) mice exhibited low serum PTH and 1,25(OH)2D concentrations, hypocalcemia, and hyperphosphatemia, whereas Cyp27b1(-/-) mice had high PTH, undetectable 1,25(OH)2D, hypocalcemia, and hypophosphatemia. Serum FGF-23 levels were decreased in both mutant models. Doxercalciferol administration increased serum FGF-23 levels in both mutant models. PTH administration to Gcm2(-/-) mice also increased serum FGF-23 levels, in association with an increase in both 1,25(OH)2D and calcium concentrations. Multiple regression analysis of pooled data indicated that changes in FGF-23 were positively correlated with serum calcium and 1,25(OH)2D but not related to changes in serum phosphate concentrations. A high-calcium diet also increased serum FGF-23 concentrations in Cyp27b1(-/-) mice in the absence of 1,25(OH)2D and in Gcm2(-/-) mice with low PTH. The addition of calcium to the culture media also stimulated FGF-23 message expression in MC3T3-E1 osteoblasts. In addition, FGF-23 promoter activity in cultured osteoblasts was inhibited by the L-calcium-channel inhibitor nifedipine and stimulated by calcium ionophores. The effects of chronic low calcium to prevent 1,25(OH)2D and PTH stimulation of FGF-23 in these mutant mouse models suggest that suppression of FGF-23 plays an important physiological adaptive response to hypocalcemia.

Treatment of Patellar Lower Pole Fracture with Modified Titanium Cable Tension Band Plus Patellar Tibial Tunnel Steel "8" Reduction Band.

PubMed

Li, Jiaming; Wang, Decheng; He, Zhiliang; Shi, Hao

2018-01-08

To determine the efficacy of modified titanium tension band plus patellar tendon tunnel steel 8 "reduction band" versus titanium cable tension band fixation for the treatment of patellar lower pole fracture. 58 patients with lower patella fracture were enrolled in this study, including 30 patients treated with modified titanium cable tension band plus patellar tibial tunnel wire "8" tension band internal fixation (modified group), and 28 patients with titanium cable tension band fixation. All patients were followed up for 9∼15 months with an average of 11.6 months. Knee flexion was significantly improved in the modified group than in the titanium cable tension band group (111.33 ± 13 degrees versus 98.21 ± 21.70 degrees, P = 0.004). The fracture healing time showed no significant difference. At the end of the follow-up, the improvement excellent rate was 93.33% in the modified group, and 82.14% in the titanium cable tension band group. Titanium cable tension band internal fixation loosening was found in 2 cases, including 1 case of treatment by two surgeries without loose internal fixation. The modified titanium cable tension band with "8" tension band fixation showed better efficacy for lower patella fractures than titanium cable tension band fixation.

Targeted Alteration of Dietary Omega-3 and Omega-6 Fatty Acids for the Treatment of Post-Traumatic Headaches

DTIC Science & Technology

2016-10-01

reduced psychological distress and improved quality-of- life in a chronic headache population. We propose to carry out a 2-arm, parallel group...emphasize the role of inflammation, cytokine modulation, microglial activation, and abnormalities in neurotransmitter activity in mediating PTH. These...anti- and pro-nociceptive lipid mediators and their precursor fatty acids, reduced psychological distress and improved quality-of-life in a chronic

Mechanisms of Bone Mineralization and Effects of Mechanical Loading

NASA Technical Reports Server (NTRS)

Babich, Michael

1996-01-01

The data suggest that PTH and PKC inhibit nodule formation, and that alternative energy sources are utilized by osteoblasts in the process of mineralization. The conditions and techniques to grow, fix, photograph, and measure bone mineralization in vitro were defined. The results are presently in preliminary form and require further assessment as follows; quantitate the surface area of nodules + treatments via computer-aided image analysis; use PTH + inhibitors of signaling pathways to determine the mechanism of nodule formation; determine how protein kinase C is involved as a promotor of nodule formation; cell proliferation vs. cell death affected by modulation of signal transduction (i.e., PTH, enzyme inhibitors and activators); identify mRNA induced or decreased in response to PTH and signaling modulators that encode proteins that regulate cell morphology, proliferation, and nodule formation. Therefore, several follow-up studies between the laboratories at NASA-Ames Research Center and my laboratory at the University of Illinois have been initiated.

Cadmium Telluride-Titanium Dioxide Nanocomposite for Photodegradation of Organic Substance.

PubMed

Ontam, Areeporn; Khaorapapong, Nithima; Ogawa, Makoto

2015-12-01

Cadmium telluride-titanium dioxide nanocomposite was prepared by hydrothermal reaction of sol-gel derived titanium dioxide and organically modified cadmium telluride. The crystallinity of titanium dioxide in the nanocomposite was higher than that of pure titanium dioxide obtained by the reaction under the same temperature and pressure conditions, showing that cadmium telluride induced the crystallization of titanium dioxide. Diffuse reflectance spectrum of the nanocomposite showed the higher absorption efficiency in the UV-visible region due to band-gap excitation of titanium dioxide. The nanocomposite significantly showed the improvement of photocatalytic activity for 4-chlorophenol with UV light.

Surface modification of titanium and titanium alloys by ion implantation.

PubMed

Rautray, Tapash R; Narayanan, R; Kwon, Tae-Yub; Kim, Kyo-Han

2010-05-01

Titanium and titanium alloys are widely used in biomedical devices and components, especially as hard tissue replacements as well as in cardiac and cardiovascular applications, because of their desirable properties, such as relatively low modulus, good fatigue strength, formability, machinability, corrosion resistance, and biocompatibility. However, titanium and its alloys cannot meet all of the clinical requirements. Therefore, to improve the biological, chemical, and mechanical properties, surface modification is often performed. In view of this, the current review casts new light on surface modification of titanium and titanium alloys by ion beam implantation. (c) 2010 Wiley Periodicals, Inc.

Improving Osteoblast Response In Vitro by a Nanostructured Thin Film with Titanium Carbide and Titanium Oxides Clustered around Graphitic Carbon.

PubMed

Longo, Giovanni; Ioannidu, Caterina Alexandra; Scotto d'Abusco, Anna; Superti, Fabiana; Misiano, Carlo; Zanoni, Robertino; Politi, Laura; Mazzola, Luca; Iosi, Francesca; Mura, Francesco; Scandurra, Roberto

2016-01-01

Recently, we introduced a new deposition method, based on Ion Plating Plasma Assisted technology, to coat titanium implants with a thin but hard nanostructured layer composed of titanium carbide and titanium oxides, clustered around graphitic carbon. The nanostructured layer has a double effect: protects the bulk titanium against the harsh conditions of biological tissues and in the same time has a stimulating action on osteoblasts. The aim of this work is to describe the biological effects of this layer on osteoblasts cultured in vitro. We demonstrate that the nanostructured layer causes an overexpression of many early genes correlated to proteins involved in bone turnover and an increase in the number of surface receptors for α3β1 integrin, talin, paxillin. Analyses at single-cell level, by scanning electron microscopy, atomic force microscopy, and single cell force spectroscopy, show how the proliferation, adhesion and spreading of cells cultured on coated titanium samples are higher than on uncoated titanium ones. Finally, the chemistry of the layer induces a better formation of blood clots and a higher number of adhered platelets, compared to the uncoated cases, and these are useful features to improve the speed of implant osseointegration. In summary, the nanostructured TiC film, due to its physical and chemical properties, can be used to protect the implants and to improve their acceptance by the bone.

Tribological Properties of Surface-Textured and Plasma-Nitrided Pure Titanium Under Oil Lubrication Condition

NASA Astrophysics Data System (ADS)

Zhang, Baosen; Dong, Qiangsheng; Ba, Zhixin; Wang, Zhangzhong; Shi, Hancheng; Xue, Yanting

2018-01-01

Plasma nitriding was conducted as post-treatment for surface texture on pure titanium to obtain a continuous nitriding layer. Supersonic fine particles bombarding (SFPB) was carried out to prepare surface texture. The surface morphologies and chemical composition were analyzed using scanning electron microscope and energy disperse spectroscopy. The microstructures of modified layers were characterized by transmission electron microscope. The tribological properties of surface-textured and duplex-treated pure titanium under oil lubrication condition were systematically investigated in the ball-on-plate reciprocating mode. The effects of applied load and sliding velocity on the tribological behavior were analyzed. The results show that after duplex treatments, the grains size in modified layer becomes slightly larger, and hardness is obviously improved. Wear resistance of duplex-treated pure titanium is significantly improved referenced to untreated and surface-textured pure titanium, which is 3.22 times as much as untreated pure titanium and 2.15 times of that for surface-textured pure titanium, respectively.

The intervention effect of zuogui pill on chronic kidney disease-mineral and bone disorder regulatory factor.

PubMed

Ma, Xiaohong; He, Liqun

2018-06-24

Chronic kidney disease-mineral and bone disorder (CKD-MBD) play a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). Zuogui pill as a traditional Chinese herbal drug has been used for nourish kidney essence improve bone malnutrition of renal bone disease by regulating the metabolism of calcium and phosphorus and participating in osteoblast metabolism. In the present study, 5/6 nephrectomy rat model was used to reveal the mechanism of zuogui pill in treatment of CKD-MBD. Compared with sham rats, the levels of serum phosphorus, PTH, iPTH and creatinine were significantly decreased, while the serum calcium level was significantly increased, and the Cbfa1 protein level was significantly decreased and FGF23 protein level was significantly increased by Zuogui pill treatment. Compared with model rats, the BMD of rat was significantly increased by Zuogui pill treatment. Histological analysis revealed that the kidney injury of rats with CKD was significantly reduced by zuogui pill treatment. Compared with model rats, the CYP27B1 mRNA level was significantly increased, and the PTH mRNA level and NaPiIIa protein level were significantly decreased in the kidney by zuogui pill treatment. We inferred that zuogui pill exhibited potential therapeutic effects on CKD-MBD in the rats by regulating bone metabolism and nourish kidney. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The effects of nocturnal compared with conventional hemodialysis on mineral metabolism: A randomized-controlled trial.

PubMed

Walsh, Michael; Manns, Braden J; Klarenbach, Scott; Tonelli, Marcello; Hemmelgarn, Brenda; Culleton, Bruce

2010-04-01

Hyperphosphatemia is common among patients receiving dialysis and is associated with increased mortality. Nocturnal hemodialysis (NHD) is a long, slow dialytic modality that may improve hyperphosphatemia and disorders of mineral metabolism. We performed a randomized-controlled trial of NHD compared with conventional hemodialysis (CvHD); in this paper, we report detailed results of mineral metabolism outcomes. Prevalent patients were randomized to receive NHD 5 to 6 nights per week for 6to 10 hours per night or to continue CvHD thrice weekly for 6 months. Oral phosphate binders and vitamin D analogs were adjusted to maintain phosphate, calcium and parathyroid hormone (PTH) levels within recommended targets. Compared with CvHD patients, patients in the NHD group had a significant decrease in serum phosphate over the course of the study (0.49 mmol/L, 95% confidence interval 0.24-0.74; P=0.002) despite a significant reduction in the use of phosphate binders. Sixty-one percent of patients in the NHD group compared with 20% in the CvHD group had a decline in intact PTH (P=0.003). Nocturnal hemodialysis lowers serum phosphate, calcium-phosphate product and requirement for phosphate binders. The effects of NHD on PTH are variable. The impact of these changes on long-term cardiovascular and bone-related outcomes requires further investigation.

Calcimimetic and Calcilytic Drugs: Feats, Flops, and Futures.

PubMed

Nemeth, E F; Goodman, W G

2016-04-01

The actions of extracellular Ca(2+) in regulating parathyroid gland and kidney functions are mediated by the extracellular calcium receptor (CaR), a G protein-coupled receptor. The CaR is one of the essential molecules maintaining systemic Ca(2+) homeostasis and is a molecular target for drugs useful in treating bone and mineral disorders. Ligands that activate the CaR are termed calcimimetics and are classified as either agonists (type I) or positive allosteric modulators (type II); calcimimetics inhibit the secretion of parathyroid hormone (PTH). Cinacalcet is a type II calcimimetic that is used to treat secondary hyperparathyroidism in patients receiving dialysis and to treat hypercalcemia in some forms of primary hyperparathyroidism. The use of cinacalcet among patients with secondary hyperparathyroidism who are managed with dialysis effectively lowers circulating PTH levels, reduces serum phosphorus and FGF23 concentrations, improves bone histopathology, and may diminish skeletal fracture rates and the need for parathyroidectomy. A second generation type II calcimimetic (AMG 416) is currently under regulatory review. Calcilytics are CaR antagonists that stimulate the secretion of PTH. Several calcilytic compounds have been evaluated as orally active anabolic therapies for postmenopausal osteoporosis but clinical development of all of them has been abandoned because they lacked clinical efficacy. Calcilytics might be repurposed for new indications like autosomal dominant hypocalcemia or other disorders beyond those involving systemic Ca(2+) homeostasis.

Current recommended 25-hydroxyvitamin D targets for chronic kidney disease management may be too low.

PubMed

Ennis, Jennifer L; Worcester, Elaine M; Coe, Fredric L; Sprague, Stuart M

2016-02-01

It is uncertain whether increasing 25-hydroxyvitamin D (25-D) levels in chronic kidney disease (CKD) patients above those recommended by current guidelines result in progressive amelioration of secondary hyperparathyroidism. Our objective was to identify a potential therapeutic 25-D target which optimally lowers plasma parathyroid hormone (PTH) without producing excessive hypercalcemia or hyperphosphatemia in CKD. We performed a cross-sectional analysis of 14,289 unselected stage 1-5 CKD patients from US primary care and nephrology practices utilizing a laboratory-based CKD clinical decision support service between September 2008 and May 2012. Estimated glomerular filtration rate (eGFR), plasma PTH, and serum 25-D, calcium, and phosphorus results were analyzed. In CKD stages 3-5, progressively higher 25-D pentiles contained progressively lower mean PTH levels. Regression analysis of log PTH on 25-D was significant in all CKD stages with no evidence of a decreasing effect of 25-D to lower PTH until 25-D levels of 42-48 ng/ml. Progressively higher 25-D concentrations were not associated with increased rates of hypercalcemia or hyperphosphatemia. We found evidence for an optimal level of 25-D above which suppression of PTH progressively diminishes. This level is more than twice that currently recommended for the general population. We found no association between these higher 25-D levels and hyperphosphatemia or hypercalcemia. Additional prospective trials seem appropriate to test the idea that 25-D levels around 40-50 ng/ml could be a safe and effective treatment target for secondary hyperparathyroidism in CKD.

[IPTH dosage as a prognosis predictor of postoperatory hypocalcemia in patients submitted to total thyroidectomy].

PubMed

Paliogiannis, Panagiotis; Attene, Federico; Torre, Carlo; Denti, Salvatore; Trignano, Emilio; Scognamillo, Fabrizio; Trignano, Mario

2011-01-01

Hypocalcemia is the most frequent complication after total thyroidectomy (TT) and represents the main cause of prolonged hospital stay because of the need to monitor the calcemic status of the patients. The aim of this study is to evaluate the role of serum iPTH as a predictor of post-thyroidectomy hypocalcemia in order to allow patients' early and safe discharge. Fifty patients who underwent TT without autotransplantation of parathyroid tissue were prospectively included in the study The mean age was 52 years and the male/female ratio was 1/6. The iPTH serum level were determined 1 hour after the operation and the calcium serum values after 24 and 48 hours. The cut-off value assumed for testing the sensitivity, specificity, PPV and NPV was 16 pg/ml. Nineteen patients (38%) presented hypocalcemia within 48 hours after TT and 16 of them (84.2%) had iPTH serum levels lower than 16 pg/ml. The normocalcemic patients were 31 (62%) and only 4 of them had iPTH serum levels inferior to the cut-off value. Postoperative iPTH serum level determined 1 hour after the operation had a sensibility of 84.2%, specificity of 87.1%, PPV and NPV of 90% and 80% respectively. The dosage of iPTH serum levels after total thyroidectomy reliably predicts patients who are likely to develop hypocalcaemia. It may be useful in clinical practice in order to reduce the number of postoperative blood tests and the hospital length of stay for the patients who are not at risk of postoperative hypocalcemia.

Management of Hypoparathyroidism: Present and Future

PubMed Central

Brandi, Maria Luisa; Cusano, Natalie E.; Mannstadt, Michael; Rejnmark, Lars; Rizzoli, René; Rubin, Mishaela R.; Winer, Karen K.; Liberman, Uri A.; Potts, John T.

2016-01-01

Context: Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and giving rise to concerns about long-term consequences including renal and brain calcifications. Replacement therapy with PTH has recently become available. This paper summarizes the results of the findings and recommendations of the Working Group on Management of Hypoparathyroidism. Evidence Acquisition: Contributing authors reviewed the literature regarding physiology, pathophysiology, and nutritional aspects of hypoparathyroidism, management of acute hypocalcemia, clinical aspects of chronic management, and replacement therapy of hypoparathyroidism with PTH peptides. PubMed and other literature search engines were utilized. Evidence synthesis: Under normal circumstances, interactions between PTH and active vitamin D along with the dynamics of calcium and phosphorus absorption, renal tubular handing of those ions, and skeletal responsiveness help to maintain calcium homeostasis and skeletal health. In the absence of PTH, the gastrointestinal tract, kidneys, and skeleton are all affected, leading to hypocalcemia, hyperphosphatemia, reduced bone remodeling, and an inability to conserve filtered calcium. Acute hypocalcemia can be a medical emergency presenting with neuromuscular irritability. The recent availability of recombinant human PTH (1–84) has given hope that management of hypoparathyroidism with the missing hormone in this disorder will provide better control and reduced needs for calcium and vitamin D. Conclusions: Hypoparathyroidism is associated with abnormal calcium and skeletal homeostasis. Control with calcium and active vitamin D can be a challenge. The availability of PTH (1–84) replacement therapy may usher new opportunities for better control with reduced supplementation requirements. PMID:26938200

Daily intermittent decreases in serum levels of parathyroid hormone have an anabolic-like action on the bones of uremic rats with low-turnover bone and osteomalacia.

PubMed

Ishii, H; Wada, M; Furuya, Y; Nagano, N; Nemeth, E F; Fox, J

2000-02-01

The calcium receptor agonist (calcimimetic) compound NPS R-568 causes rapid decreases in circulating levels of parathyroid hormone (PTH) in rats and humans. We hypothesized that daily intermittent decreases in serum PTH levels may have different effects on bone than do chronically sustained decreases. To test this hypothesis, we compared two NPS R-568 dosing regimens in rats with chronic renal insufficiency induced by two intravenous injections of adriamycin. Fourteen weeks after the second adriamycin injection, creatinine clearance was reduced by 52%, PTH levels were elevated approximately 2.5-fold, and serum 25(OH)D3 and 1,25(OH)2D3 levels were reduced substantially. Treatment by daily per os gavage, which decreased PTH levels intermittently, or continuous subcutaneous infusion, which resulted in a sustained suppression of serum PTH levels, then began for 8 weeks. Despite the hyperparathyroidism, the adriamycin-injected rats developed a low-turnover bone lesion with osteomalacia (fourfold increase in osteoid volume in the proximal tibial metaphysis) and osteopenia (67% decrease in cancellous bone volume and an 18% reduction in bone mineral density at the distal femur). Daily administered (but not infused) NPS R-568 significantly increased cancellous bone volume solely by normalizing trabecular thickness, and increased femoral bone mineral density by 14%. These results indicate that daily intermittent, but not sustained, decreases in PTH levels have an "anabolic-like" effect on bones with a low-turnover lesion in this animal model of chronic renal insufficiency.

Pth1/Vam3p is the syntaxin homolog at the vacuolar membrane of Saccharomyces cerevisiae required for the delivery of vacuolar hydrolases.

PubMed Central

Srivastava, A; Jones, E W

1998-01-01

The PEP12 homolog Pth1p (Pep twelve homolog 1) is predicted to be similar in size to Pep12p, the endosomal syntaxin homolog that mediates docking of Golgi-derived transport vesicles and, like other members of the syntaxin family, is predicted to be a cytoplasmically oriented, integral membrane protein with a C-terminal transmembrane domain. Kinetic analyses indicate that deltapth1/vam3 mutants fail to process the soluble vacuolar hydrolase precursors and that PrA, PrB and most of CpY accumulate within the cell in their Golgi-modified P2 precursor forms. This is in contrast to a pep12 mutant in which P2CpY is secreted from the cell. Furthermore, pep12 is epistatic to pth1/vam3 with respect to the CpY secretion phenotype. Alkaline phosphatase, a vacuolar membrane hydrolase, accumulates in its precursor form in the deltapth1/vam3 mutant. Maturation of pro-aminopeptidase I, a hydrolase precursor delivered directly to the vacuole from the cytoplasm, is also blocked in the deltapth1/vam3 mutant. Subcellular fractionation localizes Pth1/Vam3p to vacuolar membranes. Based on these data, we propose that Pth1/Vam3p is the vacuolar syntaxin/t-SNARE homolog that participates in docking of transport vesicles at the vacuolar membrane and that the function of Pth1/Vam3p impinges on at least three routes of protein delivery to the yeast vacuole. PMID:9475723

Evidence for an Intrinsic Renal Tubular Defect in Mice with Genetic Hypophosphatemic Rickets

PubMed Central

Cowgill, Larry D.; Goldfarb, Stanley; Lau, Kai; Slatopolsky, Eduardo; Agus, Zalman S.

1979-01-01

To investigate the role of parathyroid hormone (PTH) and(or) an intrinsic renal tubular reabsorptive defect for phosphate in mice with hereditary hypophosphatemic rickets, we performed clearance and micropuncture studies in hypophosphatemic mutants and nonaffected littermate controls. Increased fractional excretion of phosphate in mutants (47.2±4 vs. 30.8±2% in controls) was associated with reduced fractional and absolute reabsorption in the proximal convoluted tubule and more distal sites. Acute thyropara-thyroidectomy (TPTX) increased phosphate reabsorption in both mutants and controls with a fall in fractional phosphate excretion to ≅7.5% in both groups indicating that PTH modified the degree of phosphaturia in the intact mutants. Absolute reabsorption in the proximal tubule and beyond remained reduced in the mutants, however, possibly because of the reduced filtered load. Serum PTH levels were the same in intact mutants and normals as was renal cortical adenylate cyclase activity both before and after PTH stimulation. To evaluate the possibility that the phosphate wasting was caused by an intrinsic tubular defect that was masked by TPTX, glomerular fluid phosphate concentration was raised by phosphate infusion in TPTX mutants to levels approaching those of control mice. Phosphate excretion rose markedly and fractional reabsorption fell, but there was no change in absolute phosphate reabsorption in either the proximal tubule or beyond, indicating a persistent reabsorptive defect in the absence of PTH. We conclude that hereditary hypophosphatemia in the mouse is associated with a renal tubular defect in phosphate reabsorption, which is independent of PTH and therefore represents a specific intrinsic abnormality of phosphate transport. PMID:221535

Parathyroid Hormone and Bone in Dialysis Patients.

PubMed

Kazama, Junichiro James; Wakasugi, Minako

2018-06-01

Bone maintains extracellular calcium levels through a system called bone remodeling. Parathyroid hormone (PTH) is the major initiator of this system, which is secreted by the information through calcium sensing receptor in parathyroid cells. PTH modifies calcified bone morphology through a process of its bone action. Therefore, extremely hyperactivated parathyroid function seen in patients with chronic kidney disease has been considered to have a negative impact on the bone mechanical properties. While skeletal deformities and fragility fractures were common among dialysis patients up to the 1970s, after which methods for the treatment of hyperparathyroidism were developed, we now seldom encounter those cases with severe secondary hyperparathyroidism in Japan. In a three-dimensional morphometry of biopsied iliac bone samples obtained from dialysis patients, PTH level was inversely correlated with cortical bone thickness, however, this relationship disappeared among those with intact PTH < 1000 pg/mL. Higher PTH levels were associated with more complicated and irregular cancellous bone surface, but this change was not accompanied with decreased cancellous bone connectivity. These findings theoretically support the recent clinical study results that PTH levels no longer show a tight correlation with fracture risk in dialysis patients. Nevertheless, the use of calcium sensing receptor agonist is likely to be associated with reduced hip fracture risk in dialysis patients. Further study is needed to reveal its pharmacological mechanism on bone. © 2018 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.

Association between very low PTH levels and poor survival rates in haemodialysis patients: results from the French ARNOS cohort.

PubMed

Jean, G; Lataillade, D; Genet, L; Legrand, E; Kuentz, F; Moreau-Gaudry, X; Fouque, D

2011-01-01

A very low parathyroid hormone (PTH) level (VLPL) is associated with an increased risk of adynamic bone disease, vascular calcification, and mortality in haemodialysis (HD) patients. The aim of the study was to assess the frequency, the associated factors, and the prognosis of non-surgical VLPL in a cohort of prevalent HD patients. In July 2005, a cross-sectional study was performed on the French ARNOS cohort in 1,348 prevalent HD patients from 24 dialysis centres in the Rhône-Alpes area. Patients with a baseline intact PTH level <50 pg/ml (VLPL, Group 1) and ≥ 50 pg/ml (Group 2) were compared and a 42-month survival analysis was performed. Patients with prevalent or incident parathyroidectomy were excluded. We studied 1,138 prevalent HD patients. As compared to patients of Group 2 (n = 1,019), patients with VLPL (Group 1, n = 119) had lower serum albumin levels (34.5 ± 5 vs. 36.4 ± 5 g/l, p < 0.0001), less protein intake (nPCR 0.99 ± 0.28 vs. 1.1 ± 0.28 g/kg/day, p = 0.01), higher calcaemia (2.30 ± 0.2 vs. 2.26 ± 0.2 mmol/l, p = 0.01) and were more frequently treated with calcium carbonate (67 vs. 54%, p < 0.001). Patients with VLPL had a higher mortality rate (HR: 1.4 (1.07-1.8), p = 0.006) after adjustment for age, gender, diabetes, and dialysis vintage. The odds ratios of mortality for patients with VLPL remained higher in all calcaemia and serum albumin quartiles. Only 3/119 patients in Group 1 did not receive any PTH-lowering therapies (i.e. calcium carbonate (67%), alfacalcidol (38%), cinacalcet (10.1%), and dialysate calcium ≥ 1.5 mmol/l (94%)). In this observational French cohort, VLPL was observed in 10% of prevalent HD patients and was associated with poor survival rates. An inadequate therapeutic strategy could be responsible for this observation. The real consequences of this iatrogenic adynamic bone disease remain hypothetical, but it may be related to the risk of developing vascular calcification. It is hypothesized that a more adequate strategy, using fewer PTH-lowering therapies in cases of VLPL, may help in improving the poor prognosis. Copyright © 2010 S. Karger AG, Basel.

Effects of Laparoscopic Sleeve Gastrectomy on Parathyroid Hormone, Vitamin D, Calcium, Phosphorus, and Albumin Levels.

PubMed

Mihmanli, Mehmet; Isil, Riza Gurhan; Isil, Canan Tulay; Omeroglu, Sinan; Sayin, Pinar; Oba, Sibel; Ozturk, Feyza Yener; Altuntas, Yuksel

2017-12-01

Laparoscopic sleeve gastrectomy (LSG) reduces obesity-related co-morbidities, such as diabetes, hypertension, and hyperlipidemia. Endocrinological abnormalities may occur as undesired side effects. Most centers routinely prescribe folic acid, cyanocobalamin (vitB12), and protein replacement in the postoperative period, but 25-OH-vitamin-D3 (vitD) and intact parathyroid hormone (iPTH) levels are not routinely followed up. The aim of this study was to identify the effects of LSG on iPTH, vitD, calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and albumin levels. Data of morbidly obese patients who underwent LSG between January and December 2014 were studied in this prospectively designed study. Serum levels of iPTH, vitD, Ca, P, folic acid, vitB12, ALP, and albumin were measured preoperatively and postoperatively at the 3rd, 6th, and 12th months. In total, 119 patients were analyzed. All patients had normal iPTH, vitD, Ca, P, folic acid, vitB12, ALP, and albumin values preoperatively, and 31.6% had received vitD supplementation during their nutritionist observation time before surgery. At the 3rd, 6th, and 12th postoperative months, 21 (17.6%), 17 (17.3%), and 1 (0.8%) patients, respectively, had increased iPTH and ALP and decreased vitD levels. A total of 39 (32.7%) patients needed high-dose vitD treatment during a 1 year follow-up. Approximately 37.5% of the patients who received vitD supplementation preoperatively needed vitD supplementation postoperatively. Hospital records of 101 of 119 patients who underwent LSG could be screened to determine their vitD supplementation requirements previously ordered by their nutritionist for a 1-year period before LSG. Thirty-two (31.6%) of the 101 patients had received vitD supplementation during the 1-year period preoperatively. Although serum levels of iPTH, vitD, Ca, P, vitB12, ALP, and albumin may be normal preoperatively, severe vitD insufficiency requiring high-dose vitD replacement may develop in morbidly obese patients postoperatively. Instead of iPTH and vitD, which are expensive to measure, ALP serum level, which is correlated with iPTH levels, can be a good indicator to monitor calcium metabolism.

Impact of mineral and bone disorder on healthcare resource use and associated costs in the European Fresenius medical care dialysis population: a retrospective cohort study.

PubMed

Chiroli, Silvia; Mattin, Caroline; Belozeroff, Vasily; Perrault, Louise; Mitchell, Dominic; Gioni, Ioanna

2012-10-29

Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe. The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had ≥ 1 iPTH value recorded, and ≥ 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD-related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates. There were 6369 patients included in the analysis. Mean ± SD person-time at risk was 13.1 ± 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150-300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13-1.78 mmol/L and 2.10-2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses. These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe.

Biofunctionalization of titanium with bacitracin immobilization shows potential for anti-bacteria, osteogenesis and reduction of macrophage inflammation.

PubMed

Nie, Bin'en; Ao, Haiyong; Zhou, Jianliang; Tang, Tingting; Yue, Bing

2016-09-01

Titanium has been widely used in the orthopedic and dental fields, however, the inert nature of Ti makes it unsuitable for application in promoting bone cell growth，osteogenic differentiation and antibacterial ability. The aims of the current study were to investigate the antimicrobial activity and biofunction of the polypeptide antibiotic bacitracin, and obtain a multi-biofunctional titanium implant by covalently-immobilizing titanium with the bacitracin. The results showed that the bacitracin possessed low minimum inhibitory concentration (MIC) to both Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA), with the non-cytotoxicity concentration up to 500μg/mL to human bone marrow mesenchymal stem cells (hBMSCs), furthermore, the bacitracin could improve the osteogenic differentiation of hBMSCs. The results of Scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS) indicated that bacitracin had been covalently immobilized on the surface of titanium. Immobilized bacitracin could improve the hydrophilic of immobilized titanium. The results of antimicrobial assay demonstrated that the covalently-immobilized bacitracin also had excellent antimicrobial property, and the bacitracin immobilized titanium could inhibit bacterial adhesion and colonization. The results of cell biology experiments proved that the bacitracin immobilized titanium could improve hBMSCs' adhesion, proliferation and osteogenic differentiation. We also found that the macrophages were difficult to spread or activate on the surface of bacitracin immobilized titanium, and the secretion of inflammatory factors had been inhibited. In conclusion, the novel bacitracin immobilized titanium has multi-biofunctions including outstanding antibacterial properties, excellent cell biology performance, and restraining inflammation, which has exciting application prospect. Copyright © 2016 Elsevier B.V. All rights reserved.

Plasma-sprayed titanium coating to polyetheretherketone improves the bone-implant interface.

PubMed

Walsh, William R; Bertollo, Nicky; Christou, Chrisopher; Schaffner, Dominik; Mobbs, Ralph J

2015-05-01

Rapid and stable fixation at the bone-implant interface would be regarded as one of the primary goals to achieve clinical efficacy, regardless of the surgical site. Although mechanical and physical properties of polyetheretherketone (PEEK) provide advantages for implant devices, the hydrophobic nature and the lack of direct bone contact remains a limitation. To examine the effects of a plasma-sprayed titanium coated PEEK on the mechanical and histologic properties at the bone-implant interface. A preclinical laboratory study. Polyetheretherketone and plasma-sprayed titanium coated PEEK implants (Ti-bond; Spinal Elements, Carlsbad, CA, USA) were placed in a line-to-line manner in cortical bone and in a press-fit manner in cancellous bone of adult sheep using an established ovine model. Shear strength was assessed in the cortical sites at 4 and 12 weeks, whereas histology was performed in cortical and cancellous sites at both time points. The titanium coating dramatically improved the shear strength at the bone-implant interface at 4 weeks and continued to improve with time compared with PEEK. Direct bone ongrowth in cancellous and cortical sites can be achieved using a plasma-sprayed titanium coating on PEEK. Direct bone to implant bonding can be achieved on PEEK in spite of its hydrophobic nature using a plasma-sprayed titanium coating. The plasma-sprayed titanium coating improved mechanical properties in the cortical sites and the histology in cortical and cancellous sites. Copyright © 2015 Elsevier Inc. All rights reserved.

Parathyroid adenoma

MedlinePlus

... the body. They do this by producing parathyroid hormone, or PTH. PTH helps control calcium, phosphorus, and vitamin D levels in the ... from surgery include: Damage to a nerve that controls your voice Damage to the parathyroid ... hormone) and low calcium level When to Contact a ...

Incidence and aetiology of renal phosphate loss in patients with hypophosphatemia in the intensive care unit.

PubMed

Bech, Anneke; Blans, Michiel; Telting, Darryl; de Boer, Hans

2013-10-01

Hypophosphatemia is a common finding in patients in the intensive care unit (ICU). Its cause is often poorly understood. The aim of this study was to understand the incidence of renal phosphate loss in ICU-related hypophosphatemia, and to examine the role of phosphaturic hormones in its etiology. Plasma phosphate levels were measured on day 1, 3, 5 and 7 in 290 consecutive patients admitted to the ICU. Renal phosphate handling and phosphaturic hormones were studied in a subset of patients with phosphate levels <0.6 mmol/L. Renal phosphate loss was defined as a TmP/gfr < 0.6 mmol/L. Hypophosphatemia developed in 24% of all patients. This mainly occurred within the first 3 days of stay and in patients with serum creatinine levels <150 μmol/L. Renal phosphate loss was present in 80% of patients who developed hypophosphatemia, and was not related to serum levels of parathyroid hormone (PTH), PTH-related protein (PTH-rp), fibroblast growth factor 23 (FGF-23), or calcitonin. Hypophosphatemia in the ICU is commonly associated with renal phosphate loss. It mainly occurs within the first 3 days of admission, in particular in patients with preserved renal function. Renal phosphate loss is not explained by elevated PTH, PTH-rp, FGF-23 or calcitonin levels.

Estrogen receptors and biologic response in rat parathyroid tissue and C cells.

PubMed Central

Naveh-Many, T; Almogi, G; Livni, N; Silver, J

1992-01-01

The expression of the PTH and calcitonin genes is dramatically decreased by 1,25(OH)2D3 in vivo, and the PTH gene expression is increased by hypocalcemia. We have now studied the effect of estrogens on the expression of these genes in vivo. 17 beta-Estradiol, given to ovariectomized rats, led to a fourfold increase in PTH mRNA and calcitonin mRNA levels. These effects occurred 24 h after single injections of 37-145 nmol estradiol, or after constant infusions of 12 pmol/d for 1 or 2 wk, where there was no effect on serum calcium levels. The estrogen receptor mRNA was demonstrated in the thyroparathyroid tissue by polymerase chain reaction. The estrogen binding was localized to the parathyroid and C cells by immunohistochemistry. Uterus weight was increased by repeated larger doses (73 nmol/d x 7) of estradiol, but not by the small doses (12 pmol/d for 1 or 2 wk) which were effective on the PTH and calcitonin genes, suggesting a sensitive endocrine effect. These results confirm that the parathyroid and C cells are target organs for estrogen, leading to an increased expression of PTH and calcitonin, which by their combined anabolic effect on bone would help prevent osteoporosis. Images PMID:1469095

Synthesis and Characterization of Novel Biotinylated Carboxyl-terminal Parathyroid Hormone Peptides that Specifically Crosslink to the CPTH-receptor

PubMed Central

Banerjee, Santanu; Selim, Hafez; Suliman, Gihan; Geller, Andrew I.; Jüppner, Harald; Bringhurst, F. Richard; Divieti, Paola

2006-01-01

Parathyroid hormone (PTH) regulates calcium, phosphorous and skeletal homeostasis via interaction with the G protein-coupled PTH/PTHrP receptor, which is fully activated by the amino-terminal 34 amino-acid portion of the hormone. Recent evidence points to the existence of another class of receptors for PTH that recognize the carboxyl (C)-terminal region of intact PTH(1–84) (CPTHRs) and are highly expressed by osteocytes. Here we report the synthesis and characterization of two novel bifunctional CPTH ligands that include benzoylphenylalanine (Bpa) substitutions near their amino-termini and carboxyl-terminal biotin moieties, as well as a tyrosine34 substitution to enable radioiodination. These peptides are shown to bind to CPTHRs with affinity similar to that of PTH (1–84) and to be specifically and covalently cross-linked to CPTHRs upon exposure to ultraviolet light. Crosslinking to osteocytes or osteoblastic cells generates complexes of 80kDa and 220kDa, of which the larger form represents an aggregate that can be resolved into the 80kDa. The crosslinked products can be further purified using immunoaffinity and avidin-based affinity procedures. While the molecular structure of the CPTHR(s) remains undefined, these bifunctional ligands represent powerful new tools for use in isolating and characterizing CPTHR protein(s). PMID:17028061

A review of the use of ethionamide and prothionamide in childhood tuberculosis.

PubMed

Thee, S; Garcia-Prats, A J; Donald, P R; Hesseling, A C; Schaaf, H S

2016-03-01

Ethionamide (ETH) and prothionamide (PTH), both thioamides, have proven efficacy in clinical studies and form important components for multidrug-resistant tuberculosis treatment regimens and for treatment of tuberculous meningitis in adults and children. ETH and PTH are pro-drugs that, following enzymatic activation by mycobacterial EthA inhibit InhA, a target shared with isoniazid (INH), and subsequently inhibit mycolic acid synthesis of Mycobacterium tuberculosis. Co-resistance to INH and ETH is conferred by mutations in the mycobacterial inhA promoter region; mutations in the ethA gene often underlie ETH and PTH monoresistance. An oral daily dose of ETH or PTH of 15-20 mg/kg with a maximum daily dose of 1000 mg is recommended in children to achieve adult-equivalent serum concentrations shown to be efficacious in adults, although information on optimal pharmacodynamic targets is still lacking. Gastrointestinal disturbances, and hypothyroidism during long-term therapy, are frequent adverse effects observed in adults and children, but are rarely life-threatening and seldom necessitate cessation of ETH therapy. More thorough investigation of the therapeutic effects and toxicity of ETH and PTH is needed in childhood TB while child-friendly formulations are needed to appropriately dose children. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of parathyroid hormone and uremic sera on the autoagglutination and sedimentation of human red blood cells.

PubMed

Earon, Y; Blum, M; Bogin, E

1983-12-30

Parathyroid hormone (PTH) caused a dramatic acceleration of erythrocyte sedimentation rate (ESR). This effect was calcium dependent and was partially reversed by verapamil. It was not mimicked by 5 mumol/l calcium ionophore A-23187. Following the removal of PTH from the cell suspension the ESR returned to normal. PTH also caused haemagglutination, the reaction was Ca2+ dependent, pH dependent and was partially reversed by verapamil. High levels of Ca2+ ionophore A-23187 mimicked this phenomenon. Magnesium ions even at concentrations of 5 mmol/l did not replace Ca2+, while Ca2+ at concentrations of 3 mmol/l and above caused haemagglutination. The glycolytic inhibitor NaF at levels of 1 mmol/l did not inhibit haemagglutination. The polyamines pertusin and spermidin, prostaglandins PGE2 and PGF, and the calcium hormone calcitonin, did not reproduce the PTH effect. Dialysate from serum of patients with chronic renal failure and hyperparathyroidism caused haemagglutination, while dialysate from patients with chronic renal failure following parathyroidectomy and normal individuals did not cause this phenomenon. It seems that abnormal erythrocyte behaviour seen in patients with chronic renal failure is caused by PTH which leads to modified Ca2+ metabolism in these cells.

DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH.

PubMed

Liu, Zhongbo; Kennedy, Oran D; Cardoso, Luis; Basta-Pljakic, Jelena; Partridge, Nicola C; Schaffler, Mitchell B; Rosen, Clifford J; Yakar, Shoshana

2016-02-01

Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serum levels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1-mediated Ghr knockout (DMP-GHRKO) mice to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual. DMP-GHRKO mice exhibited reduced serum inorganic phosphate and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth. © FASEB.

Searching the optimal PTH target range in children undergoing peritoneal dialysis: new insights from international cohort studies.

PubMed

Haffner, Dieter; Schaefer, Franz

2013-04-01

The treatment of the mineral and bone disorder associated with chronic kidney disease (CKD-MBD) remains a major challenge in pediatric patients. The principal aims of therapeutic measures are not only to prevent the debilitating skeletal complications and to achieve normal growth but also to preserve long-term cardiovascular health. Serum parathyroid hormone (PTH) levels are used as a surrogate parameter of bone turnover. Whereas it is generally accepted that serum calcium and phosphate levels should be kept within the range for age, current pediatric consensus guidelines differ markedly with respect to the optimal PTH target range and operate on a limited evidence base. Recently, the International Pediatric Dialysis Network (IPPN) established a global registry collecting detailed clinical and biochemical information, including data relevant to CKD-MBD in children on chronic peritoneal dialysis (PD). This review highlights the current evidence basis regarding the optimal PTH target range in pediatric CKD patients, and re-assesses the current guidelines in view of the outcome data collected by the IPPN registry. Based on a comprehensive evaluation of CKD-MBD outcome measures in this global patient cohort, a PTH target range of 1.7-3 times the upper limit of normal (i.e. 100-200 pg/ml) appears reasonable in children undergoing chronic PD.

A moderately low phosphate intake may provide health benefits analogous to those conferred by UV light - a further advantage of vegan diets.

PubMed

McCarty, M F

2003-01-01

Although exposure to ultraviolet light is often viewed as pathogenic owing to its role in the genesis of skin cancer and skin aging, there is growing epidemiological evidence that such exposure may decrease risk for a number of more serious cancers, may have a favorable impact on blood pressure and vascular health, and may help to prevent certain autoimmune disorders - in addition to its well-known influence on bone density. Most likely, these health benefits are reflective of improved vitamin D status. Increased synthesis or intake of vitamin D can be expected to down-regulate parathyroid hormone (PTH), and to increase autocrine synthesis of its active metabolite calcitriol in certain tissues; these effects, in turn, may impact cancer risk, vascular health, immune regulation, and bone density through a variety of mechanisms. Presumably, a truly adequate supplemental intake of vitamin D - manyfold higher than the grossly inadequate current RDA - could replicate the benefits of optimal UV exposure, without however damaging the skin. Diets moderately low in bioavailable phosphate - like many vegan diets - might be expected to have a complementary impact on disease risks, inasmuch as serum phosphate suppresses renal calcitriol synthesis while up-regulating that of PTH. A proviso is that the impact of dietary phosphorus on bone health is more equivocal than that of vitamin D. Increased intakes of calcium, on the other hand, down-regulate the production of both PTH and calcitriol - the latter effect may explain why the impact of dietary calcium on cancer risk (excepting colon cancer), hypertension, and autoimmunity is not clearly positive. An overview suggests that a vegan diet supplemented with high-dose vitamin D should increase both systemic and autocrine calcitriol production while suppressing PTH secretion, and thus should represent a highly effective way to achieve the wide-ranging health protection conferred by optimal UV exposure.

Comparison of two different vitamin D supplementation regimens with oral calcifediol in kidney transplant patients.

PubMed

Barros, Xoana; Rodríguez, Nestor Y; Fuster, David; Rodas, Lida; Esforzado, Nuria; Mazza, Alberto; Rubello, Domenico; Campos, Francisco; Tapias, Andrés; Torregrosa, José-Vicente

2016-10-01

Vitamin D deficiency is prevalent in kidney transplant recipients (KTR) and recommendations on how to replenish vitamin D deposits are scarce. To evaluate, in KTR, the safety and efficacy of calcifediol in two different vitamin D supplementation regimens, in order to assess the most suitable dose. Prospective observational study with two calcifediol supplementation regimens randomly prescribed by clinicians in liquid form, at 266 mcg doses, monthly or biweekly. We analyzed 168 KTR with a functioning allograft for more than 6 months. Patients receiving other vitamin D forms, calcimimetics or bisphosphonates were excluded. Before calcifediol initiation (pre-treatment levels) and after at least 3 months of treatment (post-treatment levels), we measured serum levels of 25-OH vitamin D (25(OH)D), parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium (sCa), phosphate (sPO4) and creatinine (sCreat). In the monthly group (n = 72), 25(OH)D levels increased from 14 ng/ml [interquartile range, IQR 9-22] at baseline to 31 [20-38] (p = 0.000), PTH decreased from 124 pg/ml [87-172] to 114 [78-163] (p = 0.006), while sCa and sPO4 remained stable. In the biweekly group (n = 96), 25(OH)D increased from 14 ng/ml [9-20] at baseline to 39 [28-52] (p = 0), PTH decreased from 141 pg/ml [95-221] to 112 [90-180] (p = 0.000), sCa remained stable and sPO4 increased from 3.3 ± 0.6 mg/dl to 3.5 ± 0.6 (p = 0.003). Renal function remained stable in both groups. Vitamin D reposition with oral calcifediol, in a biweekly or monthly regimen, is safe and effective in improving 25(OH)D blood levels and in decreasing PTH in kidney transplant recipients.

The Clinical and Biochemical Predictors of Bone Mass in Preterm Infants.

PubMed

Czech-Kowalska, Justyna; Czekuc-Kryskiewicz, Edyta; Pludowski, Pawel; Zaniuk, Katarzyna; Jaworski, Maciej; Łuba, Anna; Grzybowska, Karolina; Piłat, Krystyna; Dobrzanska, Anna

2016-01-01

Metabolic bone disease of prematurity still occurs in preterm infants, although a significant improvement in neonatal care has been observed in recent decades. Dual-energy X-ray absorptiometry (DXA) is the precise technique for assessing bone mineral content (BMC) in preterm infants, but is not widely available. To investigate the clinical and biochemical parameters, including bone metabolism markers as potential predictors of BMC, in preterm infants up to 3 months corrected age (CA). Ca-P homeostasis, iPTH, 25-hydroxyvitamin D, osteocalcin, N-terminal propeptide, cross-linked C-telopeptide and amino-terminal pro C-type natriuretic peptide and the DXA scans were prospectively performed in 184 preterm infants (≤ 34 weeks' gestation) between term age and 3 mo CA. Lower bone mass was defined as BMC below or equal to respective median value for the whole study group, rounded to the nearest whole number. The appropriate quality DXA scans were available for 160 infants (87%) examined at term and for 130 (71%) tested at 3 mo CA. Higher iPTH level was the only independent predictor of lower BMC at term, whereas lower BMC at 3 mo CA was associated both with lower urinary phosphate excretion and higher serum osteocalcin level. ROC analysis showed that iPTH >43.6 pg/mL provided 40% sensitivity and 88% specificity in identification of preterm infants with lower BMC at term. In turn, urinary phosphate excretion (TRP>97% or UP/Cr ≤0.74 mg/mg) and serum osteocalcin >172 ng/mL provided 40% sensitivity and 93% specificity in identification of infants with decreased BMC at 3 mo CA. Serum iPTH might to be a simple predictor of reduced BMC in preterm infants at term age, but urinary phosphate excretion and serum osteocalcin might predict reduced BMC at 3 mo CA. These results represent a promising diagnostic tool based on simple, widely available biochemical measurements for bone mass assessment in preterm infants.

The Effect of Moderate Dietary Protein and Phosphate Restriction on Calcium-Phosphate Homeostasis in Healthy Older Cats.

PubMed

Geddes, R F; Biourge, V; Chang, Y; Syme, H M; Elliott, J

2016-09-01

Dietary phosphate and protein restriction decreases plasma PTH and FGF-23 concentrations and improves survival time in azotemic cats, but has not been examined in cats that are not azotemic. Feeding a moderately protein- and phosphate-restricted diet decreases PTH and FGF-23 in healthy older cats and thereby slows progression to azotemic CKD. A total of 54 healthy, client-owned cats (≥ 9 years). Prospective double-blinded randomized placebo-controlled trial. Cats were assigned to test diet (protein 76 g/Mcal and phosphate 1.6 g/Mcal) or control diet (protein 86 g/Mcal and phosphate 2.6 g/Mcal) and monitored for 18 months. Changes in variables over time and effect of diet were assessed by linear mixed models. A total of 26 cats ate test diet and 28 cats ate control diet. There was a significant effect of diet on urinary fractional excretion of phosphate (P = 0.045), plasma PTH (P = 0.005), and ionized calcium concentrations (P = 0.018), but not plasma phosphate, FGF-23, or creatinine concentrations. Plasma PTH concentrations did not significantly change in cats fed the test diet (P = 0.62) but increased over time in cats fed the control diet (P = 0.001). There was no significant treatment effect of the test diet on development of azotemic CKD (3 of 26 (12%) test versus 3 of 28 (11%) control, odds ratio 1.09 (95% CI 0.13-8.94), P = 0.92). Feeding a moderately protein- and phosphate-restricted diet has effects on calcium-phosphate homeostasis in healthy older cats and is well tolerated. This might have an impact on renal function and could be useful in early chronic kidney disease. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Ultrafine-grained titanium for medical implants

DOEpatents

Zhu, Yuntian T.; Lowe, Terry C.; Valiev, Ruslan Z.; Stolyarov, Vladimir V.; Latysh, Vladimir V.; Raab, Georgy J.

2002-01-01

We disclose ultrafine-grained titanium. A coarse-grained titanium billet is subjected to multiple extrusions through a preheated equal channel angular extrusion (ECAE) die, with billet rotation between subsequent extrusions. The resulting billet is cold processed by cold rolling and/or cold extrusion, with optional annealing. The resulting ultrafine-grained titanium has greatly improved mechanical properties and is used to make medical implants.

Improving Osteoblast Response In Vitro by a Nanostructured Thin Film with Titanium Carbide and Titanium Oxides Clustered around Graphitic Carbon

PubMed Central

Longo, Giovanni; Ioannidu, Caterina Alexandra; Scotto d’Abusco, Anna; Superti, Fabiana; Misiano, Carlo; Zanoni, Robertino; Politi, Laura; Mazzola, Luca; Iosi, Francesca; Mura, Francesco; Scandurra, Roberto

2016-01-01

Introduction Recently, we introduced a new deposition method, based on Ion Plating Plasma Assisted technology, to coat titanium implants with a thin but hard nanostructured layer composed of titanium carbide and titanium oxides, clustered around graphitic carbon. The nanostructured layer has a double effect: protects the bulk titanium against the harsh conditions of biological tissues and in the same time has a stimulating action on osteoblasts. Results The aim of this work is to describe the biological effects of this layer on osteoblasts cultured in vitro. We demonstrate that the nanostructured layer causes an overexpression of many early genes correlated to proteins involved in bone turnover and an increase in the number of surface receptors for α3β1 integrin, talin, paxillin. Analyses at single-cell level, by scanning electron microscopy, atomic force microscopy, and single cell force spectroscopy, show how the proliferation, adhesion and spreading of cells cultured on coated titanium samples are higher than on uncoated titanium ones. Finally, the chemistry of the layer induces a better formation of blood clots and a higher number of adhered platelets, compared to the uncoated cases, and these are useful features to improve the speed of implant osseointegration. Conclusion In summary, the nanostructured TiC film, due to its physical and chemical properties, can be used to protect the implants and to improve their acceptance by the bone. PMID:27031101

Transient and permanent hypocalcemia after total thyroidectomy: Early predictive factors and long-term follow-up results.

PubMed

Seo, Sung Tae; Chang, Jae Won; Jin, Jun; Lim, Young Chang; Rha, Ki-Sang; Koo, Bon Seok

2015-12-01

Post-thyroidectomy hypocalcemia is among the most common complications of total thyroidectomy. The purpose of this study was to evaluate early predictive factors and long-term changes in intact parathyroid hormone (iPTH) levels in patients with transient and permanent hypocalcemia after total thyroidectomy. A total of 349 consecutive patients who underwent total thyroidectomy with or without neck dissection between 2009 and 2011 were reviewed. PTH, total calcium (Ca), and ionized Ca (iCa) levels were evaluated at 1 hour, and 1, 3, 5, and 7 days, and 1, 3, 6, and 12 months postoperatively. Biochemical profiles at 1 hour after total thyroidectomy in patients with transient and permanent hypocalcemia were compared. Patients with postoperative hypocalcemia were followed for 12 months. Lesser preoperative serum levels of Ca and more extensive surgery were significantly associated with postoperative hypocalcemia (P < .05). The absolute level and relative decline (%) in iPTH at 1 hour were the most reliable predictors of postoperative hypocalcemia according to the receiver operating characteristics curve, with a threshold of 10.42 pg/mL and 70%. Sensitivity and specificity of the predictors were 83.4% (95% CI, 76.4-89.1), 100% (95% CI, 84.6-100.0), 84.1 (95% CI, 77.2-89.7), and 95.5% (95% CI, 77.2-99.9), respectively. Parathyroid function recovered in the first month after total thyroidectomy in 78 of 99 patients (79%) with transient hypocalcemia. However, 46 of 61 patients (74%) with a subnormal iPTH level at 3 months after surgery had permanent hypocalcemia. Mean postoperative PTH level and the mean relative decline in PTH measured 1 hour postoperatively were the most reliable predictors of postoperative or permanent hypocalcemia. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical and laboratory characteristics of neonatal hypocalcemia

PubMed Central

Cho, Won Im; Yu, Hyeoh Won; Shin, Choong Ho; Yang, Sei Won; Choi, Chang Won; Kim, Beyong Il

2015-01-01

Purpose To describe the clinical characteristics of full-term neonates with hypocalcemia and to suggest factors associated with neonatal hypocalcemia Methods The medical records of full-term neonates with hypocalcemia were reviewed. Hypocalcemia was defined as an ionized calcium (iCa) concentration of <4 mg/dL. Parathyroid hormone (PTH) insufficiency was defined as a serum PTH level of <60 pg/mL or a serum phosphorus level higher than the serum calcium level in the presence of hypocalcemia. Results Fifty-three neonates were enrolled. The median age at diagnosis of hypocalcemia was 3 days. In all the neonates, formula feeding predominance was observed. Thirty-eight neonates (69.8%) were compatible with PTH insufficiency. The number of formula-fed neonates was significantly higher than that of breast-fed patients among neonates with PTH insufficiency (P=0.017). Intact PTH was negatively correlated with serum phosphorus levels. Twelve out of 14 neonates (85.7%) had 25-hydroxy vitamin D (25OHD) levels <20 ng/mL and 9 neonates (64.3%) had 25OHD levels <10 ng/mL. Twenty-one neonates had hypocalcemic tetany. The serum calcium and iCa concentrations of neonates with tetany were 4.2-8.3 mg/dL and 1.85-3.88 mg/dL, respectively. Three neonates showed symptomatic hypocalcemia with calcium levels over 7.5 mg/dL. Among the 16 neonates who underwent electroencephalography (EEG), 12 had abnormalities, which normalized after 1-2 months. Conclusion Formula milk feeding, PTH insufficiency and low serum vitamin D concentration are associated with the development of neonatal hypocalcemia. Symptoms such as tetany and QT interval prolongation can develop in relatively mild hypocalcemia. Moreover, transient neonatal hypocalcemia can cause transient EEG abnormalities. PMID:26191512

Involvement of the cervical sympathetic nervous system in the changes of calcium homeostasis during turpentine oil-induced stress in rats.

PubMed

Stern, J E; Ladizesky, M G; Keller Sarmiento, M I; Cardinali, D P

1993-03-01

Hypocalcemia is a common finding during stress. The objective of this study was to examine: (a) the changes in circulating calcium, parathyroid hormone (PTH) and calcitonin (CT) concentration in rats stressed by being given a subcutaneous injection of turpentine oil, and (b) the involvement of the sympathetic cervical pathway in stress-induced changes of calcium homeostasis. Four hours after receiving turpentine oil or vehicle, rats were subjected either to hypocalcemia, by being given EDTA intraperitoneally, or to hypercalcemia, by being injected CaCl2 intraperitoneally. Significant changes in serum calcium (10% decrease), serum PTH (28% increase) and CT levels (40% decrease) were observed in stressed rats. EDTA administration brought about a significantly greater hypocalcemia, and a higher PTH secretory response in turpentine oil-stressed rats. During stress, the increase of serum calcium after CaCl2 was significantly smaller, and the rise of CT was greater than in controls. In the case of CT the changes were still observed in rats subjected to superior cervical ganglionectomy (SCGx) 14 days earlier. In the case of PTH, the increase found in stressed rats, but not the augmented response after EDTA, was blunted by SCGx. The potentiation of hypocalcemia brought about by turpentine oil was no longer observed in SCGx rats. In vehicle-treated controls, SCGx delayed PTH response to hypocalcemia, but did not affect the increased response of CT to CaCl2 challenge. The results indicate that a number of changes in calcium homeostasis arise during turpentine oil stress in rats. SCGx was effective to modify the set point for PTH release, but played a minor role in affecting the augmentation of CT release during stress.

Serum 25-hydroxyvitamin D3 and body composition in an elderly cohort from Germany: a cross-sectional study

PubMed Central

2012-01-01

Background Emerging evidence indicates that there is an association between vitamin D and obesity. The aim of this study was to investigate whether the level of serum 25-hydroxyvitamin D3 [25(OH)D3] in the elderly is influenced by parameters of anthropometry and body composition independent of potential confounding lifestyle factors and the level of serum intact parathyroid hormone (iPTH). Methods Cross-sectional data of 131 independently living participants (90 women, 41 men; aged 66–96 years) of the longitudinal study on nutrition and health status in senior citizens of Giessen, Germany were analysed. Concentrations of 25(OH)D3 and iPTH were ascertained by an electrochemiluminescence immunoassay. Body composition was measured by a bioelectrical impedance analysis. We performed univariate and multiple regression analyses to examine the influence of body composition on 25(OH)D3 with adjustments for age, iPTH and lifestyle factors. Results In univariate regression analyses, 25(OH)D3 was associated with body mass index (BMI), hip circumference and total body fat (TBF) in women, but not in men. Using multiple regression analyses, TBF was shown to be a negative predictor of 25(OH)D3 levels in women even after controlling for age, lifestyle and iPTH (ß = −0.247; P = 0.016), whereas the associations between BMI, hip circumference and 25(OH)D3 lost statistical significance after adjusting for iPTH. In men, 25(OH)D3 was not affected by anthropometric or body composition variables. Conclusions The results indicate that 25(OH)D3 levels are affected by TBF, especially in elderly women, independent of lifestyle factors and iPTH. PMID:22607088

The role of vitamin D in post-thyroidectomy hypocalcemia: Still an enigma.

PubMed

Cherian, Anish Jacob; Ponraj, Sam; Gowri S, Mahasampath; Ramakant, Pooja; Paul, Thomas V; Abraham, Deepak Thomas; Paul, M J

2016-02-01

There is conflicting evidence regarding the role of vitamin D deficiency in the development of post-thyroidectomy hypocalcemia. Recent reports show postoperative parathormone (PTH) is unreliable in predicting post-thyroidectomy hypocalcemia in vitamin D deficient patients. We conducted this study to analyze the role of vitamin D status in the development of post-thyroidectomy hypocalcemia and to evaluate its effect on the predictability of PTH as a marker for post-thyroidectomy hypocalcemia. A retrospective review of prospectively collected data of patients undergoing thyroidectomy between August 2007 to September 2013 (n = 150) was performed. Results of preoperative calcium, albumin, vitamin D, PTH and postoperative calcium, albumin, and PTH were collated. Patients were divided into 2 groups based on their vitamin D status: group A, vitamin D ≥ 20 ng/mL and group B, vitamin D < 20 ng/mL. Vitamin D deficiency was present in 80 (53.3%) patients and post-thyroidectomy hypocalcemia developed in 67 (44.7%). The incidence of postoperative hypocalcemia was similar in both the groups (48.6% and 41.3%, respectively). Vitamin D status was not associated with the development of post-thyroidectomy hypocalcemia (P = .23). Postoperative PTH of <8 pg/mL was strongly associated with the development of hypocalcemia in both the groups (P = .0002 and .0045, respectively). The area under the receiver operator characteristic curve in group B (0.68) was less than in group A (0.76; P = .41). The majority of patients were vitamin D deficient in this cohort, but this did not increase the risk of post-thyroidectomy hypocalcemia, nor did it interfere with the predictability of PTH as a marker of post-thyroidectomy hypocalcemia. Copyright © 2016 Elsevier Inc. All rights reserved.

[Effect of vitamin D deficiency on hypocalcaemia after total thyroidectomy due to benign goitre].

PubMed

Díez, Manuel; Vera, Cristina; Ratia, Tomás; Diego, Lucía; Mendoza, Fernando; Guillamot, Paloma; San Román, Rosario; Mugüerza, José M; Rodríguez, Angel; Medina, Carlos; Gómez, Beatriz; Granell, Javier

2013-04-01

The purpose of this study was to analyse the relationship between preoperative serum levels of vitamin D and postoperative hypocalcaemia after total thyroidectomy. A prospective observational study was conducted on 113 patients treated by total thyroidectomy due to benign disease. Preoperative vitamin D serum levels and postoperative albumin-corrected calcium and parathormone (PTH) levels were determined. Sensitivity, specificity, positive predictive value and negative predictive value of vitamin D and PTH levels, respectively, in the diagnosis of postoperative hypocalcaemia were calculated. Hypocalcaemia was diagnosed in 44 (38.9%) patients. Vitamin D levels were significantly higher in the group of patients with normal postoperative calcium (median: 25.4pg/mL; range: 4-60), compared to those who developed hypocalcaemia (median: 16.4pg/mL; range: 6.3-46.9) (P=.001). Postoperative hypocalcaemia was more frequent in patients with vitamin D < 30ng/mL (39/78) (50%), than among those with normal levels (5/35) (14.2%) (P=.001). Sensitivity, specificity, positive predictive value and negative predictive value were 88% and 68%, 43% and 82%, 50% and 71%, and 85% and 80% for vitamin D and PTH, respectively. Vitamin D and PTH showed independent prognostic values on the risk of hypocalcaemia. The OR associated with vitamin D < 30ng/mL was 4.25 (95% CI: 1.31-13.78) (P=.016), and the OR of PTH<13pg/mL was 15.4 (95% CI: 4.83-49.1) (P<.001). Vitamin D deficiency is a risk factor of hypocalcaemia after total thyroidectomy for benign goitre. The vitamin D level provides independent prognostic information, which is complementary to that given by PTH. Copyright © 2012 AEC. Published by Elsevier Espana. All rights reserved.

Restoration of parathyroid function after change of phosphate binder from calcium carbonate to lanthanum carbonate in hemodialysis patients with suppressed serum parathyroid hormone.

PubMed

Inaba, Masaaki; Okuno, Senji; Nagayama, Harumi; Yamada, Shinsuke; Ishimura, Eiji; Imanishi, Yasuo; Shoji, Shigeichi

2015-03-01

Control of phosphate is the most critical in the treatment of chronic kidney disease with mineral and bone disorder (CKD-MBD). Because calcium-containing phosphate binder to CKD patients is known to induce adynamic bone disease with ectopic calcification by increasing calcium load, we examined the effect of lanthanum carbonate (LaC), a non-calcium containing phosphate binder, to restore bone turnover in 27 hemodialysis patients with suppressed parathyroid function (serum intact parathyroid hormone [iPTH] ≦ 150 pg/mL). At the initiation of LaC administration, the dose of calcium-containing phosphate binder calcium carbonate (CaC) was withdrawn or reduced based on serum phosphate. After initiation of LaC administration, serum calcium and phosphate decreased significantly by 4 weeks, whereas whole PTH and iPTH increased. A significant and positive correlation between decreases of serum calcium, but not phosphate, with increases of whole PTH and iPTH, suggested that the decline in serum calcium with reduction of calcium load by LaC might increase parathyroid function. Serum bone resorption markers, such as serum tartrate-resistant acid phosphatase 5b, and N-telopeptide of type I collagen increased significantly by 4 weeks after LaC administration, which was followed by increases of serum bone formation markers including serum bone alkaline phosphatase, intact procollagen N-propeptide, and osteocalcin. Therefore, it was suggested that LaC attenuated CaC-induced suppression of parathyroid function and bone turnover by decreasing calcium load. In conclusion, replacement of CaC with LaC, either partially or totally, could increase parathyroid function and resultant bone turnover in hemodialysis patients with serum iPTH ≦ 150 pg/mL. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

CaPTHUS scoring model in primary hyperparathyroidism: can it eliminate the need for ioPTH testing?

PubMed

Elfenbein, Dawn M; Weber, Sara; Schneider, David F; Sippel, Rebecca S; Chen, Herbert

2015-04-01

The CaPTHUS model was reported to have a positive predictive value of 100 % to correctly predict single-gland disease in patients with primary hyperparathyroidism, thus obviating the need for intraoperative parathyroid hormone (ioPTH) testing. We sought to apply the CaPTHUS scoring model in our patient population and assess its utility in predicting long-term biochemical cure. We retrospective reviewed all parathyroidectomies for primary hyperparathyroidism performed at our university hospital from 2003 to 2012. We routinely perform ioPTH testing. Biochemical cure was defined as a normal calcium level at 6 months. A total of 1,421 patients met the inclusion criteria: 78 % of patients had a single adenoma at the time of surgery, 98 % had a normal serum calcium at 1 week postoperatively, and 96 % had a normal serum calcium level 6 months postoperatively. Using the CaPTHUS scoring model, 307 patients (22.5 %) had a score of ≥ 3, with a positive predictive value of 91 % for single adenoma. A CaPTHUS score of ≥ 3 had a positive predictive value of 98 % for biochemical cure at 1 week as well as at 6 months. In our population, where ioPTH testing is used routinely to guide use of bilateral exploration, patients with a preoperative CaPTHUS score of ≥ 3 had good long-term biochemical cure rates. However, the model only predicted adenoma in 91 % of cases. If minimally invasive parathyroidectomy without ioPTH testing had been done for these patients, the cure rate would have dropped from 98 % to an unacceptable 89 %. Even in these patients with high CaPTHUS scores, multigland disease is present in almost 10 %, and ioPTH testing is necessary.

Serum ionized calcium, intact PTH and novel markers of bone turnover in bedridden elderly patients.

PubMed

Sorva, A; Välimäki, M; Risteli, J; Risteli, L; Elfving, S; Takkunen, H; Tilvis, R

1994-12-01

Chronic immobilization could markedly affect calcium and bone metabolism in elderly people. To investigate this, and to test the theory of 'type II' osteoporosis in bedridden elderly patients with low vitamin D status, 55 such subjects were examined. Serum concentrations of ionized calcium (Ca++), intact parathyrin (PTH) and two novel markers of bone collagen formation (carboxyterminal propeptide of type I procollagen; PICP) and resorption (carboxyterminal crosslinked telopeptide of type I collagen; ICTP) were measured. The effects on these parameters after 40 weeks of supplementation with vitamin D (1000 IU d-1) and/or calcium (1 g d-1) were subsequently prospectively evaluated. Despite low (mean 11.6 nmoll-1) serum 25-hydroxyvitamin D levels (25-OHD), those of 1,25-dihydroxy-vitamin D (1,25-(OH)2D) were mostly normal. Neither correlated with Ca++ or PTH. PTH correlated negatively not only with Ca++ (r = -0.328, P < 0.05) but also with ICTP (r = -0.306, P < 0.05). Mean PICP was normal but ICTP was elevated and tended to correlate positively with Ca++ (r = 0.268, P = 0.06). Vitamin D supplementation did not change PICP or ICTP considerably, despite slightly increased 1,25-(OH)2D and slightly decreased PTH. Ca++ values were normal and remained stable. In conclusion, Ca++ and PTH are poor indicators of vitamin D status in chronically immobilized elderly subjects. Furthermore, the results suggest that the increased bone resorption is not due to 'type II' secondary hyperparathyroidism; rather the resorption is primarily increased. Correction of vitamin D deficiency does not seem to benefit ageing bones unless adequate mechanical loading is provided.

Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders.

PubMed

Galassi, Andrea; Spiegel, David M; Bellasi, Antonio; Block, Geoffrey A; Raggi, Paolo

2006-11-01

Vascular calcification and low bone turnover with a relatively low parathyroid hormone (PTH) often coexist in diabetic patients undergoing haemodialysis. Since calcium salts (CaS) are used extensively as primary phosphate binders and have been associated with progressive vascular calcification, we studied the effects of CaS on coronary arteries and parathyroid activity in incident haemodialysis diabetic patients. We measured the change in coronary artery calcium scores (CACS) with sequential electron beam computed tomography (EBCT) in 64 diabetic and 45 non-diabetic patients, randomized to CaS or sevelamer within 90 days of starting haemodialysis. CACS measurements were repeated after 6, 12 and 18 months. Serum intact PTH (iPTH), calcium and phosphorus were serially tested. During the study period, serum phosphate was similar in diabetic and non-diabetic patients. Serum calcium levels were similar at baseline (2.3+/-0.25 mmol/l for both) and increased significantly with CaS treatment (P<0.05) both in diabetic and non-diabetic patients but not with sevelamer. Diabetic patients treated with CaS showed a significantly greater CACS progression than sevelamer-treated patients (median increase 177 vs 27; P=0.05). During follow-up, diabetic patients receiving CaS were significantly more likely to develop serum iPTH values<16 pmol/l than diabetic patients treated with sevelamer (33% vs 6%, P=0.005) and had a lower mean iPTH level (24+/-16 vs 31+/-14 pmol/l; P=0.038). The management of hyperphosphataemia with CaS in haemodialysis diabetic patients is associated with a significantly greater progression of CACS than with sevelamer. These effects are accompanied by iPTH changes suggestive of low bone turnover.

Leptin Is Produced by Parathyroid Glands and Stimulates Parathyroid Hormone Secretion.

PubMed

Hoang, Don; Broer, Niclas; Sosa, Julie A; Abitbol, Nathalie; Yao, Xiaopan; Li, Fangyong; Rivera-Molina, Felix; Toomre, Derek K; Roman, Sanziana A; Sue, Gloria; Kim, Samuel; Li, Alexander Y; Callender, Glenda G; Simpson, Christine; Narayan, Deepak

2017-12-01

We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms. The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones. From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays. Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline. Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

Intermittent PTH treatment can delay the transformation of mature osteoblasts into lining cells on the periosteal surfaces.

PubMed

Jang, Mi-Gyeong; Lee, Ji Yeon; Yang, Jae-Yeon; Park, Hyojung; Kim, Jung Hee; Kim, Jung-Eun; Shin, Chan Soo; Kim, Seong Yeon; Kim, Sang Wan

2016-09-01

Mature osteoblasts have three fates: as osteocytes, quiescent lining cells, or osteoblasts that undergo apoptosis. However, whether intermittent parathyroid hormone (PTH) can modulate the fate of mature osteoblasts in vivo is uncertain. We performed a lineage-tracing study using an inducible gene system. Dmp1-CreERt2 mice were crossed with Rosa26R reporter mice to obtain targeted mature osteoblasts and their descendants, lining cells or osteocytes, which were detected using X-gal staining. Rosa26R:Dmp1-CreERt2(+) mice were injected with 0.25 mg 4-OH-tamoxifen (4-OHTam) on postnatal days 5, 7, 9, 16, and 23. In a previous study, at 22 days after the last 4-OHTam, most LacZ+ cells on the periosteal surface were inactive lining cells. On day 25 (D25), the mice were challenged with an injection of human PTH (1-34, 80 μg/kg) or vehicle daily for 10 (D36) or 20 days (D46). We evaluated the number and thickness of LacZ+ osteoblast descendants in the calvaria and tibia. In the vehicle group, the number and thickness of LacZ+ osteoblast descendants at both D36 and D46 significantly decreased compared to D25, which was attenuated in the PTH group. In line with these results, PTH inhibited the decrease in the number of LacZ+/osteocalcin-positive cells compared to vehicle at both D36 and D46. As well, the serum levels of sclerostin decreased, as did the protein expression of sclerostin in the cortical bone. These results suggest that intermittent PTH treatment can increase the number of periosteal osteoblasts by preventing mature osteoblasts from transforming into lining cells in vivo.

The High Calcium, High Phosphorus Rescue Diet Is Not Suitable to Prevent Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice.

PubMed

Grundmann, Sarah M; Brandsch, Corinna; Rottstädt, Daniela; Kühne, Hagen; Stangl, Gabriele I

2017-01-01

The vitamin D receptor (VDR) knockout (KO) mouse is a common model to unravel novel metabolic functions of vitamin D. It is recommended to feed these mice a high calcium (2%), high phosphorus (1.25%) diet, termed rescue diet (RD) to prevent hypocalcaemia and secondary hyperparathyroidism. First, we characterized the individual response of VDR KO mice to feeding a RD and found that the RD was not capable of normalizing the parathyroid hormone (PTH) concentrations in each VDR KO mouse. In a second study, we aimed to study whether RD with additional 1 and 2% calcium (in total 3 and 4% of the diet) is able to prevent secondary hyperparathyroidism in the VDR KO mice. Wild type (WT) mice and VDR KO mice that received a normal calcium and phosphorus diet (ND) served as controls. Data demonstrated that the RD was no more efficient than the ND in normalizing PTH levels. An excessive dietary calcium concentration of 4% was required to reduce serum PTH concentrations in the VDR KO mice to PTH levels measured in WT mice. This diet, however, resulted in higher concentrations of circulating intact fibroblast growth factor 23 (iFGF23). To conclude, the commonly used RD is not suitable to normalize the serum PTH in VDR KO mice. Extremely high dietary calcium concentrations are necessary to prevent secondary hyperthyroidism in these mice, with the consequence that iFGF23 concentrations are being raised. Considering that PTH and iFGF23 exert numerous VDR independent effects, data obtained from VDR KO mice cannot be attributed solely to vitamin D.

The mode of inhibitor binding to peptidyl-tRNA hydrolase: binding studies and structure determination of unbound and bound peptidyl-tRNA hydrolase from Acinetobacter baumannii.

PubMed

Kaushik, Sanket; Singh, Nagendra; Yamini, Shavait; Singh, Avinash; Sinha, Mau; Arora, Ashish; Kaur, Punit; Sharma, Sujata; Singh, Tej P

2013-01-01

The incidences of infections caused by an aerobic Gram-negative bacterium, Acinetobacter baumannii are very common in hospital environments. It usually causes soft tissue infections including urinary tract infections and pneumonia. It is difficult to treat due to acquired resistance to available antibiotics is well known. In order to design specific inhibitors against one of the important enzymes, peptidyl-tRNA hydrolase from Acinetobacter baumannii, we have determined its three-dimensional structure. Peptidyl-tRNA hydrolase (AbPth) is involved in recycling of peptidyl-tRNAs which are produced in the cell as a result of premature termination of translation process. We have also determined the structures of two complexes of AbPth with cytidine and uridine. AbPth was cloned, expressed and crystallized in unbound and in two bound states with cytidine and uridine. The binding studies carried out using fluorescence spectroscopic and surface plasmon resonance techniques revealed that both cytidine and uridine bound to AbPth at nanomolar concentrations. The structure determinations of the complexes revealed that both ligands were located in the active site cleft of AbPth. The introduction of ligands to AbPth caused a significant widening of the entrance gate to the active site region and in the process of binding, it expelled several water molecules from the active site. As a result of interactions with protein atoms, the ligands caused conformational changes in several residues to attain the induced tight fittings. Such a binding capability of this protein makes it a versatile molecule for hydrolysis of peptidyl-tRNAs having variable peptide sequences. These are the first studies that revealed the mode of inhibitor binding in Peptidyl-tRNA hydrolases which will facilitate the structure based ligand design.

Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol.

PubMed

Glendenning, Paul; Chew, Gerard T; Seymour, Hannah M; Gillett, Melissa J; Goldswain, Peter R; Inderjeeth, Charles A; Vasikaran, Samuel D; Taranto, Mario; Musk, Alexander A; Fraser, William D

2009-11-01

Vitamin D insufficiency is commonly associated with hip fracture. However, the equipotency of ergocalciferol and cholecalciferol supplementation in this patient group has not been studied in a randomized trial using high-performance liquid chromatography (HPLC) measurement of serum 25-hydroxyvitamin D (25OHD). The objective of this study was to determine if ergocalciferol and cholecalciferol are equipotent therapies in vitamin D-insufficient hip fracture patients. Ninety five hip fracture inpatients with vitamin D insufficiency (25OHD<50 nmol/L) were randomized, double-blind, to treatment with ergocalciferol 1000 IU/day (n=48) or cholecalciferol 1000 IU/day (n=47) for three months. All participants were also given a placebo matching the alternative treatment to maintain blinding of treatment allocation. The primary endpoint was total serum 25OHD measured by HPLC. Secondary endpoints included 25OHD measured by radioimmunoassay (RIA), intact parathyroid hormone (iPTH), and bioactive (1-84) whole PTH (wPTH). Seventy patients (74%) completed the study with paired samples for analysis. Cholecalciferol supplementation resulted in a 31% greater increase in total HPLC-measured 25OHD (p=0.010) and 52% greater rise in RIA-measured 25OHD (p<0.001) than supplementation with an equivalent dose of ergocalciferol. Changes in iPTH and wPTH were not significantly different between calciferol treatments (p>0.05). In vitamin D-insufficient hip fracture patients, supplementation with cholecalciferol 1000 IU/day for three months was more effective in increasing serum 25OHD than an equivalent dose of ergocalciferol. However, the lack of difference in PTH lowering between calciferol treatments raises questions about the biological importance of this observation.

Calcium-phosphate and parathyroid intradialytic profiles: A potential aid for tailoring the dialysate calcium content of patients on different hemodialysis schedules.

PubMed

Ferraresi, Martina; Pia, Anna; Guzzo, Gabriella; Vigotti, Federica Neve; Mongilardi, Elena; Nazha, Marta; Aroasio, Emiliano; Gonella, Cinzia; Avagnina, Paolo; Piccoli, Giorgina Barbara

2015-10-01

Severe hyperparathyroidism is a challenge on hemodialysis. The definition of dialysate calcium (Ca) is a pending issue with renewed importance in cases of individualized dialysis schedules and of portable home dialysis machines with low-flow dialysate. Direct measurement of calcium mass transfer is complex and is imprecisely reflected by differences in start-to-end of dialysis Ca levels. The study was performed in a dialysis unit dedicated to home hemodialysis and to critical patients with wide use of daily and tailored schedules. The Ca-phosphate (P)-parathyroid hormone (PTH) profile includes creatinine, urea, total and ionized Ca, albumin, sodium, potassium, P, PTH levels at start, mid, and end of dialysis. "Severe" secondary hyperparathyroidism was defined as PTH > 300 pg/mL for ≥3 months. Four schedules were tested: conventional dialysis (polysulfone dialyzer 1.8-2.1 m(2) ), with dialysate Ca 1.5 or 1.75 mmol/L, NxStage (Ca 1.5 mmol/L), and NxStage plus intradialytic Ca infusion. Dosages of vitamin D, calcium, phosphate binders, and Ca mimetic agents were adjusted monthly. Eighty Ca-P-PTH profiles were collected in 12 patients. Serum phosphate was efficiently reduced by all techniques. No differences in start-to-end PTH and Ca levels on dialysis were observed in patients with PTH levels < 300 pg/mL. Conversely, Ca levels in "severe" secondary hyperparathyroid patients significantly increased and PTH decreased during dialysis on all schedules except on Nxstage (P < 0.05). Our data support the need for tailored dialysate Ca content, even on "low-flow" daily home dialysis, in "severe" secondary hyperparathyroid patients in order to increase the therapeutic potentials of the new dialysis techniques. © 2015 International Society for Hemodialysis.

Differences in the prevalence of vitamin D deficiency and hip fractures in nursing home residents and independently living elderly.

PubMed

Shinkov, Alexander; Borissova, Anna-Maria; Dakovska, Lilia; Vlahov, Jordan; Kassabova, Lidia; Svinarov, Dobrin; Krivoshiev, Stefan

2016-02-23

To compare the prevalence of vitamin D deficiency and fracture history in nursing home residents and community-dwelling elderly subjects and to explore the association of vitamin D levels with various characteristics. Sixty-six nursing home residents and 139 community-dwelling elderly subjects participated. Marital status, medical history, medication including vitamin D supplements, smoking, past fractures were assessed. Weight and height were measured and body mass index calculated. Serum 25-hydroxyvitamin D (25-OHD), PTH, Ca, phosphate, creatinine and eGFR were determined. In the nursing home residents 25-OHD was lower (17.8 nmol/l, [9.4-28.6] vs. 36.7 nmol/l, [26.9-50], p < 0.001), PTH was higher (5.6 pmol/l, [3.9-8.9] vs. 4.7 pmol/l [3.6-5.8], P = 0.003) and 25-OHD deficiency was more prevalent (65.2% [53.7-76.7] vs. 22.3% [15.4-29.2], p < 0.001) as was elevated PTH (23% [12.8-33] vs. 5.8% [2-10], p = 0.001). 25-OHD correlated negatively with PTH (institutionalized r = -0.28, p = 0.025 and community-dwelling r = -0.36, p < 0.001). Hip fractures were reported by 8% of the residents and 2% of the independent elderly. The only predictor for hip fracture was elevated PTH (OR = 7.6 (1.5-36.9), p = 0.013). The prevalence of vitamin D deficiency and secondary hyperparathyroidism was high in the institutionalized subjects. Hip fracture risk was associated with elevated PTH and not directly with vitamin D levels or the residency status.

[Corrosion resistant properties of different anodized microtopographies on titanium surfaces].

PubMed

Fangjun, Huo; Li, Xie; Xingye, Tong; Yueting, Wang; Weihua, Guo; Weidong, Tian

2015-12-01

To investigate the corrosion resistant properties of titanium samples prepared by anodic oxidation with different surface morphologies. Pure titanium substrates were treated by anodic oxidation to obtain porous titanium films in micron, submicron, and micron-submicron scales. The surface morphologies, coating cross-sectional morphologies, crystalline structures, and surface roughness of these samples were characterized. Electrochemical technique was used to measure the corrosion potential (Ecorr), current density of corrosion (Icorr), and polarization resistance (Rp) of these samples in a simulated body fluid. Pure titanium could be modified to exhibit different surface morphologies by the anodic oxidation technique. The Tafel curve results showed that the technique can improve the corrosion resistance of pure titanium. Furthermore, the corrosion resistance varied with different surface morphologies. The submicron porous surface sample demonstrated the best corrosion resistance, with maximal Ecorr and Rp and minimal Icorr. Anodic oxidation technology can improve the corrosion resistance of pure titanium in a simulated body fluid. The submicron porous surface sample exhibited the best corrosion resistance because of its small surface area and thick barrier layer.

The FGF-23/klotho axis and its relationship with phosphorus, calcium, vitamin D, PTH, aldosterone, severity of disease, and outcome in hospitalised foals.

PubMed

Kamr, A M; Dembek, K A; Hildreth, B E; Morresey, P R; Rathgeber, R A; Burns, T A; Zaghawa, A A; Toribio, R E

2018-04-16

Fibroblast growth factor-23 (FGF-23) and klotho are key regulators of vitamin D and parathyroid hormone (PTH) synthesis as well as phosphorus and calcium homeostasis; however, information on the FGF-23/klotho axis in healthy and hospitalised foals is lacking. The aims of this study were to measure serum FGF-23 and klotho concentrations and determine their association with serum phosphorus, total calcium (TCa), vitamin D metabolite [25(OH)D, 1,25(OH) 2 D], PTH, and aldosterone concentrations, disease severity, and mortality in hospitalised foals. Prospective, multicentre, cross-sectional study. A total of 91 foals ≤72 h old were classified as hospitalised (n = 81; 58 septic; 23 sick non-septic [SNS]) and healthy (n = 10). Blood samples were collected on admission. Hormone concentrations were determined by immunoassays. Serum FGF-23, PTH, phosphorus, and aldosterone concentrations were higher while klotho, 25(OH)D, 1,25(OH) 2 D, and TCa concentrations were lower in septic and SNS compared to healthy foals (P<0.05). In hospitalised and septic foals, increased FGF-23 and aldosterone concentrations were associated with high phosphorus and PTH but not with TCa and vitamin D metabolite concentrations. Hospitalised foals with the highest FGF-23 and lowest klotho concentrations were more likely to die (odds ratio (OR): 3.3; 95% confidence interval (CI): 1.1-10.3 and OR: 3.1; CI: 1.1-8.0, respectively). Blood gas, ionised calcium, blood culture information not being available for many foals, and use of the sepsis score to classify hospitalised foals. Imbalances in the FGF-23/klotho axis may contribute to mineral dyshomeostasis and disease progression in critically ill foals. Elevated FGF-23 and reduced klotho, together with high phosphorus and PTH concentrations suggests FGF-23 resistance. FGF-23 and klotho are good markers of disease severity and likelihood of mortality in hospitalised foals. Aldosterone may influence phosphorus and PTH dynamics in hospitalised foals. Routine measurement of phosphorus concentrations in sick foals is recommended. © 2018 EVJ Ltd.

Current Nomenclature of Pseudohypoparathyroidism: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein Signaling Disorder

PubMed Central

Turan, Serap

2017-01-01

Disorders related to parathyroid hormone (PTH) resistance and PTH signaling pathway impairment are historically classified under the term of pseudohypoparathyroidism (PHP). The disease was first described and named by Fuller Albright and colleagues in 1942. Albright hereditary osteodystrophy (AHO) is described as an associated clinical entity with PHP, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. The classification of PHP is further divided into PHP-Ia, pseudo-PHP (pPHP), PHP-Ib, PHP-Ic and PHP-II according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gsα protein activity in peripheral erythrocyte membranes in vitro. However, PHP classification fails to differentiate all patients with different clinical and molecular findings for PHP subtypes and classification become more complicated with more recent molecular characterization and new forms having been identified. So far, new classifications have been established by the EuroPHP network to cover all disorders of the PTH receptor and its signaling pathway. Inactivating PTH/PTH-related protein signaling disorder (iPPSD) is the new name proposed for a group of these disorders and which can be further divided into subtypes - iPPSD1 to iPPSD6. These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gsα mutations (PHP-Ia, PHP-Ic and pPHP) as iPPSD2, loss of methylation of GNAS DMRs (PHP-Ib) as iPPSD3, PRKAR1A mutations (acrodysostosis type 1) as iPPSD4, PDE4D mutations (acrodysostosis type 2) as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. iPPSDx is reserved for unknown molecular defects and iPPSDn+1 for new molecular defects which are yet to be described. With these new classifications, the aim is to clarify the borders of each different subtype of disease and make the classification according to molecular pathology. The iPPSD group is designed to be expandable and new classifications will readily fit into it as necessary. PMID:29280743

Current Nomenclature of Pseudohypoparathyroidism: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein Signaling Disorder.

PubMed

Turan, Serap

2017-12-30

Disorders related to parathyroid hormone (PTH) resistance and PTH signaling pathway impairment are historically classified under the term of pseudohypoparathyroidism (PHP). The disease was first described and named by Fuller Albright and colleagues in 1942. Albright hereditary osteodystrophy (AHO) is described as an associated clinical entity with PHP, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. The classification of PHP is further divided into PHP-Ia, pseudo-PHP (pPHP), PHP-Ib, PHP-Ic and PHP-II according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gsα protein activity in peripheral erythrocyte membranes in vitro. However, PHP classification fails to differentiate all patients with different clinical and molecular findings for PHP subtypes and classification become more complicated with more recent molecular characterization and new forms having been identified. So far, new classifications have been established by the EuroPHP network to cover all disorders of the PTH receptor and its signaling pathway. Inactivating PTH/PTH-related protein signaling disorder (iPPSD) is the new name proposed for a group of these disorders and which can be further divided into subtypes - iPPSD1 to iPPSD6. These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gsα mutations (PHP-Ia, PHP-Ic and pPHP) as iPPSD2, loss of methylation of GNAS DMRs (PHP-Ib) as iPPSD3, PRKAR1A mutations (acrodysostosis type 1) as iPPSD4, PDE4D mutations (acrodysostosis type 2) as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. iPPSDx is reserved for unknown molecular defects and iPPSDn+1 for new molecular defects which are yet to be described. With these new classifications, the aim is to clarify the borders of each different subtype of disease and make the classification according to molecular pathology. The iPPSD group is designed to be expandable and new classifications will readily fit into it as necessary.

Surface modification of porous titanium with rice husk as space holder

NASA Astrophysics Data System (ADS)

Wang, Xinsheng; Hou, Junjian; Liu, Yanpei

2018-06-01

Porous titanium was characterized after its surface modification by acid and alkali solution immersion. The results show that the acid surface treatment caused the emergence of flocculent sodium titanate and induced apatite formation. The surface modification of porous titanium promotes biological activation, and the application of porous titanium is also improved as an implant material because of the existence of C and Si.

Effects of silicon coating on bond strength of two different titanium ceramic to titanium.

PubMed

Ozcan, Isil; Uysal, Hakan

2005-08-01

This study investigated the effect of silicon coating (SiO2) by magnetron sputtering on bond strength of two different titanium ceramics to titanium. Sixty cast titanium specimens were prepared following the protocol ISO 9693. Titanium specimens were divided into two test and control groups with 15 specimens in each. Test groups were silicon coated by the magnetron sputtering technique. Two titanium ceramics (Triceram and Duceratin) were applied on both test (coated) and control (uncoated) metal specimens. The titanium-ceramic specimens were subjected to a three point flexural test. The groups were compared for their bond strength. SEM and SEM/EDS analyses were performed on the delaminated titanium surfaces to ascertain bond failure. The mean bond strength of Ti-Duceratin, Ti-Triceram, Si-coated Ti-Duceratin and Si-coated Ti-Triceram were 17.22+/-2.43, 23.31+/-3.18, 23.21+/-3.81 and 24.91+/-3.70 MPa, respectively. While the improvement in bond strength was 30% for Duceratin, it was statistically insignificant for Triceram. An adhesive mode of failure was observed in the Duceratin control group. In the silicoated Duceratin specimen, the bonded ceramic boundaries were wider but less than in the silicoated Triceram specimen. In the coated Triceram specimen, the ceramic retained areas were frequent and the failure mode was generally cohesive. Silicon coating was significantly effective in both preventing titanium oxide layer formation and in improving bond strength for Duceratin. However, it was of less value for Triceram.

Mechanisms of Renal Phosphate Loss in Liver Resection-Associated Hypophosphatemia

PubMed Central

Nafidi, Otmane; Lapointe, Real W.; Lepage, Raymond; Kumar, Rajiv; D’Amour, Pierre

2014-01-01

Objective To determine precisely the role of parathyroid hormone (PTH) and of phosphatonins in the genesis of posthepatectomy hypophosphatemia. Background Posthepatectomy hypophosphatemia has recently been related to increased renal fractional excretion of phosphate (FE P). To address the cause of hypophosphatemia, we measured serum concentrations of PTH, various phosphatonins, and the number of removed hepatic segment in patients with this disorder. Methods Serum phosphate (PO4), ionized calcium (Ca++), HCO3−, pH and FE P, intact PTH (I-PTH), carboxyl-terminal fibroblast growth factor 23 (C-FGF-23) and intact fibroblast growth factor 23 (I-FGF-23), FGF-7, and secreted frizzled related-protein-4 (sFRP-4) were measured before and on postoperative (po) days 1, 2, 3, 5, and 7, in 18 patients undergoing liver resection. The number of removed hepatic segments was also assessed. Results Serum PO4 concentrations decreased within 24 hours, were lowest (0.66 ± 0.03 mmol/L; P < 0.001) at 48 hours, and returned to normal within 5 days of the procedure. FE P peaked at 25.07% ± 2.26% on po day 1 (P < 0.05). Decreased ionized calcium concentrations (1.10 ± 0.01 mmol/L; P < 0.01) were observed on po day 1 and were negatively correlated with increased I-PTH concentrations (8.8 ± 0.9 pmol/L; P < 0.01; correlation: r = −0.062, P = 0.016). FE P was positively related to I-PTH levels on po day 1 (r = 0.52, P = 0.047) and negatively related to PO4 concentrations (r = −0.56, P = 0.024). Severe hypophosphatemia and increased urinary phosphate excretion persisted for 72 hours even when I-PTH concentrations had returned to normal. I-FGF-23 decreased to its nadir of 7.8 ± 6.9 pg/mL (P < 0.001) on po day 3 and was correlated with PO4 levels on po days 0, 3, 5, and 7 (P < 0.001). C-FGF-23, FGF-7 and sFRP-4 levels could not be related to either PO4 concentrations or FE P. Conclusion Posthepatectomy hypophosphatemia is associated with increased FE P unrelated to I-FGF-23 or C-FGF-23, FGF-7, or sFRP-4. I-PTH contributes to excessive FE P partially on po day 1 but not thereafter. Other yet defined factors should explain post hepatectomy hypophosphatemia. PMID:19387319

Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German substudy.

PubMed

Hadji, P; Kauka, A; Bauer, T; Tams, J; Hasenburg, A; Kieback, D G

2012-10-01

The aim of this study was to compare the effects of exemestane and tamoxifen on hormone levels in postmenopausal patients with hormone receptor-positive breast cancer within a Germany substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Within the TEAM trial, patients were randomized to receive adjuvant treatment with exemestane for 5 years or tamoxifen for 2.5-3 years followed by exemestane for 2-2.5 years. Serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormone (PTH)-intact were measured at screening and after 3, 6 and 12 months of treatment. Data on hormone levels were available from 63 patients in the tamoxifen arm and 68 patients in the exemestane arm. Treatment with exemestane resulted in decreases from baseline in SHBG and PTH-intact levels, and increases from baseline in testosterone, DHEAS and FSH levels. Tamoxifen treatment resulted in increases from baseline in SHBG and PTH-intact, whereas levels of testosterone and FSH decreased and DHEAS levels did not change. At all time points assessed, the absolute change from baseline was significantly different between tamoxifen and exemestane for testosterone, SHBG, FSH and PTH-intact (all p < 0.0001). Exemestane and tamoxifen had statistically significantly different effects on hormone levels, including testosterone, SHBG, FSH and PTH-intact.

Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis.

PubMed

Wesseling-Perry, Katherine; Pereira, Renata C; Wang, Hejing; Elashoff, Robert M; Sahney, Shobha; Gales, Barbara; Jüppner, Harald; Salusky, Isidro B

2009-02-01

Fibroblast growth factor (FGF)-23 is produced in bone, and circulating levels are markedly elevated in patients with end-stage kidney disease, but the relationship between plasma levels of FGF-23 and bone histology in dialysis patients with secondary hyperparathyroidism is unknown. The aim of the study was to evaluate the correlation between plasma levels of FGF-23 and bone histology in pediatric patients with end-stage kidney disease who display biochemical evidence of secondary hyperparathyroidism. We performed a cross-sectional analysis of the relationship between plasma FGF-23 levels and bone histomorphometry. The study was conducted in a referral center. Participants consisted of forty-nine pediatric patients who were treated with maintenance peritoneal dialysis and who had serum PTH levels (1st generation Nichols assay) greater than 400 pg/ml. There were no interventions. Plasma FGF-23 levels and bone histomorphometry were measured. No correlation existed between values of PTH and FGF-23. Bone formation rates correlated with PTH (r = 0.44; P < 0.01), but not with FGF-23. Higher FGF-23 concentrations were associated with decreased osteoid thickness (r = -0.49; P < 0.01) and shorter osteoid maturation time (r = -0.48; P < 0.01). High levels of FGF-23 are associated with improved indices of skeletal mineralization in dialyzed pediatric patients with high turnover renal osteodystrophy. Together with other biomarkers, FGF-23 measurements may indicate skeletal mineralization status in this patient population.

[Questions about the ADVANCE study].

PubMed

Jean, Guillaume; Chazot, Charles

2012-06-01

The symptoms of secondary hyperparathyroidism (SHPT) were substantially changed by the availability of cinacalcet (CC). The recent ADVANCE study, which was a prospective randomized trial comparing two treatment strategies-CC plus low doses of calcitriol analogues (CA) versus higher doses of CA without CC-reports the absence of difference in the primary endpoint, i.e. coronary artery calcification score progression after 12 months. The progression of coronary calcification was related to the initial hypercalcemia and hyperphosphataemia, and low serum PTH level. What was the rationale for defining SHPT with only serum PTH value of more than 300 pg/mL or more than 150 pg/mL associated with a high Ca×P product? Why was this coronary score chosen as the primary endpoint and why was a seemingly short observational period used? Is it correct to consider all forms of SHPT equivalent in terms of set point, response to conventional treatment, or vascular and bone consequences? Why are the biological values of patients not provided? Were the CAs, dialysate calcium, and PTH assay values really equal? Why were only calcium-based phosphate binders used? The main controversial point of the study was to consider all HPT cases as equivalent and able to be treated by one fixed strategy. Therefore, the nephrologist community should conduct relevant independent studies in order to improve the diagnosis and treatment of SHPT. Copyright © 2011 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

Serum 25-hydroxyvitamin D and parathyroid hormone in patients with ankylosing spondylitis before and after a three-week rehabilitation treatment at high altitude during winter and spring.

PubMed

Falkenbach, A; Tripathi, R; Sedlmeyer, A; Staudinger, M; Herold, M

2001-04-30

Does a sojourn at high altitude during the winter and spring improve vitamin D status (and possibly suppress parathyroid hormone [PTH]) in patients with ankylosing spondylitis (AS)? In 73 patients with AS, serum concentrations of 25-hydroxy-vitamin D [25(OH)D] and PTH were determined before and after a three-week rehabilitation treatment at Bad Gastein (1000 m above sea level). At the first examination, serum 25(OH)D was median (25th, 75th percentile) 15.5 ng mL-1 (10.0 ng mL-1, 20.6 ng mL-1). Thirteen patients (18%) had a 25(OH)D concentration below 8 ng mL-1. In 53 patients (73%) the level was below 20 ng mL-1. After the sojourn, 25(OH)D significantly (p = 0.02) increased to 19.7 (11.3, 24.6) ng mL-1. PTH did not change significantly, being 32 (22.4, 43.9) pg mL-1 before and 30.3 (24.1, 39.9) pg mL-1 after the sojourn. Analysing different periods of sojourn, a significant (p < 0.001) increase in 25(OH)D was found in April but not in the other months. Patients with ankylosing spondylitis may have extremely low levels of 25(OH)D. The results of the present study suggest that a sojourn at high altitude in early spring is liable to reduce vitamin D deficiency.

[Cinacalcet in the management of normocalcaemic secondary hyperparathyroidism after kidney transplantation: one-year follow-up multicentre study].

PubMed

Torregrosa, Josep V; Morales, Enrique; Díaz, Juan M; Crespo, Josep; Bravo, Juan; Gómez, Gonzalo; Gentil, Miguel A; Rodríguez-Benot, Alberto; Rodríguez-García, Minerva; López-Jiménez, Verónica; Gutiérrez-Dalmau, Álex; Jimeno, Luisa; Pérez-Sáez, M José; Romero, Rafael; Gómez-Alamillo, Carlos

2014-01-01

The effect of cinacalcet in patients with persistent secondary hyperparathyroidism (SHPT) after kidney transplantation (RT) has mainly been reported in patients with secondary hypercalcaemia. Our objective was to assess the long-term effect of cinacalcet on patients with a RT and normocalcaemic SHPT. A one-year multicentre, observational, retrospective study that included kidney recipients with SHPT (intact parathyroid hormone [iPTH] >120 pg/ml) and calcium levels within the normal range (8.4-10.2 mg/dl). Patients began treatment with cinacalcet in clinical practice. 32 patients with a mean age (standard deviation [SD]) of 54 (11) years, 56% male, were included in the study. Treatment with cinacalcet began a median of 16 months after RT (median dose of 30 mg/day). Levels of iPTH decreased from a median (P25, P75) of 364 (220, 531) pg/ml at the start of the study to 187 (98, 320) after 6 months (48.6% reduction, P=.001) and to 145 (91, 195) after 12 months (60.2% reduction, P=.001), without there being changes in calcium and phosphorus levels (P=.214 and P=.216, respectively). No changes were observed in kidney function or anti-calcineuric drug levels. 3.1% of patients discontinued cinacalcet due to intolerance and 6.2% due to a lack of efficacy. In patients with normocalcaemic SHPT after RT, cinacalcet improves the control of serum PTH values without causing changes to calcaemia, phosphataemia or kidney function. Cinacalcet showed good tolerability.

Review: Microstructure Engineering of Titanium Alloys via Small Boron Additions (Preprint)

DTIC Science & Technology

2011-07-01

small amount of boron to γ titanium aluminides (TiAl) has been found to improve room temperature ductility [12]. The principal effect of boron...AFRL-RX-WP-TP-2011-4298 REVIEW: MICROSTRUCTURE ENGINEERING OF TITANIUM ALLOYS VIA SMALL BORON ADDITIONS (Preprint) D.B. Miracle...2011 Journal Article Preprint 01 July 2011 – 01 July 2011 4. TITLE AND SUBTITLE REVIEW: MICROSTRUCTURE ENGINEERING OF TITANIUM ALLOYS VIA SMALL

The effect of vacuum annealing on corrosion resistance of titanium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chikanov, V.N.; Peshkov, V.V.; Kireev, L.S.

1994-09-01

The effect of annealing on the corrosion resistance of OT4-1 sheet titanium in 25% HCl under various air pressures and self-evacuating conditions has been investigated. From the kinetic corrosion curves it follows that the least corrosion resistance of titanium is observed after vacuum annealing. Even low residual air pressure in a chamber improves corrosion resistance. The corrosion resistance of titanium decreases with vacuum-annealing time.

Method for Surface Texturing Titanium Products

NASA Technical Reports Server (NTRS)

Banks, Bruce A. (Inventor)

1998-01-01

The present invention teaches a method of producing a textured surface upon an arbitrarily configured titanium or titanium alloy object for the purpose of improving bonding between the object and other materials such as polymer matrix composites and/or human bone for the direct in-growth of orthopaedic implants. The titanium or titanium alloy object is placed in an electrolytic cell having an ultrasonically agitated solution of sodium chloride therein whereby a pattern of uniform "pock mark" like pores or cavities are produced upon the object's surface. The process is very cost effective compared to other methods of producing rough surfaces on titanium and titanium alloy components. The surface textures produced by the present invention are etched directly into the parent metal at discrete sites separated by areas unaffected by the etching process. Bonding materials to such surface textures on titanium or titanium alloy can thus support a shear load even if adhesion of the bonding material is poor.

REDUCING TITANIUM TETRACHLORIDE WITH HIGH-SURFACE SODIUM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fleck, D.C.; Wong, M.M.; Baker, D.H. Jr.

1960-01-01

A method of using sodium for reducing titanium tetrachloride, developed to improve the extractive metallurgy of titunium, is described. Finely divided titanium metal, titanium lower chlorides, or a mixture thereof was produced in a continuous operation at temperatures between 105 and 205 deg C by the reaction of molten sodium and vaporized titanium tetrachloride in an agitated bed of finely divided inert solids (powdered sodium chloride or the reaction products). Composition of the product was controlled by varying the relative quantities of sodium and titanium tetrachloride used. A description of the operations and analytical data of the reaction products aremore » given. (auth)« less

An improved biofunction of titanium for keratoprosthesis by hydroxyapatite-coating.

PubMed

Dong, Ying; Yang, Jingxin; Wang, Liqiang; Ma, Xiao; Huang, Yifei; Qiu, Zhiye; Cui, Fuzhai

2014-03-01

Titanium framework keratoprosthesis has been commonly used in the severe corneal blindness, but the tissue melting occurred frequently around titanium. Since hydroxyapatite has been approved to possess a good tissue integration characteristic, nanostructured hydroxyapatite was coated on the surface of titanium through the aerosol deposition method. In this study, nanostructured hydroxyapatite coating was characterized by X-ray diffraction, scanning electron microscopy, atomic force microscopy, and auger electronic spectrometer. Biological evaluations were performed with rabbit cornea fibroblast in vitro and an animal model in vivo. The outcomes showed the coating had a grain-like surface topography and a good atomic mixed area with substrate. The rabbit cornea fibroblasts appeared a good adhesion on the surface of nanostructured hydroxyapatite in vitro. In the animal model, nanostructured hydroxyapatite-titanium implants were stably retained in the rabbit cornea, and by contrast, the corneal stroma became thinner anterior to the implants in the control. Therefore, our findings proved that nanostructured hydroxyapatite-titanium could not only provide an improved bond for substrate but also enhance the tissue integration with implants in host. As a promising material, nanostructured hydroxyapatite-titanium-based keratoprosthesis prepared by the aerosol deposition method could be utilized for the corneal blindness treatment.

Immobilization of TiO 2 nanofibers on titanium plates for implant applications

NASA Astrophysics Data System (ADS)

Lim, Jin Ik; Yu, Bin; Woo, Kyung Mi; Lee, Yong-Keun

2008-12-01

Nanofibers have shown good biological performances such as improved cell adhesion and differentiation; therefore, nanofibrous modification of dental and bone implants might enhance osseo-integration. The purpose of this study was to investigate the nanofibrous modification of titanium implants. TiO 2 nanofibers were fabricated by the electrospinning method using a mixture of Ti(IV)isopropoxide and poly(vinyl pyrrolidone) (PVP) in acidic alcohol solution. Then the nanofibers were immobilized on the NaOH/HCl-treated titanium plates by inducing the alcohol condensation reaction of Ti(IV)isopropoxide with Ti-OH group on the titanium surface and subsequent calcination (500-1000 °C). The immobilized TiO 2 nanofibers were characterized by SEM, XRD and a simulated removal test. The diameter of the TiO 2 nanofibers could be controlled within the range of 20-350 nm by changing the amounts of Ti(IV)isopropoxide and PVP. Phase transformation from anatase to rutile was observed after calcination. After the simulated removal test, TiO 2 nanofibers remained on titanium surface. These TiO 2 nanofibers on titanium plates could be used for the surface modification of titanium implants to improve the osseo-integration.

Cell-laden hydrogel/titanium microhybrids: Site-specific cell delivery to metallic implants for improved integration.

PubMed

Koenig, Geraldine; Ozcelik, Hayriye; Haesler, Lisa; Cihova, Martina; Ciftci, Sait; Dupret-Bories, Agnes; Debry, Christian; Stelzle, Martin; Lavalle, Philippe; Vrana, Nihal Engin

2016-03-01

Porous titanium implants are widely used in dental, orthopaedic and otorhinolaryngology fields to improve implant integration to host tissue. A possible step further to improve the integration with the host is the incorporation of autologous cells in porous titanium structures via cell-laden hydrogels. Fast gelling hydrogels have advantageous properties for in situ applications such as localisation of specific cells and growth factors at a target area without dispersion. The ability to control the cell types in different regions of an implant is important in applications where the target tissue (i) has structural heterogeneity (multiple cell types with a defined spatial configuration with respect to each other); (ii) has physical property gradients essential for its function (such as in the case of osteochondral tissue transition). Due to their near immediate gelation, such gels can also be used for site-specific modification of porous titanium structures, particularly for implants which would face different tissues at different locations. Herein, we describe a step by step design of a model system: the model cell-laden gel-containing porous titanium implants in the form of titanium microbead/hydrogel (maleimide-dextran or maleimide-PVA based) microhybrids. These systems enable the determination of the effect of titanium presence on gel properties and encapsulated cell behaviour as a miniaturized version of full-scale implants, providing a system compatible with conventional analysis methods. We used a fibroblast/vascular endothelial cell co-cultures as our model system and by utilising single microbeads we have quantified the effect of gel microenvironment (degradability, presence of RGD peptides within gel formulation) on cell behaviour and the effect of the titanium presence on cell behaviour and gel formation. Titanium presence slightly changed gel properties without hindering gel formation or affecting cell viability. Cells showed a preference to move towards the titanium beads and fibroblast proliferation was significantly higher in hybrids compared to gel only controls. The MMP (Matrix Metalloproteinase)-sensitive hydrogels induced sprouting by cells in co-culture configuration which was quantified by fluorescence microscopy, confocal microscopy and qRT-PCR (Quantitative Reverse transcription polymerase chain reaction). When the microhybrid up-scaled to 3D thick structures, cellular localisation in specific areas of the 3D titanium structures was achieved, without decreasing overall cell proliferation compared to titanium only scaffolds. Microhybrids of titanium and hydrogels are useful models for deciding the necessary modifications of metallic implants and they can be used as a modelling system for the study of tissue/titanium implant interactions. This article demonstrates a method to apply cell-laden hydrogels to porous titanium implants and a model of titanium/hydrogel interaction at micro-level using titanium microbeads. The feasibility of site-specific modification of titanium implants with cell-laden microgels has been demonstrated. Use of titanium microbeads in combination with hydrogels with conventional analysis techniques as described in the article can facilitate the characterisation of surface modification of titanium in a relevant model system. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Heat treated 9 Cr-1 Mo steel material for high temperature application

DOEpatents

Jablonski, Paul D.; Alman, David; Dogan, Omer; Holcomb, Gordon; Cowen, Christopher

2012-08-21

The invention relates to a composition and heat treatment for a high-temperature, titanium alloyed, 9 Cr-1 Mo steel exhibiting improved creep strength and oxidation resistance at service temperatures up to 650.degree. C. The novel combination of composition and heat treatment produces a heat treated material containing both large primary titanium carbides and small secondary titanium carbides. The primary titanium carbides contribute to creep strength while the secondary titanium carbides act to maintain a higher level of chromium in the finished steel for increased oxidation resistance, and strengthen the steel by impeding the movement of dislocations through the crystal structure. The heat treated material provides improved performance at comparable cost to commonly used high-temperature steels such as ASTM P91 and ASTM P92, and requires heat treatment consisting solely of austenization, rapid cooling, tempering, and final cooling, avoiding the need for any hot-working in the austenite temperature range.

Increase in serum magnesium level in haemodialysis patients receiving sevelamer hydrochloride.

PubMed

Mitsopoulos, Efstathios; Griveas, Ioannis; Zanos, Stavros; Anagnostopoulos, Konstantinos; Giannakou, Anastasia; Pavlitou, Aikaterini; Sakellariou, Georgios

2005-01-01

Clinical studies have shown that sevelamer hydrochloride improves lipid profiles and attenuates the progression of the cardiovascular calcifications in haemodialysis patients. It is known that both of these properties are associated with increased magnesium levels. The effect of sevelamer on serum magnesium level is not well documented. The aim of this study was to determine the effects of sevelamer treatment on serum magnesium in haemodialysis patients and to assess the association of magnesium levels with lipid profiles and intact parathyroid hormone (iPTH). Phosphate binders were discontinued during a two week washout period. Forty-seven patients, whose serum phosphate was greater than 6.0 mg/dl at the end of washout, received sevelamer hydrochloride for eight weeks. The patients were then washed off sevelamer for another two weeks. Mean serum phosphorus concentration declined from 7.5 +/- 1.3 to 6.4 +/- 1.2 mg/dl (P < 0.001), mean serum magnesium levels increased from 2.75 +/- 0.35 to 2.90 +/- 0.41 mg/dl (P < 0.001) and median serum iPTH levels decreased from 297 to 213 pg/ml (P=0.001) during the eight weeks of sevelamer treatment. After the two week post-treatment washout phosphorus levels increased to 7.3 +/- 1.3 mg/dl (P < 0.001), magnesium levels were reduced to 2.77 +/- 0.39 mg/dl (P < 0.001) and iPTH levels increased to 240 pg/ml (P=0.012). No change was observed in serum calcium levels during the sevelamer treatment period and the subsequent washout period. The mean decline in total and low density lipoprotein (LDL) cholesterol during sevelamer treatment was 16.3 and 28.3 (P < 0.001), respectively. The mean increase in high density lipoprotein (HDL) cholesterol and in apolipoprotein A1 was 2.9 +/- 5.8 mg/dl (P=0.004) and 6.8 +/- 11.1 mg/dl (P=0.001), respectively. Multivariate analysis showed that the rise in serum magnesium concentration significantly correlated with reductions in iPTH levels (r=-0.40, P=0.016), but did not have any significant correlation with the changes in lipid profiles. Our findings indicate that patients on haemodialysis receiving sevelamer have a significant increase in serum magnesium concentrations. This increase in serum magnesium is associated with reduction in iPTH levels. The changes in lipid profiles of these patients however are not related to changes in serum magnesium levels.

Pump Design

NASA Technical Reports Server (NTRS)

1981-01-01

A NASA handbook on a general purpose titanium alloy was used by Sundstrand Corporation in design calculation for casting titanium impellers. Information contributed substantially to improved impeller design.

On the pth moment estimates of solutions to stochastic functional differential equations in the G-framework.

PubMed

Faizullah, Faiz

2016-01-01

The aim of the current paper is to present the path-wise and moment estimates for solutions to stochastic functional differential equations with non-linear growth condition in the framework of G-expectation and G-Brownian motion. Under the nonlinear growth condition, the pth moment estimates for solutions to SFDEs driven by G-Brownian motion are proved. The properties of G-expectations, Hölder's inequality, Bihari's inequality, Gronwall's inequality and Burkholder-Davis-Gundy inequalities are used to develop the above mentioned theory. In addition, the path-wise asymptotic estimates and continuity of pth moment for the solutions to SFDEs in the G-framework, with non-linear growth condition are shown.

Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets.

PubMed

Kamins, Joshua; Charles, Andrew

2018-06-01

Frequent or continuous headache, often refractory to medical therapy, is a common occurrence after head trauma. In addition to being the most common acute symptom after traumatic brain injury (TBI), headache is also one of the most persistent and disabling symptoms. Different studies indicate that 18-58% of those suffering a TBI will have significant headache at 1 year following the trauma. In addition to being disabling on its own, posttraumatic headache (PTH) is a predictor of overall outcome after concussion. Despite its remarkable prevalence and associated social and economic costs, many fundamental and important questions about PTH remain unanswered. The purpose of this review is to identify key questions regarding the clinical characteristics of posttraumatic headache, its basic mechanisms, and its optimal management. We discuss phenotypic features of PTH, pathophysiological mechanisms of TBI including potential overlaps with those of migraine and other primary headache disorders, and potential novel targets for treatment. We suggest different strategies to finding answers to the questions regarding PTH in order to advance the understanding of the disorder and develop more effective therapies. © 2018 American Headache Society.

Transient Overexpression of Sonic Hedgehog Alters the Architecture and Mechanical Properties of Trabecular Bone

PubMed Central

Kiuru, Maija; Solomon, Jason; Ghali, Bassem; van der Meulen, Marjolein; Crystal, Ronald G; Hidaka, Chisa

2009-01-01

Bone formation and remodeling involve coordinated interactions between osteoblasts and osteoclasts through signaling networks involving a variety of molecular pathways. We hypothesized that overexpression of Sonic hedgehog (Shh), a morphogen with a crucial role in skeletal development, would stimulate osteoblastogenesis and bone formation in adult animals in vivo. Systemic administration of adenovirus expressing the N-terminal form of Shh into adult mice resulted in a primary increase in osteoblasts and their precursors. Surprisingly, however, this was associated with altered trabecular morphology, decreased bone volume, and decreased compressive strength in the vertebrae. Whereas no change was detected in the number of osteoclast precursors, bone marrow stromal cells from Shh-treated mice showed enhanced osteoclastogenic potential in vitro. These effects were mediated by the PTH/PTH-related protein (PTHrP) pathway as evidenced by increased sensitivity to PTH stimulation and upregulation of the PTH/PTHrP receptor (PPR). Together, these data show that Shh has stimulatory effects on osteoprogenitors and osteoblasts in adult animals in vivo, which results in bone remodeling and reduced bone strength because of a secondary increase in osteoclastogenesis. PMID:19338448

[Relation between parathyroid hormone and cardiovascular risk in patients with vitamin D deficiency].

PubMed

Casado Cerrada, Jesús; Parra Caballero, Pedro; Vega Piris, Lorena; Suárez Fernández, Carmen

2013-10-05

Vitamin D deficiency and parathyroid hormone (PTH) are associated with an increased cardiovascular risk and arterial stiffness. The aim of our study is to compare the cardiovascular risk in subjects with low vitamin D, attending to the PTH concentration, as well as evaluating the response after administration of vitamin D. Prospective study of patients with a concentration of 25(OH)-vitamin D below 30nmol/l. We evaluated vascular risk parameters as blood pressure, arterial stiffness, lipid profile and glucose metabolism. Patients received vitamin D supplements for 3 months, after which the previous parameters were reassessed. A total of 32 patients were included. Those with PTH over 65pg/ml were older, had worse renal function, higher systolic blood pressure, pulse pressure and arterial stiffness. Treatment with vitamin D showed a statistically significant trend to lower blood pressure and pulse wave velocity. The increase in PTH in patients with low vitamin D involves poor control of blood pressure and increased vascular stiffness. Vitamin D replacement shows a tendency to reduce these parameters. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Parathyroid hormone and serum calcium levels measurements as predictors of postoperative hypocalcemia in total thyroidectomy

PubMed Central

Algarni, Mohammed; Dionigi, Gianlorenzo; Hadi, Al-Hakami; AlSubayea, Haia

2017-01-01

Background The rules of quantitative measures such as parathyroid hormone (PTH) levels in the first hours following total thyroidectomy have since been validated repeatedly. Such measures play an integral rule in identifying patients at significant risk for hypocalcaemia and have allowed for earlier supplementation of these patients with calcium with or without vitamin D. Methods A retrospective analysis was conducted of 40 consecutive patients with well differentiated thyroid cancer (WDTC) who underwent total thyroidectomy without central neck dissection (CND) as an initial surgery and no comorbidity at King Abdulaziz Medical City (National Guard hospital), between July 2011 and July 2012. A blood testing protocol was applied for all patients that measured serum calcium PTH at 6 hours postoperatively. Results Following total thyroidectomy, women were found to experience transient hypocalcaemia in 12.5% of cases (4/32), whereas no men cases encountered this postoperative complication (0/8). However, most probably due to small sample size, this difference was not statistically significant. PTH level was significantly associated with post thyroidectomy hypocalcaemia (43.7±39.3 versus 13.40±24.9 ng/L), P=0.014. Only negligible differences in the length of hospital stay were observed with and without post-thyroidectomy hypocalcaemia. Conclusions Using post-thyroidectomy PTH levels to predict hypocalcaemia has been confirmed in the current study. So, the use of PTH levels allows for early risk stratification of our patients and we feel this has resulted in better patient satisfaction. PMID:29142830

Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone.

PubMed

Laxman, Navya; Rubin, Carl-Johan; Mallmin, Hans; Nilsson, Olle; Tellgren-Roth, Christian; Kindmark, Andreas

2016-03-01

We investigated the impact of treatment with parathyroid hormone (PTH) and dexamethasone (DEX) for 2 and 24h by RNA sequencing of miRNAs in primary human bone (HOB) cells. A total of 207 million reads were obtained, and normalized absolute expression retrieved for 373 most abundant miRNAs. In naïve control cells, 7 miRNAs were differentially expressed (FDR<0.05) between the two time points. Ten miRNAs exhibited differential expression (FDR <0.05) across two time points and treatments after adjusting for expression in controls and were selected for downstream analyses. Results show significant effects on miRNA expression when comparing PTH with DEX at 2h with even more pronounced effects at 24h. Interestingly, several miRNAs exhibiting differences in expression are predicted to target genes involved in bone metabolism e.g. miR-30c2, miR-203 and miR-205 targeting RUNX2, and miR-320 targeting β-catenin (CTNNB1) mRNA expression. CTNNB1and RUNX2 levels were decreased after DEX treatment and increased after PTH treatment. Our analysis also identified 2 putative novel miRNAs in PTH and DEX treated cells at 24h. RNA sequencing showed that PTH and DEX treatment affect miRNA expression in HOB cells and that regulated miRNAs in turn are correlated with expression levels of key genes involved in bone metabolism. Copyright © 2016 Elsevier Inc. All rights reserved.

DEVELOPMENT OF IMPROVED TITANIUM ORGANIC COMPOUNDS FOR USE AS HYDRAULIC FLUIDS

DTIC Science & Technology

HYDRAULIC FLUIDS, *METALORGANIC COMPOUNDS, *TITANATES, *TITANIUM COMPOUNDS, ALKYL RADICALS, CATALYSTS , CHLORIDES, COMPLEX COMPOUNDS, FLUIDS, PHOSPHORIC ACIDS, PROPYL RADICALS, VISCOSITY, ZINC COMPOUNDS

Parathormone--25(OH)-vitamin D axis and bone status in children and adolescents with type 1 diabetes mellitus.

PubMed

Hamed, Enas A; Faddan, Nagla H Abu; Elhafeez, Hebh A Adb; Sayed, Douaa

2011-09-01

Skeletal involvement in patients with type 1 diabetes mellitus (T1DM) has complex pathogenesis and despite numerous researches on this problem, many questions remain unanswered. This study aimed to assess bone status by measurement parathormone (PTH), 25-hydroxy vitamin D [25(OH)D] serum levels in children and adolescents with T1DM and its relation to insulin-like growth factor-1 (IGF-1), disease duration, puberty stage, and metabolic control. This study included 36 children and adolescents with T1DM and 15 apparently healthy controls. Serum levels of 25(OH)D, PTH, IGF-1 measured using enzyme-linked immunosorbent assay (ELISA), while glycosylated hemoglobin (HbA1c), calcium (Ca), inorganic phosphorus (PO(4) ) using autoanalyzer. Bone quality assessed using dual energy X-ray absorptiometry (DEXA). Diabetic patients showed significant increase in PO(4) and PTH levels, while significant decrease in Ca, IGF-1, and 25(OH)D serum levels. As much as 52.8% of patients showed reduced 25(OH)D, and 30.65% showed elevated PTH serum levels. In diabetic patients, abnormal bone status (osteopenia-osteoporosis) found mostly in total body (94.40%) then lumber-spine (88.90%), ribs (88.90%), pelvis (86.10%), thoracic-spine (80.60%), arms (80.60%) and legs (77.80%), while head bones showed no abnormalities. Long diabetic duration had negative; meanwhile PTH, onset age, and puberty age had positive impact on bone status. Children and adolescent with T1DM have abnormal bone status mostly in axial skeleton which may be contributed to impairment of formation of 25(OH)D and IGF-1. Physical activity, calcium and vitamin D supplement seem important in T1DM. Elevated serum PTH level in diabetic patients is not uncommon and its positive correlation with bone status needs further investigations. © 2011 John Wiley & Sons A/S.

Mice lacking bone sialoprotein (BSP) lose bone after ovariectomy and display skeletal site-specific response to intermittent PTH treatment.

PubMed

Wade-Gueye, Ndéye Marième; Boudiffa, Maya; Laroche, Norbert; Vanden-Bossche, Arnaud; Fournier, Carole; Aubin, Jane E; Vico, Laurence; Lafage-Proust, Marie-Hélène; Malaval, Luc

2010-11-01

Bone sialoprotein (BSP) belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, whose members play multiple and distinct roles in the development, turnover, and mineralization of bone and dentin. The functions of BSP in bone remodeling are not yet well established. We previously showed that BSP knockout (BSP(-/-)) mice exhibit a higher trabecular bone volume, concomitant with lower bone remodeling, than wild-type (BSP(+/+)) mice. To determine whether bone turnover can be stimulated in the absence of BSP, we subjected BSP(+/+) and BSP(-/-) mice to catabolic [ovariectomy (OVX)] or anabolic (intermittent PTH administration) hormonal challenges. BSP(-/-) mice progressively develop hypocalcemia and high serum PTH between 2 and 4 months of age. Fifteen and 30 d after OVX, microtomography analysis showed a significant decrease of trabecular bone volume in tibiae of both genotypes. Histomorphometric parameters of bone formation and resorption were significantly increased by OVX. PTH treatment resulted in an increase of trabecular thickness and both bone formation and resorption parameters at all skeletal sites in both genotypes and a decrease of trabecular bone volume in tibiae of BSP(+/+) but not BSP(-/-) mice. PTH increased cortical thickness and bone area in BSP(+/+) but not BSP(-/-) mice and stimulated the bone formation rate specifically in the endosteum of BSP(+/+) mice and the periosteum of BSP(-/-) mice. PTH enhanced the expression of RANKL, MEPE, and DMP1 in both genotypes but increased OPG and OPN expression only in BSP(-/-) mice. In conclusion, despite the low basal turnover, both catabolic and anabolic challenges increase bone formation and resorption in BSP(-/-) mice, suggesting that compensatory pathways are operative in the skeleton of BSP-deficient mice. Although up-regulation of one or several other SIBLINGs is a possible mechanism, further studies are needed to analyze the interplay and cross-regulation involved in compensating for the absence of BSP.

Effects of calcium-fortified ice cream on markers of bone health.

PubMed

Ferrar, L; van der Hee, R M; Berry, M; Watson, C; Miret, S; Wilkinson, J; Bradburn, M; Eastell, R

2011-10-01

Premenopausal women with low calcium intakes consumed calcium-fortified ice cream daily for 28 days. Bone markers, NTX, CTX and PTH decreased significantly by 7 days, with some evidence of a calcium dose-dependent effect. Bone marker responses were observed within 1 h of consuming ice cream. Body weight remained constant over 28 days. Dietary calcium is important for lifelong bone health. Milk is a good source of bioavailable calcium, but consumption has declined among young adults. The aims were to determine whether calcium-fortified ice cream, a palatable source of calcium, produces significant, sustainable changes in bone turnover markers and parathyroid hormone (PTH) in premenopausal women with calcium intake below recommended UK levels. Eighty women, ages 20-39 years (calcium intake <750 mg/day) were randomised to consume lower saturated fat/sugar ice cream containing 96, 244, 459 or 676 mg calcium daily for 28 days. Urinary NTX/Cr, serum CTX, PINP, 1,25D and PTH were measured (baseline, days 1, 7 and 28). Acute changes in CTX and PTH were measured over 5 h (n = 29 women). There were significant mean decreases by 7 days in NTX/Cr, CTX, PTH and 1,25D and increases in PINP (one sample t tests), with a significant dose-dependent effect on CTX analysis of covariance. Only CTX remained suppressed at 28 days. Serum CTX and PTH decreased within 1 h. Body weight did not change significantly between baseline and 28 days. Daily consumption of calcium-fortified ice cream by premenopausal women may significantly reduce levels of the bone resorption marker serum CTX, without stimulating weight gain. The ice cream could be incorporated into the diet to replace low-calcium snacks and thus help individuals with habitually low calcium intakes to meet recommended intakes. The 244 mg calcium preparation would provide more than a quarter of the UK daily recommended nutrient intake for premenopausal women.

Falls relate to vitamin D and parathyroid hormone in an Australian nursing home and hostel.

PubMed

Stein, M S; Wark, J D; Scherer, S C; Walton, S L; Chick, P; Di Carlantonio, M; Zajac, J D; Flicker, L

1999-10-01

To determine whether falling relates to serum levels of vitamin D and parathyroid hormone. A cross-sectional study with retrospective analysis. An aged-care institution in Melbourne Australia. Ambulant nursing home and hostel residents (n = 83). Frequency of falling, frequency of going outdoors, use of cane or walker, age, sex, weight, type of accommodation, and duration of residence. Serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone (PTH). Plasma concentrations of albumin, calcium, phosphate, and creatinine. Use of furosemide or non-benzodiazepine anticonvulsants. Median age of residents was 84 years. The cohort was vitamin D deficient with a median (interquartile range) 25-hydroxyvitamin D level of 27 (18-37) nmol/L (one-third the reference range median), P < .001. The median (interquartile range) PTH of 5.2 (3.8-7.7) pmol/L exceeded the reference range median, P < .001. Residents who fell (n = 33) had lower serum 25-hydroxyvitamin D levels than other residents (medians 22 vs 29 nmol/L, P = .02) and higher serum PTH levels (medians 6.2 vs 4.8 pmol/L, P < .01). Sixty residents lived in the hostel (72%), and 41 (49%) walked without any walking aid. In a multiple logistic regression for falling, higher serum PTH remained independently associated with falling, with an odds ratio (95% confidence interval) for falling of 5.6 (1.7-18.5) per unit of the natural logarithm of serum PTH. Other terms in the regression were hostel accommodation, odds ratio .04 (.01-.25), and ability to walk without aids, odds ratio .07 (.01-.37). In ambulant nursing home and hostel residents, residents who fall have lower serum 25-hydroxyvitamin D and higher serum parathyroid hormone levels than other residents. The association between falling and serum PTH persists after adjustment for other variables.

Mixed-treatment comparison of anabolic (teriparatide and PTH 1-84) therapies in women with severe osteoporosis.

PubMed

Migliore, A; Broccoli, S; Massafra, U; Bizzi, E; Frediani, B

2012-03-01

The recent development of compounds with anabolic action on bone have increased the range of therapeutic options for the treatment of osteoporosis and the prevention of fractures. Two major PTH analogs, the synthetic full-length 1-84 PTH molecule and the recombinant 1-34 N-terminal fragment (teriparatide), are available for the treatment of osteoporosis in many countries. There have bee no comparative trials on the bone anabolic effects of these compounds. In this study we applied a mixed treatment comparison (MTC) to compare the efficacy of teriparatide versus PTH 1-84 for the prevention of vertebral and non-vertebral fractures in women with severe osteoporosis. With this approach the relative treatment effect of one intervention over another can be obtained in the absence of head-to-head comparison. Among the candidate papers selected for analysis, two randomized controlled trials investigating the effects of teriparatide and PTH 1-84 met the selection criteria and underwent MTC analysis. Based on a fixed-effect MTC model analysis of data from two RCTs, teriparatide (20 µg/day) showed a 70% and 94% probability of being the best treatment for the prevention of vertebral and non-vertebral fractures, respectively. Together with a lack of statistical significance, this study has additional limitations. Some differences in trial procedures and populations exist; another limitation concerns the impossibility of carrying out a randomized-effect model MTC, due to sample exiguity. Furthermore, in order to consider unknown or unmeasured differences of covariates across trials, a random-effects approach would be preferred in order to assess the presence of heterogeneity across comparisons. In contrast, in our analysis a fixed-effect MTC model only was used. Teriparatide is expected to provide a greater efficacy over PTH 1-84 with both vertebral and non-vertebral fracture prevention in postmenopausal women with severe osteoporosis.

Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone-resistance due to heterozygous Gαs disruption

PubMed Central

Turan, Serap; Fernandez-Rebollo, Eduardo; Aydin, Cumhur; Zoto, Teuta; Reyes, Monica; Bounoutas, George; Chen, Min; Weinstein, Lee S.; Erben, Reinhold G.; Marshansky, Vladimir; Bastepe, Murat

2013-01-01

Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of Gαs activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH-resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH-resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH-resistance caused by the maternal loss of Gαs, i.e. hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (three-weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH-resistance in patients with PHP-Ia. PMID:23956044

The Mode of Inhibitor Binding to Peptidyl-tRNA Hydrolase: Binding Studies and Structure Determination of Unbound and Bound Peptidyl-tRNA Hydrolase from Acinetobacter baumannii

PubMed Central

Kaushik, Sanket; Singh, Nagendra; Yamini, Shavait; Singh, Avinash; Sinha, Mau; Arora, Ashish; Kaur, Punit; Sharma, Sujata; Singh, Tej P.

2013-01-01

The incidences of infections caused by an aerobic Gram-negative bacterium, Acinetobacter baumannii are very common in hospital environments. It usually causes soft tissue infections including urinary tract infections and pneumonia. It is difficult to treat due to acquired resistance to available antibiotics is well known. In order to design specific inhibitors against one of the important enzymes, peptidyl-tRNA hydrolase from Acinetobacter baumannii, we have determined its three-dimensional structure. Peptidyl-tRNA hydrolase (AbPth) is involved in recycling of peptidyl-tRNAs which are produced in the cell as a result of premature termination of translation process. We have also determined the structures of two complexes of AbPth with cytidine and uridine. AbPth was cloned, expressed and crystallized in unbound and in two bound states with cytidine and uridine. The binding studies carried out using fluorescence spectroscopic and surface plasmon resonance techniques revealed that both cytidine and uridine bound to AbPth at nanomolar concentrations. The structure determinations of the complexes revealed that both ligands were located in the active site cleft of AbPth. The introduction of ligands to AbPth caused a significant widening of the entrance gate to the active site region and in the process of binding, it expelled several water molecules from the active site. As a result of interactions with protein atoms, the ligands caused conformational changes in several residues to attain the induced tight fittings. Such a binding capability of this protein makes it a versatile molecule for hydrolysis of peptidyl-tRNAs having variable peptide sequences. These are the first studies that revealed the mode of inhibitor binding in Peptidyl-tRNA hydrolases which will facilitate the structure based ligand design. PMID:23844024

Hip fracture patients in India have vitamin D deficiency and secondary hyperparathyroidism.

PubMed

Dhanwal, D K; Sahoo, S; Gautam, V K; Saha, R

2013-02-01

This study evaluated the parameters of bone mineral homeostasis including 25(OH)D and PTH in 90 Indian patients with hip fracture and 90 controls. Hypovitaminosis D, secondary hyperparathyroidism, and biochemical osteomalacia was present in 77, 69, and 50 % patients, respectively, significantly higher compared to controls. Vitamin D deficiency is an important risk factor for hip fracture. The prevalence of vitamin D deficiency is not well known in hip fracture patients from India. Therefore, the present study was conducted to evaluate the parameters of bone mineral homeostasis including 25(OH)D and intact PTH in hip fracture from North India. Ninety consecutive patients with hip fracture and similar number of age- and sex-matched controls were enrolled in the study. The fasting venous samples were analyzed for 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium, and phosphorus. Vitamin D deficiency was defined as serum 25-OHD of <20 ng/dl. The mean age of hip fracture subjects was 65.9 ± 12.6 which was comparable in men and women. Majority of study subjects were women (70 women and 20 men). The serum 25(OH)D and calcium levels were significantly lower, whereas the intact PTH and ALP levels were significantly higher in patients compared to controls. There was significant negative correlation between serum 25(OH)D and PTH. In the hip fracture group, 76.7 % of the subjects had vitamin D deficiency, and 68.9 % had secondary hyperparathyroidism. In the control group, vitamin D deficiency and elevated PTH levels were seen in 32.3 and 42.2 %, respectively. About three fourths of hip fracture patients have vitamin D deficiency, and two thirds have secondary hyperparathyroidism. Therefore, the serum 25-OHD level may be a useful index for the assessment of risk of hip fracture in India.

Therapy of Hypoparathyroidism With PTH(1–84): A Prospective Six Year Investigation of Efficacy and Safety

PubMed Central

Cusano, Natalie E.; Fan, Wen-Wei; Delgado, Yasmine; Zhang, Chengchen; Costa, Aline G.; Cremers, Serge; Dworakowski, Elzbieta; Bilezikian, John P.

2016-01-01

Context: Human recombinant (rh)PTH(1–84) was recently approved for the treatment of refractory hypoparathyroidism, based upon a short-term phase 3 clinical trial. Long-term data are needed, because no time limit was placed on the treatment period. Objective: We studied the effect of long-term rhPTH(1–84) treatment in hypoparathyroidism for up to 6 years. Design: Prospective open-label study. Setting: Referral center. Patients: A total of 33 subjects with hypoparathyroidism. Interventions: rhPTH(1–84) treatment was initiated at a starting dose of 100 μg every other day for 6 years. Due to the availability of new dosages during the 6-year time period of the study, the dose could be and was adjusted for most patients to a daily dosing regimen. Main Outcome Measures: Supplemental calcium and vitamin D requirements, serum and urinary calcium (monthly for 6 mo and then biannually), serum phosphorus, bone turnover markers, and bone mineral density (BMD) biannually. Results: Treatment with rhPTH(1–84) progressively reduced supplemental calcium requirements over 6 years by 53% (P < .0001) and 1,25-dihydroxyvitamin D requirements by 67% (P < .0001). Sixteen subjects (48%) were able to eliminate 1,25-dihydroxyvitamin D supplementation completely. Serum calcium concentration remained stable, and urinary calcium excretion fell. Lumbar spine BMD increased (3.8 ± 1%, P = .004) as did total hip BMD (2.4 ± 1%, P = .02), whereas femoral neck BMD remained stable and the distal one third radius decreased (−4.4 ±1%, P < .0001). Bone turnover markers increased significantly, reaching a 3-fold peak above baseline values at 1 year and subsequently declining but remaining higher than pretreatment values. Hypercalcemia was uncommon (12 episodes over 6 y; 2.5% of all values). Conclusions: Long-term, continuous therapy of hypoparathyroidism for 6 years with rhPTH(1–84) is associated with reductions in supplemental calcium and calcitriol requirements, stable serum calcium concentration, and reduced urinary calcium excretion. The safety profile remains good. These data represent the longest experience with the therapeutic use of PTH for any condition and demonstrate its long-term efficacy and safety in hypoparathyroidism. PMID:27144931

[The replacement therapy of rPTH(1-84) in established rat model of hypothyroidism].

PubMed

Ding, Zhiwei; Li, Tiancheng; Liu, Yuhe; Xiao, Shuifang

2015-12-01

To investigate the replacement therapy of rPTH(1-84) (recombinant human parathyroid hormone (1-84)) to hypothyroidism in established rat model. Rat model of hypothyroidism was established by resecting parathyroids. A total of 30 rats with removal of parathyroids were divided into 6 groups randomly, 5 in each group, and applied respectively with saline injection (negative control group), calcitriol treatment (positive control group) and quadripartite PTH administration with dose of 20, 40, 80 and 160 µg/kg (experimental groups). Saline and rPTH(1-84) were injected subcutaneously daily. Calcitriol was gavaged once a day. Sham-operation was conducted in 5 rats of negative control group. To verify the authenticity of the rat model with hypothyroidism, the serum was insolated centrifugally from rat blood that was obtained from angular vein at specific time to measure calcium and phosphorus concentration. Urine in 12 hours was collected by metabolic cages and the calcium concentration was measured. After 10-week drug treatment, the experiment was terminated and bilateral femoral bone and L2-5 lumbar vertebra were removed from rats. Bone mineral density (BMD)of bilateral femoral bone and lumbar vertebra was analyzed by dual X-ray absorptiometry (DXA). The concentration of bone alkaline phosphatase (BALP) in serum was determined by radioimmunoassay. The rat model with hypothyroidism was obtained by excising parathyroid gland and was verified by monitoring calcium and phosphorus concentration subsequently. Administration of rPTH(1-84) in the dose of 80 or 160 µg/kg made serum calcium and phosphorus back to normal levels, with no significant difference between the doses (P>0.05). The BMD in each group of rats with rPTH(1-84) administration was increased significantly (P<0.05). The levels of urinary calcium and serum BALP in rats of maximum rPTH(1-84) injection group (160 µg/kg) were higher than those of normal control group (P<0.05). The rats treated with calcitriol had normal calcium levels and showed the increase of BMD and phosphorus concentration compared with normal control group (P<0.05). The amount of urinary calcium also exceeded the other groups (P<0.05), but no with significant difference in BMD of bilateral femoral bone and lumbar vertebra between negative control group and normal control group (P>0.05). Calcium and phosphorus return to normal level by administration of rPTH(1-84) in the dose of 80 µg/kg or 160 µg/kg, with increase in BMD. Calcitriol can return the level of calcium to normal and increase BMD, but can not correspondingly decrease the phosphorus concentration and increase the excretion of calcium in urine.

Production of Diesel Engine Turbocharger Turbine from Low Cost Titanium Powder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muth, T. R.; Mayer, R.

2012-05-04

Turbochargers in commercial turbo-diesel engines are multi-material systems where usually the compressor rotor is made of aluminum or titanium based material and the turbine rotor is made of either a nickel based superalloy or titanium, designed to operate under the harsh exhaust gas conditions. The use of cast titanium in the turbine section has been used by Cummins Turbo Technologies since 1997. Having the benefit of a lower mass than the superalloy based turbines; higher turbine speeds in a more compact design can be achieved with titanium. In an effort to improve the cost model, and develop an industrial supplymore » of titanium componentry that is more stable than the traditional aerospace based supply chain, the Contractor has developed component manufacturing schemes that use economical Armstrong titanium and titanium alloy powders and MgR-HDH powders. Those manufacturing schemes can be applied to compressor and turbine rotor components for diesel engine applications with the potential of providing a reliable supply of titanium componentry with a cost and performance advantage over cast titanium.« less

Microstructure analysis and wear behavior of titanium cermet femoral head with hard TiC layer.

PubMed

Luo, Yong; Ge, Shirong; Liu, Hongtao; Jin, Zhongmin

2009-12-11

Titanium cermet was successfully synthesized and formed a thin gradient titanium carbide coating on the surface of Ti6Al4V alloy by using a novel sequential carburization under high temperature, while the titanium cermet femoral head was produced. The titanium cermet phase and surface topography were characterized with X-ray diffraction (XRD) and backscattered electron imaging (BSE). And then the wear behavior of titanium cermet femoral head was investigated by using CUMT II artificial joint hip simulator. The surface characterization indicates that carbon effectively diffused into the titanium alloys and formed a hard TiC layer on the Ti6Al4V alloys surface with a micro-porous structure. The artificial hip joint experimental results show that titanium cermet femoral head could not only improve the wear resistance of artificial femoral head, but also decrease the wear of UHMWPE joint cup. In addition, the carburized titanium alloy femoral head could effectively control the UHMWPE debris distribution, and increase the size of UHMWPE debris. All of the results suggest that titanium cermet is a prospective femoral head material in artificial joint.

Radiographic Outcomes Following Lateral Column Lengthening With a Porous Titanium Wedge.

PubMed

Gross, Christopher E; Huh, Jeannie; Gray, Joni; Demetracopoulos, Constantine; Nunley, James A

2015-08-01

Lateral column lengthening (LCL) is commonly utilized in treating stage II posterior tibialis tendon dysfunction. This study aimed to analyze the outcomes of LCL with porous titanium wedges compared to historic controls of iliac crest autograft and allograft. We hypothesized that the use of a porous titanium wedge would have radiographic improvement and union rates similar to those with the use of autograft and allograft in LCL. Between May 2009 and May 2014, 28 feet in 26 patients were treated with LCL using a porous titanium wedge. Of the 26 patients, 9 were males (34.6%). The average age for males was 43 years (range, 17.9-58.7), 48.7 years (range, 21-72.3) for females. Mean follow-up was 14.6 months. Radiographs were examined for correction of the flatfoot deformity and forefoot abduction. All complications were noted. Radiographically, the patients had a significant deformity correction in the anteroposterior talo-first metatarsal angle, talonavicular coverage angle, lateral talo-first metatarsal angle, and calcaneal pitch. All but 1 patient (96%) had bony incorporation of the porous titanium wedge. The average preoperative visual analog scale pain score was 5; all patients but 3 (12%) had improvements in their pain score, with a mean change of 3.4. LCL with porous titanium had low nonunion rates, improved radiographic correction, and pain relief. Level IV, case series. © The Author(s) 2015.

The Effects of Different Wavelength UV Photofunctionalization on Micro-Arc Oxidized Titanium

PubMed Central

Zhou, Lei; Guo, Zehong; Rong, Mingdeng; Liu, Xiangning; Lai, Chunhua; Ding, Xianglong

2013-01-01

Many challenges exist in improving early osseointegration, one of the most critical factors in the long-term clinical success of dental implants. Recently, ultraviolet (UV) light-mediated photofunctionalization of titanium as a new potential surface treatment has aroused great interest. This study examines the bioactivity of titanium surfaces treated with UV light of different wavelengths and the underlying associated mechanism. Micro-arc oxidation (MAO) titanium samples were pretreated with UVA light (peak wavelength of 360 nm) or UVC light (peak wavelength of 250 nm) for up to 24 h. UVC treatment promoted the attachment, spread, proliferation and differentiation of MG-63 osteoblast-like cells on the titanium surface, as well as the capacity for apatite formation in simulated body fluid (SBF). These biological influences were not observed after UVA treatment, apart from a weaker effect on apatite formation. The enhanced bioactivity was substantially correlated with the amount of Ti-OH groups, which play an important role in improving the hydrophilicity, along with the removal of hydrocarbons on the titanium surface. Our results showed that both UVA and UVC irradiation altered the chemical properties of the titanium surface without sacrificing its excellent physical characteristics, suggesting that this technology has extensive potential applications and merits further investigation. PMID:23861853

SLM produced porous titanium implant improvements for enhanced vascularization and osteoblast seeding.

PubMed

Matena, Julia; Petersen, Svea; Gieseke, Matthias; Kampmann, Andreas; Teske, Michael; Beyerbach, Martin; Murua Escobar, Hugo; Haferkamp, Heinz; Gellrich, Nils-Claudius; Nolte, Ingo

2015-04-02

To improve well-known titanium implants, pores can be used for increasing bone formation and close bone-implant interface. Selective Laser Melting (SLM) enables the production of any geometry and was used for implant production with 250-µm pore size. The used pore size supports vessel ingrowth, as bone formation is strongly dependent on fast vascularization. Additionally, proangiogenic factors promote implant vascularization. To functionalize the titanium with proangiogenic factors, polycaprolactone (PCL) coating can be used. The following proangiogenic factors were examined: vascular endothelial growth factor (VEGF), high mobility group box 1 (HMGB1) and chemokine (C-X-C motif) ligand 12 (CXCL12). As different surfaces lead to different cell reactions, titanium and PCL coating were compared. The growing into the porous titanium structure of primary osteoblasts was examined by cross sections. Primary osteoblasts seeded on the different surfaces were compared using Live Cell Imaging (LCI). Cross sections showed cells had proliferated, but not migrated after seven days. Although the cell count was lower on titanium PCL implants in LCI, the cell count and cell spreading area development showed promising results for titanium PCL implants. HMGB1 showed the highest migration capacity for stimulating the endothelial cell line. Future perspective would be the incorporation of HMGB1 into PCL polymer for the realization of a slow factor release.

Effects of deployment on diet quality and nutritional status markers of elite U.S. Army special operations forces soldiers.

PubMed

Farina, Emily K; Taylor, Jonathan C; Means, Gary E; Murphy, Nancy E; Pasiakos, Stefan M; Lieberman, Harris R; McClung, James P

2017-07-03

Special Operations Forces (SOF) Soldiers deploy frequently and require high levels of physical and cognitive performance. Nutritional status is linked to cognitive and physical performance. Studies evaluating dietary intake and nutritional status in deployed environments are lacking. Therefore, this study assessed the effects of combat deployment on diet quality and serum concentrations of nutritional status markers, including iron, vitamin D, parathyroid hormone (PTH), glucose, and lipids, among elite United States (U.S.) Army SOF Soldiers. Changes from baseline to post-deployment were determined with a repeated measure within-subjects design for Healthy Eating Index-2010 (HEI-2010) scores, intake of foods, food groups, key nutrients, and serum nutritional status markers. Dietary intake was assessed with a Block Food Frequency Questionnaire. The association between post-deployment serum 25-hydroxy vitamin D (25-OH vitamin D) and PTH was determined. Analyses of serum markers were completed on 50 participants and analyses of dietary intake were completed on 33 participants. In response to deployment, HEI-2010 scores decreased for total HEI-2010 (70.3 ± 9.1 vs. 62.9 ± 11.1), total fruit (4.4 ± 1.1 vs. 3.7 ± 1.5), whole fruit (4.6 ± 1.0 vs. 4.2 ± 1.4), dairy (6.2 ± 2.7 vs. 4.8 ± 2.4), and empty calories (14.3 ± 3.2 vs. 11.1 ± 4.5) (P ≤ 0.05). Average daily intakes of foods and food groups that decreased included total dairy (P < 0.01), milk (P < 0.01), and non-juice fruit (P = 0.03). Dietary intake of calcium (P = 0.05) and vitamin D (P = 0.03) decreased. PTH increased from baseline (3.4 ± 1.6 vs. 3.8 ± 1.4 pmol/L, P = 0.04), while there was no change in 25-OH vitamin D. Ferritin decreased (385 ± 173 vs. 354 ± 161 pmol/L, P = 0.03) and soluble transferrin receptor increased (16.3 ± 3.7 vs. 17.1 ± 3.5 nmol/L, P = 0.01). There were no changes in glucose or lipids. Post-deployment, serum 25-OH vitamin D was inversely associated with PTH (r = -0.43, P < 0.01). HEI-2010 scores and dietary intake of milk, calcium, and vitamin D decreased following deployment. Serum PTH increased and iron stores were degraded. No Soldiers were iron deficient. Personnel that deploy frequently should maintain a high diet quality in the U.S. and while deployed by avoiding empty calories and consuming fruits, vegetables, and adequate sources of calcium, vitamin D, and iron. Improving availability and quality of perishable food during deployment may improve diet quality.

Nanoscale Visualization of Elastic Inhomogeneities at TiN Coatings Using Ultrasonic Force Microscopy

NASA Astrophysics Data System (ADS)

Hidalgo, J. A.; Montero-Ocampo, C.; Cuberes, M. T.

2009-12-01

Ultrasonic force microscopy has been applied to the characterization of titanium nitride coatings deposited by physical vapor deposition dc magnetron sputtering on stainless steel substrates. The titanium nitride layers exhibit a rich variety of elastic contrast in the ultrasonic force microscopy images. Nanoscale inhomogeneities in stiffness on the titanium nitride films have been attributed to softer substoichiometric titanium nitride species and/or trapped subsurface gas. The results show that increasing the sputtering power at the Ti cathode increases the elastic homogeneity of the titanium nitride layers on the nanometer scale. Ultrasonic force microscopy elastic mapping on titanium nitride layers demonstrates the capability of the technique to provide information of high value for the engineering of improved coatings.

Ceramic modifications of porous titanium: effects on macrophage activation.

PubMed

Scislowska-Czarnecka, A; Menaszek, E; Szaraniec, B; Kolaczkowska, E

2012-12-01

Porous titanium is one of the most widely used implant materials because of its mechanical properties, however, it is also characterised by low bioactivity. To improve the above parameter we prepared three modifications of the porous (30 wt%) titanium (Ti) surface by covering it with bioactive hydroxyapatite (HA), bioglass (BG) and calcium silicate (CS). Subsequently we tested the impact of the modifications on macrophages directing the inflammatory response that might compromise the implant bioactivity. In the study we investigated the in vitro effects of the materials on murine cell line RAW 264.7 macrophage adherence, morphology and activation (production/release of metalloproteinase MMP-9 and pro- and anti-inflammatory cytokines). CS Ti decreased the macrophage adherence and up-regulated the release of several pro-inflammatory mediators, including TNF-α, IL-6, IL-12. Also HA Ti reduced the cell adherence but other parameters were generally not increased, except of TNF-α. In contrast, BG Ti improved macrophage adherence and either decreased production of multiple mediators (MMP-9, TNF-α, IFN-γ, MCP-1) or did not change it in comparison to the porous titanium. We can conclude that analyzing the effects on the inflammatory response initiated by macrophages in vitro, calcium silicate did not improve the biological properties of the porous titanium. The improved bioactivity of titanium was, however, achieved by the application of the hydroxyapatite and bioglass layers. The present in vitro results suggest that these materials, HA Ti and especially BG Ti, may be suitable for in vivo application and thus justify their further investigation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Increase of bioavailable testosterone is associated with gain in bone mineral density after cure of primary hyperparathyroidism in postmenopausal women.

PubMed

Almqvist, Erik G; Becker, Charlotte; Bondeson, Anne-Greth; Bondeson, Lennart; Svensson, Johan

2006-01-01

The recovery of bone mineral density (BMD) after surgical cure of primary hyperparathyroidism (PHPT) seems to be multifactorial and not just dependent on declining PTH. The aim of the present study was to evaluate the role of sex steroids in this context. Thirty-six postmenopausal women with PHPT were examined before and 1 year after curative parathyroidectomy. Their mean age at inclusion in the study was 71.7 +/- 1.1 years (range 54-83). BMD was measured in hip and lumbar spine using dual energy X-ray absorptiometry. No patient received any replacement therapy with sex hormones or treatment with corticosteroids, oestrogen receptor modulators or bisphosphonates. Serum concentrations of oestradiol, testosterone, androstenedione, dehydroepiandrosterone sulphate, SHBG, PTH and calcium. Postoperative increase of free (bioavailable) testosterone was positively correlated to the change of BMD in the hip (P < 0.01), whereas the change of PTH in serum correlated to the change of BMD in the lumbar spine (P < 0.05). Multiple regression analysis showed that bioavailable testosterone was the most important determinant of change in BMD in both spine and hip (femoral neck: P < 0.05; Ward's triangle: P < 0.001; trochanter: P < 0.01; lumbar spine: P < 0.05). The increase of bioavailable testosterone after curative parathyroidectomy was related to declining SHBG. An increase of bioavailable testosterone following surgical cure of PHPT is related to improvement of hip and lumbar spine BMD in postmenopausal women. This previously unknown hormonal interaction may also be important to other aspects of hyperparathyroidism.

The impact of advanced nurse practitioners on patient outcomes in chronic kidney disease: A systematic review.

PubMed

McCrory, Geraldine; Patton, Declan; Moore, Zena; O'Connor, Tom; Nugent, Linda

2018-06-11

Management of individuals with chronic kidney disease (CKD) requires a collaborative approach. Nurses have diversified their skills to take on roles which have been traditionally physician-led. The impact of such roles, mainly that of the advanced nurse practitioner (ANP), has not been previously assessed using a systematic approach. The aim of this systematic review (SR) was to determine the impact of the addition of an ANP on patient outcomes in adults with CKD. A SR, following the guidance of PRISMA was undertaken. Population: adults with CKD. ANP. Databases searched included The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Embase and Medline. Outcome measures were blood pressure (BP), lipids, haemoglobin A1c (HbA1c), phosphate and parathormone (PTH) measures and recommended medication use. Four studies met the inclusion criteria. All possessed external validity and demonstrated low risk for random sequence generation and allocation concealment but were at high risk of performance bias and detection bias. The addition of an ANP resulted in the superior management of BP in all studies. Three studies reported improved control of low-density lipoprotein (LDL) and PTH. One study reported greater achievement of phosphate control. Glycaemic control was equal in both groups. All studies reported higher rates of recommended medication use. The addition of an ANP is superior or equal to the usual care models for the management of BP, LDL, PTH and glycaemic control in adults with CKD. © 2018 European Dialysis and Transplant Nurses Association/European Renal Care Association.

[Treatment of enophthalmos after severe malar-maxillary complex fracture with titanium mesh and high density polyethylene (Medpor)].

PubMed

Zhao, Yan-feng; Lu, Ping; Zhou, Xiao-nan; Qu, Chang-feng

2010-03-01

To study the surgical management of enophthalmos after severe malar maxillary complex fracture. The X-ray and CT examination were performed before operation to diagnose the orbital fracture and intraorbital tissue displacement. The fractured orbital rim was repositioned intraoperatively, followed by implantation of shaped titanium mesh to rebuild the orbital floor. The Medpor was inserted above the titanium mesh to correct the enophthalmos. From Sept. 2007 to Jan. 2009, 6 cases of enophthalmos after severe malar-maxillary complex fracture were treated. The enophthalmos was corrected or improved obviously in all the patients. The enophthalmos after severe malar-maxillary complex fracture can be corrected or obviously improved. Shaped titanium mesh can be used to rebuild the orbital floor with the Medpor to reconstruct the intraorbital tissue volume.

Hypocalcemia in Malignancy - Unexpected but Common

PubMed Central

Sternberg, Evan; Shakuntala, Shrestha; Chiha, Maguy; Khosla, Pam

2015-01-01

One of the most common metabolic abnormalities found in patients with malignancy is hypercalcemia. Hypocalcemia is a rare occurrence and is often found to be associated with renal failure and patients taking bisphosphonate therapy for bone metastasis in this patient population. Here, we present two different case reports with hypocalcemia. A 66-year-old female with a recent diagnosis of tonsillar diffuse B-cell lymphoma admitted with complaints of generalized weakness after one cycle of R-CHOP, found to have neutropenia, a low calcium level, high PTH, and low 25-hydroxy Vitamin D levels. She was given calcium gluconate and supplemental 25-hydroxy Vitamin D. On day 2, the patient's symptoms and counts improved. The second patient was a 64-year-old male with recurrent metastatic laryngeal carcinoma, along with a second locally advanced primary rectal adenocarcinoma, presented with severe hypocalcemia and a low PTH level. The patient was on adjuvant chemotherapy and exhibited Chvostek’s sign, along with perioral numbness, tingling, and twitching sensations, which eventually led to dysphagia. He was treated with calcium gluconate, calcitriol, and calcium carbonate. Signs and symptoms, along with lab values, improved on day 4. These cases suggest that calcium kinetics and 25-hydroxy Vitamin D levels need to be monitored in these patient populations in a routine manner. PMID:26858923

Biochemical Assessment of Bone Health in Working Obese Egyptian Females with Metabolic Syndrome; the Effect of Weight Loss by Natural Dietary Therapies

PubMed Central

Moaty, Maha I. A.; Fouad, Suzanne; Shebini, Salwa M. El; Kazem, Yusr I.; Tapozada, Salwa T.

2015-01-01

AIM: To investigate the relation between bone parameters and the metabolic syndrome criteria, before and after the administration of two different natural dietary supplements in middle aged working obese Egyptian women suffering from metabolic syndrome (MetS). SUBJECTS AND METHODS: Fifty eight middle aged obese female volunteers suffering from metabolic syndrome were divided into two groups. During the first period, group (A) consumed a low caloric diet and nutritional supplement consisting of doum flour biscuits, while group (B) consumed whole meal wheat flour biscuit with the same instructions. During the second period, both supplements were omitted. Assessment of blood pressure, relevant anthropometric parameters, lipid accumulation product, fasting blood glucose, uric acid, 25 hydroxy vitamin D (25 (OH) D), parathyroid hormone (PTH) and bone-specific alkaline phosphatase were performed. RESULTS: Data showed that although both supplements improved the MetS criteria and the bone health parameters, the supplement containing the doum flour proved to be more effective. CONCLUSION: These results confirm the benefit of doum in improving bone health parameter [25 (OH) D/PTH axis] in the MetS patients, beside the MetS criteria. So, we can conclude that natural effective supplements lead towards the optimization of biochemical parameters in favor of a healthy outcome. PMID:27275291

Oncogenic Osteomalacia Caused by a Phosphaturic Mesenchymal Tumor of the Oral Cavity: A Case Report

PubMed Central

Yang, In Myung; Park, Yong Koo; Hyun, Yong Jun; Kim, Deog Yoon; Woo, Jeong Taek; Kim, Sung Woon; Kim, Jin Woo; Kim, Young Seol; Choi, Young Kil

1997-01-01

We report a case of oncogenic osteomalacia associated with a phosphaturic mesenchymal tumor in a 31-year-old woman. She was presented with severe generalized bone and muscle pain and was restricted to bed. She lost 20cm in height over the 8 years since she had first noticed a pain in her thigh. A walnut-sized, hard, soft tissue tumor was found very easily beside her lower molar teeth. Radiologic examination revealed a remarkable decrease in bone density and multiple pathologic fractures of spine, femur and phalangeal bones. Severe hypophosphatemia, hyperphosphaturia, low plasma 1,25-dihydroxyvitamin D3 level and high plasma PTH level were disclosed at presentation. Histomorphometric examination revealed an extensive area of unmineralized osteoid and little mineralizing activity. A pharmacologic dose of 1α-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 slightly increased the serum phosphate level and renal tubular reabsorption of phosphate, and slightly decreased plasma PTH level without any symptomatic improvement. Histologic examination of the tumor revealed a mixed connective tissue tumor that consisted of central woveh bones and surrounding primitive spindle cells with prominent vascularities. After removal of the tumor, all biochemical, hormonal and radiologic abnormalities disappeared with remarkable symptomatic improvement. PMID:9159046

Validity of early parathyroid hormone assay as a diagnostic tool for sub-total thyroidectomy related hypocalcaemia.

PubMed

Riaz, Umbreen; Shah, Syed Aslam; Zahoor, Imran; Riaz, Arsalan; Zubair, Muhammad

2014-07-01

To determine the validity of early (one hour postoperatively) parathyroid hormone (PTH) assay (² 10 pg/ml), keeping gold standard as the serum ionic calcium level, for predicting sub-total thyroidectomy-related hypocalcaemia and to calculate the sensitivity and specificity of latent signs of tetany. Cross-sectional validation study. Department of General Surgery, Pakistan Institute of Medical Sciences, Islamabad from August 2008 to August 2010. Patients undergoing sub-total thyroidectomy were included by convenience sampling. PTH assay was performed 1 hour post sub-total thyroidectomy. Serum calcium levels were performed at 24 and 48 hours, 5th day and 2 weeks after surgery. Cases that developed hypocalcaemia were followed-up for a period of 6 months with monthly calcium level estimation to identify cases of permanent hypocalcaemia. Symptoms and signs of hypocalcaemia manifesting in our patients were recorded. Data was analyzed through SPSS version 10. 2 x 2 tables were used to calculate sensitivity and specificity of PTH in detecting post-thyroidectomy hypocalcaemia. Out of a total of 110 patients included in the study, 16.36% (n=18) developed hypocalcaemia including 1.81% (n=2) cases of permanent hypoparathyroidism. The sensitivity of one hour postoperative PTH assay as a predictive tool for post-thyroidectomy related hypocalcaemia was 94.4% while its specificity was 83.6% with 53% positive predictive value and 98.7% negative predictive value. One hour post sub-total thyroidectomy PTH assay can be helpful in predicting post sub-total thyroidectomy hypocalcaemia. Moreover, it can be useful in safe discharge of day-care thyroidectomy patients.

Accentuated hyperparathyroidism in type II Bartter syndrome.

PubMed

Landau, Daniel; Gurevich, Evgenia; Sinai-Treiman, Levana; Shalev, Hannah

2016-07-01

Bartter syndrome (BS) may be associated with different degrees of hypercalciuria, but marked parathyroid hormone (PTH) abnormalities have not been described. We compared clinical and laboratory data of patients with either ROMK-deficient type II BS (n = 14) or Barttin-deficient type IV BS (n = 20). Only BS-IV patients remained mildly hypokalemic in spite of a higher need for potassium supplementation. Estimated glomerular filtration rate (eGFR) was mildly decreased in only four BS-IV patients. Average PTH values were significantly higher in BS-II (160.6 ± 85.8 vs. 92.5 ± 48 pg/ml in BS-IV, p = 0.006). In both groups, there was a positive correlation between age and log(PTH). Levels of 25(OH) vitamin D were not different. Total serum calcium was lower (within normal limits) and age-related serum phosphate (Pi)-SDS was increased in BS-II (1.19 ± 0.71 vs. 0.01 ± 1.04 in BS-IV, p < 0.001). The GFR threshold for Pi reabsorption was higher in BS-II (5.63 ± 1.25 vs. 4.36 ± 0.98, p = 0.002). Spot urine calcium/creatinine ratio and nephrocalcinosis rate (100 vs. 16 %) were higher in the BS-II group. PTH, serum Pi levels, and urinary threshold for Pi reabsorption are significantly elevated in type II vs. type IV BS, suggesting a PTH resistance state. This may be a response to more severe long-standing hypercalciuria, leading to a higher rate of nephrocalcinosis in BS-II.

Anharmonicity of three minerals at high temperature: Forsterite, fayalite, and periclase

NASA Astrophysics Data System (ADS)

Anderson, O. L.; Suzuki, I.

1983-04-01

Recent data on Ks (the adiabatic bulk modulus) and α (the volume coefficient of thermal expansion) versus T (temperature) at high temperatures (500°C < T < 1000°C) have been published or are in press. These data, taken at ambient pressure, extend the measurement of single-crystal elastic constants for forsterite, fayalite and periclase to record temperatures. The high temperature anharmonic properties of forsterite and fayalite are presented for the first time in this paper, and they are compared with similar previously published data for MgO. The anharmonic properties referred to above concern the dependence of γ (the Grüneisen ratio), PTH (the thermal pressure), and Cv (the specific heat) with T. If γ (at constant V) is independent of T at high T, the anharmonicity in γ is said to be nil; similarly, for Cv. If PTH at constant V is proportional to T at high T, then the anharmonicity in PTH is said to be nil. The anharmonicity determined by these experiments indicates that the minerals are not alike with regard to their properties γ, PTH, and Cv. The γ versus T at constant V indicates that there is anharmonicity for all three minerals, but the effects are opposite in fayalite and forsterite in such a way that anharmonicity should be absent in olivine. For PTH at 1 bar, anharmonicity is detectable and positive in forsterite, absent in fayalite, and detectable and negative in periclase. It would be slight in olivine. In all three solids, anharmonicity in Cv is pronounced and positive.

UVB radiation and its role in the treatment of postmenopausal women with osteoporosis

NASA Astrophysics Data System (ADS)

Falkenbach, A.; Sedlmeyer, Annette; Unkelbach, Uwe

In humans, the serum concentration of parathyroid hormone (PTH) is higher in winter than in summer. The increase of PTH can be suppressed by oral vitamin D supplements, which is considered beneficial to those with osteoporosis. The present study investigates whether this effect can also be achieved by serial ultraviolet (UV) irradiation of the skin. In total, 34 women suffering from postmenopausal osteoporosis were included in the open trial. In late winter, 20 patients were irradiated with a spectrum containing UVB, eight times over a period of 4 weeks. The serum concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], PTH, osteocalcin, alkaline phosphatase (AP), calcium and phosphorus were measured before the first, and 2 days after the last, dose of radiation. The data were compared to the controls (n=14, no UV exposure), who were evaluated once at the start of the study and then again 4 weeks later. After UV irradiation the level of 25(OH)D was increased, whilst that of PTH remained unchanged. The serum level of osteocalcin decreased in the control group, but did not change in the group of women who had been exposed to UV radiation. The present study of osteoporotic women does not confirm previous findings in studies of healthy volunteers i.e. that PTH can be suppressed by exposure to UVB radiation in winter. Further studies are required to specify whether there are subgroups of osteoporotic people who may benefit from exposure to UVB radiation during winter.

Is there a reverse J-shaped association between 25-Hydroxyvitamin D and all-cause mortality? Results from the US Nationally Representative NHANES

USDA-ARS?s Scientific Manuscript database

The concentration or threshold of 25-Hydroxyvitamin D [25(OH)D] needed to maximally suppress intact serum parathyroid hormone (iPTH) has been suggested as a measure of optimal vitamin D status. Depending upon the definition of maximal suppression of iPTH and the two-phase regression approach used, ...

A case of teriparatide-induced severe hypophosphatemia and hypercalcemia.

PubMed

Hajime, Maiko; Okada, Yosuke; Mori, Hiroko; Tanaka, Yoshiya

2014-09-01

PTH (teriparatide) is used in the treatment of osteoporosis, and can sometimes cause transient hypercalcemia, but to date there have been no reports of persistent hypercalcemia and hypophosphatemia resulting from its use. We describe a case with marked hypophosphatemia and hypercalcemia associated with the use of teriparatide. The patient was a 49-year-old woman who was followed up for acute intermittent porphyria and glucocorticoid-induced osteoporosis (following administration of prednisolone at 22.5 mg/day), and presented with unexplained fracture of the left tibia, for which treatment with teriparatide at 20 μg/day was started. Two weeks after treatment with teriparatide, the patient developed hypophosphatemia, hypercalcemia, hyperalkaline phosphatasemia, low TmP/GFR, FEca, BAP, and urinary NT×, with low intact PTH. These changes were considered to be related to teriparatide. Cessation of teriparatide treatment resulted in normalization of all parameters at 10 weeks (serum P 3.6 mg/dl, corrected Ca 8.8 mg/dl, ALP 273 IU/l, intact PTH 63 pg/ml). The observed abnormalities were considered to be in part related to acute intermittent porphyria, which is known to delay hepatic teriparatide clearance, with subsequent delay of PTH action despite its intermittent use, resulting in hypercalcemia and hypophosphatemia.

The Results of Ultrasonography-Guided Percutaneous Radiofrequency Ablation in Hyperparathyroid Patients in Whom Surgery Is Not Feasible

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sormaz, Ismail Cem, E-mail: icsormaz@gmail.com; Poyanlı, Arzu, E-mail: arzupoyanli@yahoo.com; Açar, Sami, E-mail: acarrsami@gmail.com

BackgroundThe aim of the study was to evaluate the results of ultrasonography (US)-guided percutaneous radiofrequency ablation (RFA) in hyperparathyroid patients who refused surgery or had high surgical risks.Patients and MethodsFive patients with hyperparathyroidism (HPT) underwent US-guided RFA for a single hyperfunctioning parathyroid lesion. Post-ablation serum calcium and parathormone (PTH) assays were performed. All patients underwent imaging studies 6 months after the ablation to visualize the post-ablation change in the size of the treated parathyroid lesions.ResultsAll patients were normocalcemic on the post-ablation 1st day and 6th month. The post-ablation PTH levels were normal in three patients but remained elevated in two patients.more » The size of the parathyroid lesion was ≥30 mm in the two patients with elevated PTH, whereas the lesion was smaller than 30 mm in those with normal post-ablation PTH values.ConclusionAlthough this is a limited case series, it demonstrates the potential feasibility of RFA for HPT. Benefits were achieved particularly in patients with small parathyroid lesions.« less

Effect of parathyroid hormone and calcium ions on substrate oxidation by isolated glomeruli of the rat.

PubMed

Wang, M S; Kurokawa, K

1981-11-05

Effect of Ca2+ and parathyroid hormone (PTH) on 14 CO2 production from certain metabolic substrates by isolated glomeruli of rat kidney were examined. Increasing calcium concentration in the incubation medium inhibited 14CO2 production from 14C-labeled alpha-ketoglutarate and succinate, stimulated 14CO2 production from [1-14C]glucose and [1-14C]glutamate, but was without effect on that from [6-14C]glucose. PTH in the presence but not in the absence of Ca2+ inhibited 14CO2 production from labeled alpha-ketoglutarate and glutamate but not from labeled glucose. Additions of cyclic AMP as well as hormonal agents known to act directly on the glomureli, such as histamine, epinephrine, prostaglandin E2, vasopressin, angiotensin II and insulin, did not alter 14 CO2 production from labeled alpha-ketoglutarate. These data show the presence of calcium-dependent inhibitory actions on PTH on oxidation of alpha-ketoglutarate and glutamate which may be independent of cyclic AMP. These metabolic effects of PTH may underlie the alteration in the glomerular ultrafiltration coefficient and glomerular filtration induced by the hormone.

Antimicrobial and Osseointegration Properties of Nanostructured Titanium Orthopaedic Implants.

PubMed

Jäger, Marcus; Jennissen, Herbert P; Dittrich, Florian; Fischer, Alfons; Köhling, Hedda Luise

2017-11-13

The surface design of titanium implants influences not only the local biological reactions but also affects at least the clinical result in orthopaedic application. During the last decades, strong efforts have been made to improve osteointegration and prevent bacterial adhesion to these surfaces. Following the rule of "smaller, faster, cheaper", nanotechnology has encountered clinical application. It is evident that the hierarchical implant surface micro- and nanotopography orchestrate the biological cascades of early peri-implant endosseous healing or implant loosening. This review of the literature gives a brief overview of nanostructured titanium-base biomaterials designed to improve osteointegration and prevent from bacterial infection.

Plasma Electrolytic Oxidation of Titanium Implant Surfaces: Microgroove-Structures Improve Cellular Adhesion and Viability.

PubMed

Hartjen, Philip; Hoffmann, Alexia; Henningsen, Anders; Barbeck, Mike; Kopp, Alexander; Kluwe, Lan; Precht, Clarissa; Quatela, Olivia; Gaudin, Robert; Heiland, Max; Friedrich, Reinhard E; Knipfer, Christian; Grubeanu, Daniel; Smeets, Ralf; Jung, Ole

2018-01-01

Plasma electrolytic oxidation (PEO) is an established electrochemical treatment technique that can be used for surface modifications of metal implants. In this study we to treated titanium implants with PEO, to examine the resulting microstructure and to characterize adhesion and viability of cells on the treated surfaces. Our aim was to identify an optimal surface-modification for titanium implants in order to improve soft-tissue integration. Three surface-variants were generated on titanium alloy Ti6Al4V by PEO-treatment. The elemental composition and the microstructures of the surfaces were characterized using energy dispersive X-ray spectroscopy, scanning electron microscopy and profilometry. In vitro cytocompatibility of the surfaces was assessed by seeding L929 fibroblasts onto them and measuring the adhesion, viability and cytotoxicity of cells by means of live/dead staining, XTT assay and LDH assay. Electron microscopy and profilometry revealed that the PEO-surface variants differed largely in microstructure/topography, porosity and roughness from the untreated control material as well as from one another. Roughness was generally increased after PEO-treatment. In vitro, PEO-treatment led to improved cellular adhesion and viability of cells accompanied by decreased cytotoxicity. PEO-treatment provides a promising strategy to improve the integration of titanium implants with surrounding tissues. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The role of the domain size and titanium dopant in nanocrystalline hematite thin films for water photolysis

DOE PAGES

Yan, Danhua; Tao, Jing; Kisslinger, Kim; ...

2015-10-13

Here we develop a novel technique for preparing high quality Ti-doped hematite thin films for photoelectrochemical (PEC) water splitting, through sputtering deposition of metallic iron films from an iron target embedded with titanium (dopants) pellets, followed by a thermal oxidation step that turns the metal films into doped hematite. It is found that the hematite domain size can be tuned from ~10 nm to over 100 nm by adjusting the sputtering atmosphere from more oxidative to mostly inert. The better crystallinity at a larger domain size ensures excellent PEC water splitting performance, leading to record high photocurrent from pure planarmore » hematite thin films on FTO substrates. Titanium doping further enhances the PEC performance of hematite photoanodes. The photocurrent is improved by 50%, with a titanium dopant concentration as low as 0.5 atom%. As a result, it is also found that the role of the titanium dopant in improving the PEC performance is not apparently related to the films’ electrical conductivity which had been widely believed, but is more likely due to the passivation of surface defects by the titanium dopants.« less

Sonosynthesis of nano TiO2 on wool using titanium isopropoxide or butoxide in acidic media producing multifunctional fabric.

PubMed

Behzadnia, Amir; Montazer, Majid; Rashidi, Abousaeid; Rad, Mahnaz Mahmoudi

2014-09-01

This study presents a novel idea to prepare nanocrystalline structure of TiO2 under ambient pressure at 60-65 °C using in situ sonochemical synthesis by hydrolysis of either titanium isopropoxide or titanium butoxide in an acidic aqueous solution. The nano titanium dioxide coated wool fabrics possess significant antibacterial/antifungal activity and self-cleaning property by discoloring Methylene blue stain under sunlight irradiation. This process has no negative effect on cytotoxicity and tensile strength of the sonotreated fabric even reduces alkaline solubility and photoyellowing and improves hydrophilicity. More titanium isopropoxide or titanium butoxide as a precursor led to higher photocatalytic activities of the treated fabrics. Also introducing more ethanol improved the adsorption of TiO2 on the wool fabric surface leading to enhanced photocatalytic activity. EDS and XRD patterns, SEM images, X-ray mapping confirmed the presence of nano TiO2 particles on the fabric surface. The role of both solvent and precursor concentrations on the various properties of the fabric was investigated and the optimized conditions were obtained using response surface methodology. Copyright © 2014 Elsevier B.V. All rights reserved.

Comparison of titanium and Robinson stainless steel stapes piston prostheses.

PubMed

Lippy, William H; Burkey, John M; Schuring, Arnold G; Berenholz, Leonard P

2005-09-01

Although stainless steel stapes prostheses have generally been considered magnetic resonance imaging safe, there is concern that this may change with the development of more powerful imaging systems. The objective of the study was to determine whether a titanium piston stapes prosthesis would be audiometrically and surgically equivalent to a Robinson stainless steel piston for stapedectomy. Retrospective chart review. Private otology practice. In all, 50 patients underwent stapedectomy with a Gyrus titanium piston prosthesis. These patients were matched on the basis of age and preoperative bone-conduction scores with patients who underwent stapedectomy with a Robinson stainless steel piston prosthesis. Audiometric results are analyzed, and surgical complications noted. There was no significant difference between groups in hearing improvement or postoperative air-bone gap. The mean four-frequency hearing improvement was 27.7 dB for the stainless steel group and 27.8 dB for the titanium group. The mean postoperative air-bone gap was 2.65 dB for the stainless steel group and 2.60 for the titanium group. Neither group had a surgical complication. The titanium stapes prosthesis is a good alternative to a stainless steel prosthesis.

Surface Modification of Dental Titanium Implant by Layer-by-Layer Electrostatic Self-Assembly

PubMed Central

Shi, Quan; Qian, Zhiyong; Liu, Donghua; Liu, Hongchen

2017-01-01

In vivo implants that are composed of titanium and titanium alloys as raw materials are widely used in the fields of biology and medicine. In the field of dental medicine, titanium is considered to be an ideal dental implant material. Good osseointegration and soft tissue closure are the foundation for the success of dental implants. Therefore, the enhancement of the osseointegration and antibacterial abilities of titanium and its alloys has been the focus of much research. With its many advantages, layer-by-layer (LbL) assembly is a self-assembly technique that is used to develop multilayer films based on complementary interactions between differently charged polyelectrolytes. The LbL approach provides new methods and applications for the surface modification of dental titanium implant. In this review, the application of the LbL technique to surface modification of titanium including promoting osteogenesis and osseointegration, promoting the formation and healing of soft tissues, improving the antibacterial properties of titanium implant, achieving local drug delivery and sustained release is summarized. PMID:28824462

Microarc oxidized TiO2 based ceramic coatings combined with cefazolin sodium/chitosan composited drug film on porous titanium for biomedical applications.

PubMed

Wei, Daqing; Zhou, Rui; cheng, Su; Feng, Wei; Li, Baoqiang; Wang, Yaming; Jia, Dechang; Zhou, Yu; Guo, Haifeng

2013-10-01

Porous titanium was prepared by pressureless sintering of titanium beads with diameters of 100, 200, 400 and 600 μm. The results indicated that the mechanical properties of porous titanium changed significantly with different bead diameters. Plastic deformations such as necking phenomenon and dimple structure were observed on the fracture surface of porous titanium sintered by beads with diameter of 100 μm. However, it was difficult to find this phenomenon on the porous titanium with a titanium bead diameter of 600 μm. The microarc oxidized coatings were deposited on its surface to improve the bioactivity of porous titanium. Furthermore, the cefazolin sodium/chitosan composited films were fabricated on the microarc oxidized coatings for overcoming the inflammation due to implantation, showing good slow-release ability by addition of chitosan. And the release kinetic process of cefazolin sodium in composited films could be possibly fitted by a polynomial model. Copyright © 2013 Elsevier B.V. All rights reserved.

Mechanical properties and grindability of dental cast Ti-Nb alloys.

PubMed

Kikuchi, Masafumi; Takahashi, Masatoshi; Okuno, Osamu

2003-09-01

Aiming at developing a dental titanium alloy with better mechanical properties and machinability than unalloyed titanium, a series of Ti-Nb alloys with Nb concentrations up to 30% was made. They were cast into magnesia-based molds using a dental casting machine and the mechanical properties and grindability of the castings were examined. The hardness of the alloys with Nb concentrations of 5% and above was significantly higher than that of titanium. The yield strength and tensile strength of the alloys with Nb concentrations of 10% and above were significantly higher than those of titanium, while the elongation was significantly lower. A small addition of niobium to titanium did not contribute to improving the grindability of titanium. The Ti-30% Nb alloy exhibited significantly better grindability at low grinding speed with higher hardness, strength, and Young's modulus than titanium, presumably due to precipitation of the omega phase in the beta matrix.

Pseudohypoparathyroidism: a rare but important cause of hypocalcaemia

PubMed Central

Chong, Pui Lin; Meeking, Darryl R

2013-01-01

We present a 46-year-old Caucasian lady with symptomatic hypocalcaemia. Investigations revealed markedly raised parathyroid hormone (PTH) levels with vitamin D deficiency. A number of conditions causing secondary hyperparathyroidism were ruled out from her medical history and initial investigations. The main differential diagnoses were vitamin D deficiency and PTH resistance (pseudohypoparathyroidism, PHP). With high-normal serum phosphate and normal alkaline phosphatase, and a lack of symptoms associated with osteomalacia, vitamin D deficiency alone was unlikely to be the cause of hypocalcaemia. Given a normal physical appearance, genetic testing was arranged and confirmed the diagnosis of PHP type Ib. She is currently taking activated vitamin D to maintain calcium homeostasis. PTH resistance is the hallmark of PHP, a rare complex genetic disorder, which can be easily missed resulting in potentially serious consequences. PMID:23345494

On the melt infiltration of copper coated silicon carbide with an aluminium alloy

NASA Technical Reports Server (NTRS)

Asthana, R.; Rohatgi, P. K.

1992-01-01

Pressure-assisted infiltration of porous compacts of Cu coated and uncoated single crystals of platelet shaped alpha (hexagonal) SiC was used to study infiltration dynamics and particulate wettability with a 2014 Al alloy. The infiltration lengths were measured for a range of experimental variables which included infiltration pressure, infiltration time, and SiC size. A threshold pressure (P(th)) for flow initiation through compacts was identified from an analysis of infiltration data; P(th) decreased while penetration lengths increased with increasing SiC size (more fundamentally, due to changes in interparticle pore size) and with increasing infiltration times. Cu coated SiC led to lower P(th) and 60-80 percent larger penetration lengths compared to uncoated SiC under identical processing conditions.

LARC-13 adhesive development

NASA Technical Reports Server (NTRS)

Hill, S. G.; Sheppard, C. H.; Johnson, J. C.

1980-01-01

A LARC-13 type adhesive system was developed and property data obtained that demonstrated improved thermomechanical properties superior to base LARC-13 adhesive. An improved adhesive for 589 K (600 F) use was developed by physical or chemical modification of LARC-13. The adhesive was optimized for titanium and composite bonding, and a compatible surface preparation for titanium and composite substrates was identified. The data obtained with the improved adhesive system indicated it would meet the 589 K (600 F) properties desired for application on space shuttle components. Average titanium lap shear data were: (1) 21.1 MPa (3355 psi) at RT, (2) 13.0 MPa (1881 psi) at 600 F, and (3) 16.4 MPa (2335) after aging 125 hours at 600 F and tested at 600 F.

Surface modification of 17-4PH stainless steel by DC plasma nitriding and titanium nitride film duplex treatment

NASA Astrophysics Data System (ADS)

Qi, F.; Leng, Y. X.; Huang, N.; Bai, B.; Zhang, P. Ch.

2007-04-01

17-4PH stainless steel was modified by direct current (DC) plasma nitriding and titanium nitride film duplex treatment in this study. The microstructure, wear resistance and corrosion resistance were characterized by X-ray diffraction (XRD), pin-on-disk tribological test and polarization experiment. The results revealed that the DC plasma nitriding pretreatment was in favor of improving properties of titanium nitride film. The corrosion resistance and wear resistance of duplex treatment specimen was more superior to that of only coated titanium nitride film.

Pressure-reaction synthesis of titanium composite materials

DOEpatents

Oden, Laurance L.; Ochs, Thomas L.; Turner, Paul C.

1993-01-01

A pressure-reaction synthesis process for producing increased stiffness and improved strength-to-weight ratio titanium metal matrix composite materials comprising exothermically reacting a titanium powder or titanium powder alloys with non-metal powders or gas selected from the group consisting of C, B, N, BN, B.sub.4 C, SiC and Si.sub.3 N.sub.4 at temperatures from about 900.degree. to about 1300.degree. C., for about 5 to about 30 minutes in a forming die under pressures of from about 1000 to 5000 psi.

SLM Produced Porous Titanium Implant Improvements for Enhanced Vascularization and Osteoblast Seeding

PubMed Central

Matena, Julia; Petersen, Svea; Gieseke, Matthias; Kampmann, Andreas; Teske, Michael; Beyerbach, Martin; Murua Escobar, Hugo; Haferkamp, Heinz; Gellrich, Nils-Claudius; Nolte, Ingo

2015-01-01

To improve well-known titanium implants, pores can be used for increasing bone formation and close bone-implant interface. Selective Laser Melting (SLM) enables the production of any geometry and was used for implant production with 250-µm pore size. The used pore size supports vessel ingrowth, as bone formation is strongly dependent on fast vascularization. Additionally, proangiogenic factors promote implant vascularization. To functionalize the titanium with proangiogenic factors, polycaprolactone (PCL) coating can be used. The following proangiogenic factors were examined: vascular endothelial growth factor (VEGF), high mobility group box 1 (HMGB1) and chemokine (C-X-C motif) ligand 12 (CXCL12). As different surfaces lead to different cell reactions, titanium and PCL coating were compared. The growing into the porous titanium structure of primary osteoblasts was examined by cross sections. Primary osteoblasts seeded on the different surfaces were compared using Live Cell Imaging (LCI). Cross sections showed cells had proliferated, but not migrated after seven days. Although the cell count was lower on titanium PCL implants in LCI, the cell count and cell spreading area development showed promising results for titanium PCL implants. HMGB1 showed the highest migration capacity for stimulating the endothelial cell line. Future perspective would be the incorporation of HMGB1 into PCL polymer for the realization of a slow factor release. PMID:25849656

Laser-modified titanium surfaces enhance the osteogenic differentiation of human mesenchymal stem cells.

PubMed

Bressel, Tatiana A B; de Queiroz, Jana Dara Freires; Gomes Moreira, Susana Margarida; da Fonseca, Jéssyca T; Filho, Edson A; Guastaldi, Antônio Carlos; Batistuzzo de Medeiros, Silvia Regina

2017-11-28

Titanium surfaces have been modified by various approaches with the aim of improving the stimulation of osseointegration. Laser beam (Yb-YAG) treatment is a controllable and flexible approach to modifying surfaces. It creates a complex surface topography with micro and nano-scaled patterns, and an oxide layer that can improve the osseointegration of implants, increasing their usefulness as bone implant materials. Laser beam irradiation at various fluences (132, 210, or 235 J/cm 2 ) was used to treat commercially pure titanium discs to create complex surface topographies. The titanium discs were investigated by scanning electron microscopy, X-ray diffraction, and measurement of contact angles. The surface generated at a fluence of 235 J/cm 2 was used in the biological assays. The behavior of mesenchymal stem cells from an umbilical cord vein was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a mineralization assay, and an alkaline phosphatase activity assay and by carrying out a quantitative real-time polymerase chain reaction for osteogenic markers. CHO-k1 cells were also exposed to titanium discs in the MTT assay. The best titanium surface was that produced by laser beam irradiation at 235 J/cm 2 fluence. Cell proliferation analysis revealed that the CHO-k1 and mesenchymal stem cells behaved differently. The laser-processed titanium surface increased the proliferation of CHO-k1 cells, reduced the proliferation of mesenchymal stem cells, upregulated the expression of the osteogenic markers, and enhanced alkaline phosphatase activity. The laser-treated titanium surface modulated cellular behavior depending on the cell type, and stimulated osteogenic differentiation. This evidence supports the potential use of laser-processed titanium surfaces as bone implant materials, and their use in regenerative medicine could promote better outcomes.

Rough titanium alloys regulate osteoblast production of angiogenic factors.

PubMed

Olivares-Navarrete, Rene; Hyzy, Sharon L; Gittens, Rolando A; Schneider, Jennifer M; Haithcock, David A; Ullrich, Peter F; Slosar, Paul J; Schwartz, Zvi; Boyan, Barbara D

2013-11-01

Polyether-ether-ketone (PEEK) and titanium-aluminum-vanadium (titanium alloy) are used frequently in lumbar spine interbody fusion. Osteoblasts cultured on microstructured titanium generate an environment characterized by increased angiogenic factors and factors that inhibit osteoclast activity mediated by integrin α2β1 signaling. It is not known if this is also true of osteoblasts on titanium alloy or PEEK. The purpose of this study was to determine if osteoblasts generate an environment that supports angiogenesis and reduces osteoclastic activity when grown on smooth titanium alloy, rough titanium alloy, or PEEK. This in vitro study compared angiogenic factor production and integrin gene expression of human osteoblast-like MG63 cells cultured on PEEK or titanium-aluminum-vanadium (titanium alloy). MG63 cells were grown on PEEK, smooth titanium alloy, or rough titanium alloy. Osteogenic microenvironment was characterized by secretion of osteoprotegerin and transforming growth factor beta-1 (TGF-β1), which inhibit osteoclast activity and angiogenic factors including vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), and angiopoietin-1 (ANG-1). Expression of integrins, transmembrane extracellular matrix recognition proteins, was measured by real-time polymerase chain reaction. Culture on titanium alloy stimulated osteoprotegerin, TGF-β1, VEGF-A, FGF-2, and angiopoietin-1 production, and levels were greater on rough titanium alloy than on smooth titanium alloy. All factors measured were significantly lower on PEEK than on smooth or rough titanium alloy. Culture on titanium alloy stimulated expression of messenger RNA for integrins that recognize Type I collagen in comparison with PEEK. Rough titanium alloy stimulated cells to create an osteogenic-angiogenic microenvironment. The osteogenic-angiogenic responses to titanium alloy were greater than PEEK and greater on rough titanium alloy than on smooth titanium alloy. Surface features regulated expression of integrins important in collagen recognition. These factors may increase bone formation, enhance integration, and improve implant stability in interbody spinal fusions. Copyright © 2013 Elsevier Inc. All rights reserved.

The effect of porosity on the mechanical properties of porous titanium scaffolds: comparative study on experimental and analytical values

NASA Astrophysics Data System (ADS)

Khodaei, Mohammad; Fathi, Mohammadhossein; Meratian, Mahmood; Savabi, Omid

2018-05-01

Reducing the elastic modulus and also improving biological fixation to the bone is possible by using porous scaffolds. In the present study, porous titanium scaffolds containing different porosities were fabricated using the space holder method. Pore distribution, formed phases and mechanical properties of titanium scaffolds were studied by Scanning Electron Microscope (SEM), x-ray diffraction (XRD) and cold compression test. Then the results of compression test were compared to the Gibson-Ashby model. Both experimentally measured and analytically calculated elastic modulus of porous titanium scaffolds decreased by porosity increment. The compliance between experimentally measured and analytically calculated elastic modulus of titanium scaffolds are also increased by porosity increment.

Maximizing PTH Anabolic Osteoporosis Therapy. Revision

DTIC Science & Technology

2016-09-01

Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for Public Release; Distribution Unlimited...SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick...mono-therapy and PTH+ anti-catabolic combination therapies on Nmp4-/- and wild type (WT) mice. The scope of the research comprises the following

Papillary Tubal Hyperplasia. The Putative Precursor of Ovarian Atypical Proliferative (Borderline) Serous Tumors, Noninvasive Implants and Endosalpingiosis

PubMed Central

Kurman, Robert J.; Vang, Russell; Junge, Jette; Hannibal, Charlotte Gerd; Kjaer, Susanne K.; Shih, Ie-Ming

2011-01-01

In contrast to the controversy regarding the terminology and behavior of ovarian noninvasive low-grade serous tumors (atypical proliferative serous tumor [APST] and serous borderline tumor [SBT]), little attention has been directed to their origin. Similarly, until recently, proliferative lesions in the fallopian tube have not been extensively studied. The recent proposal that ovarian high-grade serous carcinomas are derived from intraepithelial carcinoma in the fallopian tube prompted us to evaluate the possible role of the fallopian tube in the genesis of low-grade serous tumors. We have identified a lesion, designated “papillary tubal hyperplasia (PTH)”, characterized by small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen and which are frequently associated with APSTs. Twenty-two cases in this study were selected from a population-based study in Denmark of approximately 1000 patients with low-grade ovarian serous tumors in whom implants were identified on the fallopian tube. Seven additional cases were seen recently in consultation at The Johns Hopkins Hospital (JHH). These 7 cases were not associated with an ovarian tumor. Papillary tubal hyperplasia was found in 20 (91%) of the 22 cases in the Danish study. Based on this association of PTH with APSTs with implants and the close morphologic resemblance of PTH, not only to the primary ovarian APSTs but also to the noninvasive epithelial implants and endosalpingiosis, we speculate that the small papillae and clusters of cells from the fallopian tubes implant on ovarian and peritoneal surfaces to produce these lesions. The 7 JHH cases of PTH that were not associated with an ovarian tumor support the view that PTH is the likely precursor lesion. We propose a model for the development of ovarian and extraovarian low-grade serous proliferations (APST, noninvasive epithelial implants and endosalpingiosis) that postulates that all of these lesions are derived from PTH, which appears to be induced by chronic inflammation. If this hypothesis is confirmed, then it can be concluded that low- and high-grade ovarian tumors develop from tubal epithelium and involve the ovary secondarily. PMID:21997682

Targeted surgical parathyroidectomy in end-stage renal disease patients and long-term metabolic control: A single-center experience in the current era.

PubMed

Fülöp, Tibor; Koch, Christian A; Farah Musa, Abdeen R; Clark, Christopher M; Gharaibeh, Kamel A; Lengvársky, Zsolt; Hamrahian, Mehrdad; Pitman, Karen T; Dixit, Mehul P

2018-02-15

The long-term results of surgical parathyroidectomy (PTX) in end-stage renal disease (ESRD) patients are less well known in the modern era of newer activated vitamin-D analogs, calcimimetics and intraoperative monitoring of parathyroid hormone (PTH). We performed a retrospective chart review of all ESRD patients undergoing PTX at the University of Mississippi Medical Center between January 2005 and August 2011, with follow-up data as available up to 4 years. All PTXs were performed with intraoperative second-generation PTH monitoring and targeted gland size reduction. The cohort (N = 37) was relatively young with a mean (±SD) age of 48.4 ± 13.9. 94.6% of the subjects were African American and 59.5% female. Preoperatively, 45.9% received cinacalcet (CNC) at a mean dose of 63.5 ± 20.9 mg. The size of the largest removed glands measured 1.7 ± 0.8 cm and almost all (94.6%) glands had hyperplasia on histology. The mean length of inpatient stay was 5.5 ± 2.4 days. Preoperative calcium/phosphorus measured 9.6 ± 1.2/6.6 ± 1.7 mg/dL with PTH concentrations of 1589 ± 827 pg/mL. Postoperative PTH values measured 145.4 ± 119.2 pg/mL. Preoperative PTH strongly correlated (P < 0.0001) with both alkaline phosphatase (ALP) levels (r: 0.596) and the number of inpatient days (r: 0.545), but not with CNC administration. Independent predictors for the duration of hospitalization were preoperative ALP (beta 0.469; P = 0.001) and age (beta -0.401; P = 0.005) (R 2 0.45); for postoperative hypocalcemia, age (beta: -0.321; P = 0.006) and preoperative PTH (beta: 0.431; P = 0.036) were significant in linear regression models with stepwise selection. Gland-sparing PTX achieved acceptable control of ESRD-associated hyperparathyroidism in most patients from a socioeconomically challenged, underserved population of the United States. © 2018 International Society for Hemodialysis.

Serum 25-hydroxyvitamin D and bone turnover markers in Palestinian postmenopausal osteoporosis and normal women.

PubMed

Kharroubi, Akram; Saba, Elias; Smoom, Riham; Bader, Khaldoun; Darwish, Hisham

2017-12-01

This study evaluated the association of vitamin D and bone markers with the development osteoporosis in Palestinian postmenopausal women. Even though vitamin D deficiency was very high for the recruited subjects, it was not associated with osteoporosis except for bones of the hip. Age and obesity were the strongest determining factors of the disease. The purpose of this study was to investigate the association of bone mineral density (BMD) with serum vitamin D levels, parathyroid hormone (PTH), calcium, obesity, and bone turnover markers in Palestinian postmenopausal women. Three hundred eighty-two postmenopausal women (≥45 years) were recruited from various women clinics for BMD assessment (131 women had osteoporosis and 251 were normal and served as controls). Blood samples were obtained for serum calcium, PTH, 25(OH)D, bone formation (N-terminal propeptide (PINP)), and bone resorption (serum C-terminal telopeptide of type I collagen (CTX1)) markers. Women with osteoporosis had statistically significant lower mean weight, height, body mass index (BMI), and serum calcium (p < 0.05) compared to controls. No significant differences were detected between the mean values of bone turnover markers (CTX and PINP), 25(OH)D, and PTH of the two groups. Women with vitamin D deficiency (severe and insufficiency) represented 85.9% of the study subjects. Multiple and logistic regression showed that age and BMI significantly affected BMD and vitamin D had a significant association with BMD only at the lumbar spine. BMI was positively correlated with BMD and PTH but negatively correlated with vitamin D. Logistic regression showed that the odds ratio (OR) for having osteoporosis decreased with increasing BMI (overweight OR = 0.11, p = 0.053; obese OR = 0.05, p = 0.007). There was no direct correlation between BMD and PTH, bone turnover markers, and vitamin D except at the lumbar spine. A negative correlation between BMD and age and a positive correlation with BMI were observed. The protective effect of obesity on osteoporosis was complicated by the effect of obesity on vitamin D and PTH.

Vitamin D, parathyroid hormone, and acroosteolysis in systemic sclerosis.

PubMed

Braun-Moscovici, Yolanda; Furst, Daniel E; Markovits, Doron; Rozin, Alexander; Clements, Philip J; Nahir, Abraham Menahem; Balbir-Gurman, Alexandra

2008-11-01

.Sclerodactyly with acroosteolysis (AO) and calcinosis are prominent features of systemic sclerosis (SSc), but the pathogenesis of these findings is poorly understood. Vitamin D and parathyroid hormone (PTH) have a crucial role in bone metabolism and resorption and may affect AO and calcinosis. We assessed vitamin D and PTH in patients with SSc. Medical records of 134 consecutive patients with SSc (American College of Rheumatology criteria) followed at the rheumatology department during the years 2003-2006 were reviewed for clinical assessment, laboratory evaluation [including 25(OH) vitamin D, calcium, phosphorus, alkaline phosphatase, PTH, creatinine, and albumin]; imaging data confirming AO and/or calcinosis. Patients followed routinely at least once a year were included (81 patients). Of these, 60 patients' medical records were found to have complete, relevant clinical, laboratory, and radiographic imaging. Thirteen patients had diffuse disease and 47 limited disease - 51 women and 9 men, 44 Jews and 16 Arabs; mean age 55 +/- 14 years; disease duration 8 +/- 6 years. AO with or without calcinosis was observed in 42 patients (70%). Vitamin D deficiency was found in 46% of patients (16 out of 44 Jewish patients, 10 out of 16 Arab patients). PTH was elevated in 21.7% of patients. Significant correlations were observed between acroosteolysis and PTH (p = 0.015), calcinosis (p = 0.009), and disease duration (p = 0.008), and between PTH and vitamin D levels (p = 0.01). All patients had normal serum concentrations of calcium, phosphorus, magnesium, and albumin, and liver and kidney functions. In this group of Mediterranean patients with SSc, the incidence of vitamin D deficiency and secondary hyperparathyroidism was surprisingly high. This finding correlated with the occurrence of AO and calcinosis. Low levels of vitamin D may reflect silent malabsorption and might be a risk factor for secondary hyperparathyroidism and bone resorption. Traditional dress habits and low exposure to sun may contribute to vitamin D deficiency in an Arab population but do not explain all the findings. The pathogenesis of these findings needs to be corroborated in other SSc populations.

Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies

PubMed Central

2010-01-01

Background Vitamin D supplementation for fracture prevention is widespread despite conflicting interpretation of relevant randomised controlled trial (RCT) evidence. This study summarises quantitatively the current evidence from RCTs and observational studies regarding vitamin D, parathyroid hormone (PTH) and hip fracture risk. Methods We undertook separate meta-analyses of RCTs examining vitamin D supplementation and hip fracture, and observational studies of serum vitamin D status (25-hydroxyvitamin D (25(OH)D) level), PTH and hip fracture. Results from RCTs were combined using the reported hazard ratios/relative risks (RR). Results from case-control studies were combined using the ratio of 25(OH)D and PTH measurements of hip fracture cases compared with controls. Original published studies of vitamin D, PTH and hip fracture were identified through PubMed and Web of Science databases, searches of reference lists and forward citations of key papers. Results The seven eligible RCTs identified showed no significant difference in hip fracture risk in those randomised to cholecalciferol or ergocalciferol supplementation versus placebo/control (RR = 1.13[95%CI 0.98-1.29]; 801 cases), with no significant difference between trials of <800 IU/day and ≥800 IU/day. The 17 identified case-control studies found 33% lower serum 25(OH)D levels in cases compared to controls, based on 1903 cases. This difference was significantly greater in studies with population-based compared to hospital-based controls (χ21 (heterogeneity) = 51.02, p < 0.001) and significant heterogeneity was present overall (χ216 (heterogeneity) = 137.9, p < 0.001). Serum PTH levels in hip fracture cases did not differ significantly from controls, based on ten case-control studies with 905 cases (χ29 (heterogeneity) = 149.68, p < 0.001). Conclusions Neither higher nor lower dose vitamin D supplementation prevented hip fracture. Randomised and observational data on vitamin D and hip fracture appear to differ. The reason for this is unclear; one possible explanation is uncontrolled confounding in observational studies. Post-fracture PTH levels are unrelated to hip fracture risk. PMID:20540727

Association of the cystatin C/creatinine ratio with the renally cleared hormones parathyroid hormone (PTH) and brain natriuretic peptide (BNP) in primary care patients: a cross-sectional study.

PubMed

Risch, Martin; Risch, Lorenz; Purde, Mette-Triin; Renz, Harald; Ambühl, Patrice; Szucs, Thomas; Tomonaga, Yuki

2016-09-01

The ratio of cystatin C to creatinine (cysC/crea) is regarded as a marker of glomerular filtration quality and predicts mortality. It has been hypothesized that increased mortality may be mediated by the retention of biologically active substances due to shrinking glomerular pores. The present study investigated whether cysC/crea is independently associated with the levels of two renally cleared hormones, which have been linked to increased mortality. We conducted a multicenter, cross-sectional study with a random selection of general practitioners (GPs) from all GP offices in seven Swiss cantons. Markers of glomerular filtration quality were investigated together with estimated glomerular filtration rate (eGFR), albuminuria and urinary neutrophil gelatinase associated lipocalin (uNGAL) as well as two renally cleared low-molecular-weight protein hormones (i.e. BNP and PTH), Morbidity was assessed with the Charlson Comorbidity Index (CCI). A total of 1000 patients (433 males; mean age 57 ± 17 years) were included. There was a significant univariate association of BNP (r = 0.36, p < 0.001) and PTH (r = 0.18, p < 0.001) with cysC/crea. An adjusted model that accounted for kidney function (eGFR), altered glomerular structure (albuminuria), renal stress (uNGAL), and CCI showed that BNP and PTH were independently associated with cysC/crea as well as with the ratio of cystatin C-based to creatinine-based eGFR. In conclusion, in primary care patients, BNP and PTH are independently associated both with markers of glomerular filtration quality and eGFR regardless of structural kidney damage or renal stress. These findings offer an explanation, how altered glomerular filtration quality could contribute to increased mortality.

Prophylactic oral calcium supplementation therapy to prevent early post thyroidectomy hypocalcemia and evaluation of postoperative parathyroid hormone levels to detect hypocalcemia: A prospective randomized study.

PubMed

Arer, Ilker Murat; Kus, Murat; Akkapulu, Nezih; Aytac, Huseyin Ozgur; Yabanoglu, Hakan; Caliskan, Kenan; Tarim, Mehmet Akin

2017-02-01

Postoperative hypocalcemia is the most common complication after total thyroidectomy. Postoperative parathyroid hormone (PTH) measurement is one of the methods to detect or prevent postoperative hypocalcemia. Prophylactic oral calcium supplementation is another method to prevent early postoperative hypocalcemia. The aim of this study is to detect the accurate timing of PTH and evaluate efficacy of routine oral calcium supplementation for postoperative hypocalcemia. A total of 106 patients were performed total thyroidectomy. Rotuine oral calcium supplementation was given to group 1 and no treatment to group 2 according to randomization. Serum calcium and PTH level of patients in group 2 at postoperative 6, 12 and 24 h and patients in both groups at postoperative day 7 were evaluated. Patients were compared according to age, sex, operation findings, serum calcium and PTH levels and symptomatic hypocalcemia. Half of the patients (50%) were in group 1. Most of the patients were female (83%). The most common etiology of thyroid disease was multinodular goiter (64.1%). Oral calcium supplementation was given to 18 (33.9%) patients in group 2. Symptomatic hypocalcemia for group 1 and 2 was found to be 1.9 and 33.9% respectively (p < 0.05). No statistical difference can be observed regarding the timing of serum biomarkers. Serum PTH levels at postoperative 12 and 24 h can predict early post-thyroidectomy hypocalcemia. Prophylactic oral calcium supplementation therapy can prevent early post-thyroidectomy hypocalcemia with advantages of being cost effective and safe. Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Vitamin C deficiency and secondary hyperparathyroidism in chronic haemodialysis patients.

PubMed

Richter, Anja; Kuhlmann, Martin K; Seibert, Eric; Kotanko, Peter; Levin, Nathan W; Handelman, Garry J

2008-06-01

Maintenance haemodialysis patients often suffer from secondary hyperparathyroidism and serum parathyroid hormone levels may be influenced by nutritional variables. We examined serum bio-intact parathyroid hormone (BiPTH) and plasma vitamin C in 117 chronic haemodialysis patients. Plasma vitamin C was measured by high-performance liquid chromatography with electrochemical detection, on samples collected before start of the dialysis treatment. Plasma vitamin C showed a significant positively skewed distribution, ranging from <2 microM to >300 microM. We found 15% (n = 17) of the patients with severe vitamin C deficiency (<10 microM), 66% (n = 77) in the range 10-80 microM, and 19% (n = 23) with plasma vitamin C >80 microM, the upper limit of normal for non-renal disease population. High plasma vitamin C was associated with lower plasma BiPTH (P = 0.005, one-way analysis of variance), and this association persisted after stepwise multiple regression for other factors known to influence PTH. Low vitamin C levels were also associated with increased serum alkaline phosphatase, a further indicator of the impact of vitamin C status on bone metabolism. Patients who reported dietary vitamin C intake of >or=100 mg/day had lower BiPTH (P = 0.015), consistent with findings from plasma measurements of vitamin C. This novel observation of the interaction between PTH and vitamin C may result from effects of vitamin C on cAMP-linked signalling pathways in bone and parathyroid gland. This finding does not yet warrant therapeutic intervention with supplemental vitamin C to remedy secondary hyperparathyroidism. However, further research may indicate a key interaction between vitamin C and the parathyroid hormone linked signalling pathways, and may uncover mechanisms of therapeutic importance.

A new mutation in the calcium-sensing receptor gene causing hypocalcaemia: case report of a father and two sons.

PubMed

Schoutteten, M K; Bravenboer, B; Seneca, S; Stouffs, K; Velkeniers, B

2017-07-01

Regulation of calcium is mediated by parathyroid hormone (PTH) and 1.25-dihydroxyvitamine D3. The calcium-sensing receptor (CaSR) regulates PTH release by a negative feedback system. Gain-of-function mutations in the CaSR gene reset the calcium-PTH axis, leading to hypocalcaemia. We analysed a family with hypocalcaemia. The proband was a 47-year-old man (index, patient I1), who presented with paraesthesias in both limbs. He has two sons (patient II1 a nd I I2). The probands' lab results showed: serum calcium of 1.95 mmol/l, albumin 41 g/l, phosphate 0.81 mmol/l and PTH 6.6 ng/l (normal 15-65 ng/l). Based on this analysis, we suspected a hereditary form of hypocalcaemia and performed genetic testing by polymerase chain reaction and Sanger sequencing of the coding regions and intron boundaries of the CaSR gene. Genetic analysis revealed a new heterozygous mutation: c.2195A>G, p.(Asn732Ser) in exon 7. The lab results of patient II1 showed: serum calcium of 1.93 mmol/l, phosphate 1.31 mmol/l, albumin 41 g/l, and PTH 24.3 ng/l. His genotype revealed the same activating mutation and, like his father, he also lost his scalp hair at an early adolescent age. Patient II2 is asymptomatic, and has neither biochemical abnormalities, nor the familial CaSR gene mutation. He still has all his scalp hair. 1) The c.2195A>G, p.(Asn732Ser) mutation in exon 7 of the CaSR gene leads to hypocalcaemia, and has not been reported before in the medical literature. 2) Possibly, this mutation is linked to premature baldness.

Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases.

PubMed

Martin, T John

2016-07-01

Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects. Copyright © 2016 the American Physiological Society.

Relationship of associated secondary hyperparathyroidism to serum fibroblast growth factor-23 in end stage renal disease: A case-control study

PubMed Central

Sliem, Hamdy; Tawfik, Gamal; Moustafa, Fadia; Zaki, Heba

2011-01-01

Introduction: Secondary hyperparathyroidism (SHPT) is an insidious disease that develops early in the course of chronic kidney disease (CKD) and increases in severity as the glomerular filtration rate deteriorates. Recent studies have identified fibroblast growth factor-23 (FGF23) as a new protein with phosphaturic activity. It is mainly secreted by osteoblasts and is now considered the most important factor for regulation of phosphorus homeostasis. It is not yet proven if there is any direct relation between parathyroid hormone (PTH) and FGF23. The present study aims to evaluate the relation between serum FGF23, phosphorus, and PTH in end-stage renal disease in patients with SHPT on regular hemodialysis. Materials and Methods: Forty-six consecutive CKD adult patients (case group) and 20 healthy adults (control group) were included in the study. All patients had SHPT and were on regular hemodialysis. Both groups were subjected to full medical history, clinical examination and biochemical studies. Serum phosphorus, calcium, ferritin, hemoglobin level, blood urea, creatinine, PTH, and FGF23 were analyzed. Results: Levels of FGF23 were significantly higher in the case group in comparison with those in the control group, viz., 4-fold, and positively correlated with PTH. Phosphorus levels in the case group were significantly high in spite of the increasing levels of FGF23. Both PTH and FGF23 were positively correlated with phosphorus and negatively with hemoglobin levels. Conclusion: SHPT and FGF23 may have a partial role in the development of anemia in patients with CKD. FGF23 could be a central factor in the pathogenesis of SHPT. Its role in controlling hyperphosphatemia in CKD is vague. PMID:21731867

Circulating osteoprotegerin and sRANKL concentrations in the perinatal period at term. The impact of intrauterine growth restriction.

PubMed

Briana, Despina D; Boutsikou, Maria; Baka, Stavroula; Hassiakos, Demetrios; Gourgiotis, Demetrios; Malamitsi-Puchner, Ariadne

2009-01-01

Intrauterine growth restriction (IUGR) has been associated with low bone mass in infancy and increased risk for osteoporosis development in adult life. Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) are main determinants of bone resorption. To investigate OPG and soluble RANKL (sRANKL) concentrations in maternal, fetal and neonatal serum of IUGR patients and appropriate for gestational age (AGA) pregnancies. Additionally, plasma intact parathormone (PTH) concentrations were evaluated. Circulating OPG, sRANKL and PTH concentrations were measured in 40 mothers and their singleton full-term fetuses-neonates (AGA: n = 20, and IUGR: n =20) on postnatal days 1 (N1) and 4 (N4). No significant differences in OPG, sRANKL or PTH concentrations were observed between AGA and IUGR groups. In both groups, maternal OPG concentrations were elevated compared with fetal, and N1 and N4 concentrations (p < or = 0.045 in all cases). N4 sRANKL concentrations were elevated compared with maternal, fetal and N1 ones (p < or = 0.01 in all cases). Fetal and N1 sRANKL concentrations correlated positively with PTH levels (r = 0.642, p = 0.024 and r = 0.584, p = 0.046, respectively). The lack of a difference in circulating OPG, sRANKL or PTH concentrations between IUGR cases and AGA controls suggests that the low bone mass of IUGR infants may not be related to higher bone resorption rates. The increased maternal, compared with fetal/neonatal, OPG concentrations may suggest their placental origin. The lower OPG and higher sRANKL concentrations in fetuses and neonates could represent high bone resorption rates. Copyright 2009 S. Karger AG, Basel.

Cloning and regulation of rat tissue inhibitor of metalloproteinases-2 in osteoblastic cells

NASA Technical Reports Server (NTRS)

Cook, T. F.; Burke, J. S.; Bergman, K. D.; Quinn, C. O.; Jeffrey, J. J.; Partridge, N. C.

1994-01-01

Rat tissue inhibitor of metalloproteinases-2 (TIMP-2) was cloned from a UMR 106-01 rat osteoblastic osteosarcoma cDNA library. The 969-bp full-length clone demonstrates 98 and 86% sequence identity to human TIMP-2 at the amino acid and nucleic acid levels, respectively. Parathyroid hormone (PTH), at 10(-8) M, stimulates an approximately twofold increase in both the 4.2- and 1.0-kb transcripts over basal levels in UMR cells after 24 h of exposure. The PTH stimulation of TIMP-2 transcripts was not affected by the inhibitor of protein synthesis, cycloheximide (10(-5) M), suggesting a primary effect of the hormone. This is in contradistinction to regulation of interstitial collagenase (matrix metalloproteinase-1) by PTH in these same cells. Nuclear run-on assays demonstrate that PTH causes an increase in TIMP-2 transcription that parallels the increase in message levels. Parathyroid hormone, in its stimulation of TIMP-2 mRNA, appears to act through a signal transduction pathway involving protein kinase A (PKA) since the increase in TIMP-2 mRNA is reproduced by treatment with the cAMP analogue, 8-bromo-cAMP (5 x 10(-3) M). The protein kinase C and calcium pathways do not appear to be involved due to the lack of effect of phorbol 12-myristate 13-acetate (2.6 x 10(-6) M) and the calcium ionophore, ionomycin (10(-7) M), on TIMP-2 transcript abundance. In this respect, regulation of TIMP-2 and collagenase in osteoblastic cells by PTH are similar. However, we conclude that since stimulation of TIMP-2 transcription is a primary event, the PKA pathway must be responsible for a direct increase in transcription of this gene.

Urbanization of black South African women may increase risk of low bone mass due to low vitamin D status, low calcium intake, and high bone turnover.

PubMed

Kruger, Marlena C; Kruger, Iolanthé M; Wentzel-Viljoen, Edelweiss; Kruger, Annamarie

2011-10-01

Globally, rural to urban migration is accompanied by changes in dietary patterns and lifestyle that have serious health implications, including development of low bone mass. We hypothesized that serum 25 (OH) vitamin D3 (25[OH]D3) levels will be lower, bone turnover higher, and nutrition inadequate in urban postmenopausal black women, increasing risk for low bone mass. We aimed to assess the prevalence of risk factors for low bone mass in 1261 black women from rural and urban areas in the North West Province of South Africa (Prospective Urban and Rural Epidemiology-South Africa project). Fasting blood samples were taken; and participants were interviewed to complete questionnaires on self-reported diseases, fractures, and dietary intakes. Bone health markers were assessed in a subgroup of 658 women older than 45 years. Specific lifestyle risk factors identified were inactivity, smoking, injectable progestin contraception use, and high alcohol consumption. Dietary risk factors identified were low calcium and high animal protein, phosphorous, and sodium intakes. The 25(OH)D3 and C-terminal telopeptide (CTX) levels were significantly higher in the rural vs the urban women older than 50 years. Parathyroid hormone (PTH) levels increased with age in both groups. The 25(OH)D levels were inversely correlated with CTX and PTH in rural women. In urban women, PTH and CTX were correlated while dietary calcium was inversely correlated with CTX and PTH with 25(OH)D3. The combination of low dietary calcium (<230 mg/d), marginally insufficient 25(OH)D3 status, and raised PTH may result in increased bone resorption. Further research is required to assess bone health and fracture risk in black African women. Copyright © 2011 Elsevier Inc. All rights reserved.

Prevalence of secondary hyperparathyroidism in patients with stage 3 and 4 chronic kidney disease seen in internal medicine.

PubMed

Bureo, Juan Carlos; Arévalo, Jose Carlos; Antón, Joaquín; Adrados, Gaspar; Jiménez Morales, Jose Luis; Robles, Nicolás Roberto

2015-01-01

Despite the high prevalence of chronic kidney disease in the elderly population, few data are available on the frequency of secondary hyperparathyroidism in the Spanish population affected by this problem. We undertook a study on this issue in patients attending the internal medicine departments in our area. An observational, cross-sectional survey performed at internal medicine departments on 415 patients with stage 3 and 4 chronic kidney disease. Clinical history and risk factors were collected using a standardized protocol. Serum creatinine, phosphate, calcium, intact parathormone (PTH) and 25-hydroxy-cholecalciferol (25-OH-vitD) levels were measured in all patients. Among stage 3 patients, 62.9% had PTH levels ≥70pg/mL and 32.7% levels ≥110pg/mL. Median PTH level in stage 4 patients was 120pg/mL (p <0.001), and 77.9% of these patients had PTH ≥70pg/mL (p <0.001) and 54.1% ≥110pg/mL (p=0.015). Adequate 25-hydroxy-cholecalciferol levels were found in only 7.2% of stage 3 patients and 4.1% of stage 4 patients. Only 7.2% of stage 3 patients had hyperphosphatemia, as compared to 25.4% of stage 4 patients (p <0.001). Hyperparathyroidism is a common complication of stage 3 and 4 chronic kidney disease which is not associated to detectable changes in serum calcium and phosphate levels. It is therefore advisable to measure PTH levels in all patients with decreased glomerular filtration rate. Copyright © 2015 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Pathway to Hope: an indigenous approach to healing child sexual abuse.

PubMed

Payne, Diane; Olson, Kimber; Parrish, Jared W

2013-01-01

The Alaska Native (AN) population has endured multiple historical traumatic events. This population has poorer health outcomes on nearly all factors compared with Alaska non-Natives with more than 75% reportedly being physically assaulted in their lifetime, and child sexual abuse nearly 6 times the national average. This article describes the Pathway to Hope (PTH) program, which is an indigenous approach to ending silence and denial related to child sexual abuse and encourages multigenerational healing. PTH was developed by ANs who believe that each community is unique, thus strategies for ending denial and support for healing must be woven from the historical context, cultural strengths of individual communities. Strengths-based solutions built on truth, honesty, compassion and shared responsibility for healing and protecting today's children have been profound and successful. The PTH curriculum addresses child sexual abuse from a historical perspective; that the higher rates of sexual abuse among certain Tribes, regions and communities is linked in part to years of victimisation, but may also be perpetuated by internalised oppression and lateral violence among Tribal members. Data suggest that community-based dialogue and wisdom of Native elders and spiritual leaders paired with readiness of community service providers are necessary for sustained change. At all levels, this Indigenous model for learning, sharing, helping and healing brings hope for an end to denial and silence about child sexual abuse for Native people. The PTH program utilises the wisdom and values that have sustained Native people for generations. Ending silence and denial about child sexual abuse and building upon strengths have assisted many Indigenous communities begin the journey toward wellness. Through the PTH, communities have taken steps to accept the challenges associated with establishing safety for children, supporting child victims in healing and to holding offenders accountable.

Vitamin D and its relation with ionic calcium, parathyroid hormone, maternal and neonatal characteristics in pregnancy after roux-en-Y gastric bypass.

PubMed

Medeiros, Marina; Matos, Andréa C; Pereira, Silvia E; Saboya, Carlos; Ramalho, Andréa

2016-03-01

The objective of this study was to evaluate vitamin D nutritional status and its relation with ionic calcium, parathyroid hormone (PTH), maternal anthropometry and perinatal outcomes in pregnant women who previously underwent Roux-en-Y gastric bypass (RYGB) surgery. In a clinic specialized in obesity control located in the city of Rio de Janeiro (Brazil), the following information were collected for adult women who underwent RYGB before pregnancy: serum concentrations of vitamin D [25(OH)D], calcium and PTH per gestational trimester and data on maternal anthropometry, gestational intercurrences and perinatal outcomes. The present study included 46 post-RYGB pregnant women. The prevalence of pregnant women with deficiency (≤20 ng/mL) or insufficiency (≥21 and 29 ng/mL) of vitamin D was above 70% in all trimesters. The prevalence of calcium deficiency was 15.2% in the first and in the second trimesters and 20% in the third trimester, while the prevalence of excess PTH was 19.6, 30.4 and 32.6% in the first, the second and the third trimesters, respectively. In the second and the third trimesters, a significant difference was observed between concentrations of 25(OH)D, and a negative correlation was observed between concentrations of calcium and PTH. Association of 25(OH)D with urinary tract infection (UTI) was found, but there was no association with calcium, PTH, maternal anthropometry, type of delivery and weight and gestational age at birth The post-RYGB pregnant women showed an elevated serum inadequacy (deficiency or insufficiency) of 25(OH)D during pregnancy. Maternal vitamin D status showed no association with maternal variables, except UTI, and the neonatal variables analyzed.

Effects of TNF Inhibitors on Parathyroid Hormone and Wnt Signaling Antagonists in Rheumatoid Arthritis.

PubMed

Adami, Giovanni; Orsolini, Giovanni; Adami, Silvano; Viapiana, Ombretta; Idolazzi, Luca; Gatti, Davide; Rossini, Maurizio

2016-10-01

Tumor necrosis factor α inhibitors (TNFi) are the major class of biologic drug used for the treatment of Rheumatoid arthritis (RA). Their effects on inflammation and disease control are well established, but this is not true also for bone metabolism, especially for key factors as parathyroid hormone and Wnt pathway. Those two pathways are gaining importance in the pathogenesis RA bone damage, both systemic and local, but how the new treatment affects them is still largely unknown. We studied 54 RA patients who were starting an anti-TNFα treatment due to the failure of the conventional synthetic disease-modifying antirheumatic drugs. Serum levels of Wnt/βcatenin pathway inhibitors (Dickkopf-related protein 1, Dkk1, and Sclerostin), Parathyroid hormone (PTH), vitamin D, and bone turnover markers were measured at baseline in the morning after fasting and after 6 months of therapy. We found a significant percentage increase in serum PTH (+32 ± 55 %; p = 0.002) and a decrease in Dkk1 mean serum levels (-2.9 ± 12.1; p = 0.05). PTH percentage changes were positively correlated both with C-terminal telopeptide of type I collagen and Dkk1 percentage changes. Sclerostin serum levels showed no significant difference. TNFi treatment provokes in the short term a rise in PTH levels and a decrease in Dkk1 serum levels. The increase of PTH might promote bone resorption and blunt the normalization of Dkk1 serum levels in RA. Those data give a new insight into TNFi metabolic effects on bone and suggest new strategies to achieve better results in terms of prevention of bone erosions and osteoporosis with TNFi treatment in RA.

Racial differences in cortical bone and their relationship to biochemical variables in black and white children in the early stages of puberty

PubMed Central

Warden, Stuart J.; Hill, Kathleen M.; Ferira, Ashley J.; Laing, Emma M.; Martin, Berdine R.; Hausman, Dorothy B.; Weaver, Connie M.; Peacock, Munro; Lewis, Richard D.

2014-01-01

Introduction Racial differences in bone structure likely have roots in childhood as bone size develops predominantly during growth. This study aimed to compare cortical bone health within the tibial diaphysis of black and white children in the early stages of puberty, and explore the contributions of biochemical variables in explaining racial variation in cortical bone properties. Methods A cross-sectional study was performed comparing peripheral quantitative computed tomography-derived cortical bone measures of the tibial diaphysis and biochemical variables in 314 participants (n=155 males; n=164 blacks) in the early stages of puberty. Results Blacks had greater cortical volumetric bone mineral density, mass and size compared to whites (all p<0.01), contributing to blacks having 17.0% greater tibial strength (polar strength-strain index [SSIP]) (p<0.001). Turnover markers indicated blacks had higher bone formation (osteocalcin [OC] and bone specific alkaline phosphatase) and lower bone resorption (N-terminal telopeptide) than whites (all p<0.01). Blacks also had lower 25-hydroxyvitamin D [25(OH)D], and higher 1,25-dihydroxyvitamin D [1,25(OH)2D] and parathyroid hormone (PTH) (all p<0.05). There were no correlations between tibial bone properties, and 25(OH)D and PTH in whites (all p≥0.10); however, SSIP was negatively and positively correlated with 25(OH)D and PTH in blacks, respectively (all p≤0.02). Variation in bone cross-sectional area and SSIP attributable to race was partially explained by tibial length, 25(OH)D/PTH and OC. Conclusions Divergence in tibial cortical bone properties between blacks and whites is established by the early stages of puberty with the enhanced cortical bone properties in black children possibly being explained by higher PTH and OC. PMID:23093348

Synergistic effects of fibronectin and bone morphogenetic protein on the bioactivity of titanium metal.

PubMed

Biao, M N; Chen, Y M; Xiong, S B; Wu, B Y; Yang, B C

2017-09-01

To improve the biological properties of bioactive titanium metal, recombinant human bone morphogenetic protein 2(rhBMP-2) and fibronectin (Fn) were adsorbed on its surface solely or contiguously to modify the anodic oxidized titanium (AO-Ti), acid-alkali-treated titanium (AA-Ti), and polished titanium (P-Ti). It is found that the different bioactive titanium surface structures had great influence on protein adsorption. The adsorption amounts of BMP adsorbed solely and Fn/BMP adsorbed contiguously were AA-Ti > P-Ti > AO-Ti, and that for Fn adsorbed solely was AA-Ti ≈ P-Ti > AO-Ti. The conformation of proteins was changed remarkably after the adsorption. For BMP, the α-helix decreased on AA-Ti and stabilized on P-Ti and AO-Ti. For Fn, the β-sheet on PT-Ti and AA-Ti increased significantly. For Fn/BMP, the percentage of β-sheet on AA-Ti increased, and that of α-helix on all samples was stable. MSCs showed greater adhesion and spreading on Fn/BMP groups. MTT and Elisa tests showed that the synergistic effects of proteins made the cells proliferate and differentiate faster. It indicated both the surface structure and the synergistic effects of proteins could influence the biological properties of titanium metals. It provides research foundation for improving the biological properties of bioactive titanium metals by simultaneous application of several proteins. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2485-2498, 2017. © 2017 Wiley Periodicals, Inc.

Fabrication of titanium thermal protection system panels by the NOR-Ti-bond process

NASA Technical Reports Server (NTRS)

Wells, R. R.

1971-01-01

A method for fabricating titanium thermal protection system panels is described. The method has the potential for producing wide faying surface bonds to minimize temperature gradients and thermal stresses resulting during service at elevated temperatures. Results of nondestructive tests of the panels are presented. Concepts for improving the panel quality and for improved economy in production are discussed.

Antimicrobial and Osseointegration Properties of Nanostructured Titanium Orthopaedic Implants

PubMed Central

Dittrich, Florian; Köhling, Hedda Luise

2017-01-01

The surface design of titanium implants influences not only the local biological reactions but also affects at least the clinical result in orthopaedic application. During the last decades, strong efforts have been made to improve osteointegration and prevent bacterial adhesion to these surfaces. Following the rule of “smaller, faster, cheaper”, nanotechnology has encountered clinical application. It is evident that the hierarchical implant surface micro- and nanotopography orchestrate the biological cascades of early peri-implant endosseous healing or implant loosening. This review of the literature gives a brief overview of nanostructured titanium-base biomaterials designed to improve osteointegration and prevent from bacterial infection. PMID:29137166

Development and installation of an advanced beam guidance system on Viking`s 2.4 megawatt EB furnace

DOE Office of Scientific and Technical Information (OSTI.GOV)

Motchenbacher, C.A.; Grosse, I.A.

1994-12-31

Viking Metallurgical is a manufacturer of titanium alloy and superalloy seamless ring forgings for the aerospace industry. For more than 20 years Viking has used electron beam cold hearth melting to recover titanium alloy scrap and to produce commercially pure titanium ingot for direct forging. In the 1970`s Viking pioneered electron beam cold hearth melting and in 1983 added a two-gun, 2.4 MW furnace. As part of Vikings efforts to improve process control we have commissioned and installed a new electron beam guidance system. The system is capable of generating virtually unlimited EB patterns resulting in improved melt control.

Characterization of poly(Sodium Styrene Sulfonate) Thin Films Grafted from Functionalized Titanium Surfaces

PubMed Central

Zorn, Gilad; Baio, Joe E.; Weidner, Tobias; Migonney, Veronique; Castner, David G.

2011-01-01

Biointegration of titanium implants in the body is controlled by their surface properties. Improving surface properties by coating with a bioactive polymer is a promising approach to improve the biological performance of titanium implants. To optimize the grafting processes, it is important to fully understand the composition and structure of the modified surfaces. The main focus of this study is to provide a detailed, multi-technique characterization of a bioactive poly(sodium styrene sulfonate) (pNaSS) thin film grafted from titanium surfaces via a two-step procedure. Thin titanium films (~50 nm thick with an average surface roughness of 0.9±0.2nm) prepared by evaporation onto silicon wafers were used as smooth model substrates. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed that the titanium film was covered with a TiO2 layer that was at least 10nm thick and contained hydroxyl groups present at the outermost surface. These hydroxyl groups were first modified with a 3-methacryloxypropyltrimethoxysilane (MPS) cross linker. XPS and ToF-SIMS showed that a monolayer of the MPS molecules were successfully attached onto the titanium surfaces. The pNaSS film was grafted from the MPS modified titanium through atom transfer radical polymerization. Again, XPS and ToF-SIMS were used to verify that the pNaSS molecules were successfully grafted onto the modified surfaces. Atomic force microscopy analysis showed that the film was smooth and uniformly covered the surface. Fourier transform infrared spectroscopy indicated an ordered array of grafted NaSS molecules were present on the titanium surfaces. Sum frequency generation vibration spectroscopy and near edge X-ray absorption fine structure spectroscopy illustrated that the NaSS molecules were grafted onto the titanium surface with a substantial degree of orientational order in the styrene rings. PMID:21892821

The enhancement of photoresponse of an ordered inorganic-organic hybrid architecture by increasing interfacial contacts.

PubMed

Zhang, Bin; Chen, Xudong; Ma, Shaohua; Chen, Yujie; Yang, Jin; Zhang, Mingqiu

2010-02-10

A modified ZnO quantum dot/polythiophene (ZnO/PTh) inorganic-organic hybrid architecture was fabricated by using ordered mesoporous silica (SBA-15) as the retaining template. First, a two-step strategy was developed to synthesize an ordered organic conducting polymer composite (PTh/SBA-15). Then, ZnO quantum dots were in situ formed on the pore walls of the ordered PTh/SBA-15 composite. Photoresponse of the inorganic-organic hybrid was studied with respect to its incident photon to collected electron conversion efficiency (IPCE) and morphology. The presence of SBA-15 proved to be critical for controlling the interfacial morphology and hence enlarging the interfacial area of the inorganic-organic heterojunction. The proposed approach may act as a key method to open up potential applications in photovoltaic devices.

Novel antioxidant capability of titanium induced by UV light treatment.

PubMed

Ueno, Takeshi; Ikeda, Takayuki; Tsukimura, Naoki; Ishijima, Manabu; Minamikawa, Hajime; Sugita, Yoshihiko; Yamada, Masahiro; Wakabayashi, Noriyuki; Ogawa, Takahiro

2016-11-01

The intracellular production of reactive oxygen species (ROS) is a representative form of cellular oxidative stress and plays an important role in triggering adverse cellular events, such as the inflammatory reaction and delayed or compromised differentiation. Osteoblastic reaction to titanium with particular focus on ROS production remains unknown. Ultraviolet (UV) light treatment improves the physicochemical properties of titanium, specifically the induction of super hydrophilicity and removal of hydrocarbon, and eventually enhances its osteoconductivity. We hypothesized that there is a favorable regulatory change of ROS production within osteoblasts in contact with UV-treated titanium. Osteoblasts were cultured on titanium disks with or without UV-pretreatment. The intracellular production of ROS was higher on acid-etch-created rough titanium surfaces than on machine-prepared smooth ones. The ROS production was reduced by 40-50% by UV pretreatment of titanium regardless of the surface roughness. Oxidative DNA damage, as detected by 8-OHdG expression, was alleviated by 50% on UV-treated titanium surfaces. The expression of inflammatory cytokines was consistently lower in osteoblasts cultured on UV-treated titanium. ROS scavenger, glutathione, remained more without being depleted in osteoblasts on UV-treated titanium. Bio-burden test further showed that culturing osteoblasts on UV-treated titanium can significantly reduce the ROS production even with the presence of hydrogen peroxide, an oxidative stress inducer. These data suggest that the intracellular production of ROS and relevant inflammatory reaction, which unavoidably occurs in osteoblasts in contact with titanium, can be significantly reduced by UV pretreatment of titanium, implying a novel antioxidant capability of the particular titanium. Copyright © 2016 Elsevier Ltd. All rights reserved.

Improved Mechanical Compatibility and Cytocompatibility of Ta/Ti Double-Layered Composite Coating

NASA Astrophysics Data System (ADS)

Ding, Ding; Xie, Youtao; Li, Kai; Huang, Liping; Zheng, Xuebin

2017-08-01

In order to improve the mechanical compatibility and cytocompatibility of titanium implants, a composite coating with double layers composed of tantalum and titanium was designed and prepared using plasma spraying technology. In the composite coating, the upper tantalum layer provides a good biocompatibility, and the sublayer of titanium with a porous structure ensures the low elastic modulus. Results show that the fabricated composite coating exhibits a relatively low elastic modulus of 26.7 GPa, which is close to the elastic modulus of human cortical bone. In vitro cytocompatibility evaluation of the composite coating shows that the human bone marrow stromal cells exhibit enhanced adhesion and spreading performance on the double-layered composite coating in comparison with the single-layered titanium coating. In order to eliminate the misgivings of chemical stability of the composite coating in clinical application, electrochemical corrosion of the coating was examined. The results obtained revealed a very weak galvanic corrosion between the tantalum and titanium in the composite coating, which would ensure the safety of the coating in vivo.

Fabrication of anticoagulation layer on titanium surface by sequential immobilization of poly (ethylene glycol) and albumin.

PubMed

Pan, Chang-Jiang; Hou, Yan-Hua; Zhang, Bin-Bin; Zhang, Lin-Cai

2014-01-01

This paper presents a simple method to sequentially immobilize poly (ethylene glycol) (PEG) and albumin on titanium surface to enhance the blood compatibility. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) analysis indicated that PEG and albumin were successfully immobilized on the titanium surface. Water contact angle results showed a better hydrophilic surface after the immobilization. The immobilized PEG or albumin can not only obviously prevent platelet adhesion and activation but also prolong activated partial thromboplastin time (APTT), leading to the improved anticoagulation. Moreover, immobilization of albumin on PEG-modified surface can further improve the anticoagulation. The approach in the present study provides an effective and efficient method to improve the anticoagulation of blood-contact biomedical devices such as coronary stents.

Treatment of Sleep Disorders after Traumatic Brain Injury

PubMed Central

Castriotta, Richard J.; Atanasov, Strahil; Wilde, Mark C.; Masel, Brent E.; Lai, Jenny M.; Kuna, Samuel T.

2009-01-01

Study Objectives: Determine whether treatment of sleep disorders identified in brain injured adults would result in resolution of those sleep disorders and improvement of symptoms and daytime function. Methods: Prospective evaluation of unselected traumatic brain injury patients with nocturnal polysomnography (NPSG), multiple sleep latency test (MSLT), Epworth Sleepiness Scale (ESS), and neuropsychological testing including Psychomotor Vigilance Test (PVT), Profile of Mood States (POMS), and Functional Outcome of Sleep Questionnaire (FOSQ) before and after treatment with continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA), modafinil (200 mg) for narcolepsy and posttraumatic hypersomnia (PTH), or pramipexole (0.375 mg) for periodic limb movements in sleep (PLMS). Setting: Three academic medical centers. Participants: Fifty-seven (57) adults ≥ 3 months post traumatic brain injury (TBI). Measurements And Results: Abnormal sleep studies were found in 22 subjects (39%), of whom 13 (23%) had OSA, 2 (3%) had PTH, 3 (5%) had narcolepsy, 4 (7%) had PLMS, and 12 had objective excessive daytime sleepiness with MSLT score < 10 minutes. Apneas, hypopneas, and snoring were eliminated by CPAP in OSA subjects, but there was no significant change in MSLT scores. Periodic limb movements were eliminated with pramipexole. One of 3 narcolepsy subjects and 1 of 2 PTH subjects had resolution of hypersomnia with modafinil. There was no significant change in FOSQ, POMS, or PVT results after treatment. Conclusions: Treatment of sleep disorders after TBI may result in polysomnographic resolution without change in sleepiness or neuropsychological function. Citation: Castriotta RJ; Atanasov S; Wilde MC; Masel BE; Lai JM; Kuna ST. Treatment of sleep disorders after traumatic brain injury. J Clin Sleep Med 2009;5(2):137-144. PMID:19968047

Combustion Enhancement of Liquid Fuels via Nanoparticle Additions: Screening, Dispersion, and Characterization

DTIC Science & Technology

2015-06-04

These include but are not limited to aluminum, boron, boron carbide (B4C), carbon (graphene), titanium, and tungsten nano-sized particles. When...of plots displaying calculated values for aluminum, titanium, and tungsten additives are shown in Figure 1 to illustrate the potential benefits...of additive weight percent and oxidizer/fuel mixture ratio for aluminum, titanium, and tungsten . With recent improvements in the production and

An investigation of chatter and tool wear when machining titanium

NASA Technical Reports Server (NTRS)

Sutherland, I. A.

1974-01-01

The low thermal conductivity of titanium, together with the low contact area between chip and tool and the unusually high chip velocities, gives rise to high tool tip temperatures and accelerated tool wear. Machining speeds have to be considerably reduced to avoid these high temperatures with a consequential loss of productivity. Restoring this lost productivity involves increasing other machining variables, such as feed and depth-of-cut, and can lead to another machining problem commonly known as chatter. This work is to acquaint users with these problems, to examine the variables that may be encountered when machining a material like titanium, and to advise the machine tool user on how to maximize the output from the machines and tooling available to him. Recommendations are made on ways of improving tolerances, reducing machine tool instability or chatter, and improving productivity. New tool materials, tool coatings, and coolants are reviewed and their relevance examined when machining titanium.

In vitro osteoinduction of human mesenchymal stem cells in biomimetic surface modified titanium alloy implants.

PubMed

Santander, Sonia; Alcaine, Clara; Lyahyai, Jaber; Pérez, Maria Angeles; Rodellar, Clementina; Doblaré, Manuel; Ochoa, Ignacio

2012-01-01

Interaction between cells and implant surface is crucial for clinical success. This interaction and the associated surface treatment are essential for achieving a fast osseointegration process. Several studies of different topographical or chemical surface modifications have been proposed previously in literature. The Biomimetic Advanced Surface (BAS) topography is a combination of a shot blasting and anodizing procedure. Macroroughness, microporosity of titanium oxide and Calcium/Phosphate ion deposition is obtained. Human mesenchymal stem cells (hMCSs) response in vitro to this treatment has been evaluated. The results obtained show an improved adhesion capacity and a higher proliferation rate when hMSCs are cultured on treated surfaces. This biomimetic modification of the titanium surface induces the expression of osteblastic differentiation markers (RUNX2 and Osteopontin) in the absence of any externally provided differentiation factor. As a main conclusion, our biomimetic surface modification could lead to a substantial improvement in osteoinduction in titanium alloy implants.

Multifunctional zirconium nitride/copper multilayer coatings on medical grade 316L SS and titanium substrates for biomedical applications.

PubMed

Kumar, D Dinesh; Kaliaraj, Gobi Saravanan

2018-01-01

Protecting from wear and corrosion of many medical devices in the biomedical field is an existing scientific challenge. Surface modification with multilayer ZrN/Cu coating was deposited on medical grade stainless steel (SS) and titanium substrates to enhance their surface properties. Structural results revealed that the ZrN/Cu coatings are highly crystalline and uniform microstructure on both the substrates. Dry and wet tribological measurements of the coated titanium substrate exhibit enhanced wear resistance and low friction coefficient due to the improved microstructure. Similarly, the corrosion resistance was exceptionally improved on titanium substrates, resulting from the high inertness of coating to the SBF electrolyte solution. Antibacterial activity and epifluorescence results signify the effective killing of pathogens by means of ion release killing as well as contact killing mechanisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced Cellular Adhesion on Titanium by Silk Functionalized with titanium binding and RGD peptides

PubMed Central

Vidal, Guillaume; Blanchi, Thomas; Mieszawska, Aneta J.; Calabrese, Rossella; Rossi, Claire; Vigneron, Pascale; Duval, Jean-Luc; Kaplan, David L.; Egles, Christophe

2012-01-01

Soft tissue adhesion on titanium represents a challenge for implantable materials. In order to improve adhesion at the cell/material interface we used a new approach based on the molecular recognition of titanium by specific peptides. Silk fibroin protein was chemically grafted with titanium binding peptide (TiBP) to increase adsorption of these chimeric proteins to the metal surface. Quartz Crystal Microbalance was used to quantify the specific adsorption of TiBP-functionalized silk and an increase in protein deposition by more than 35% was demonstrated due to the presence of the binding peptide. A silk protein grafted with TiBP and fibronectin-derived RGD peptide was then prepared. The adherence of fibroblasts on the titanium surface modified with the multifunctional silk coating demonstrated an increase in the number of adhering cells by 60%. The improved adhesion was demonstrated by Scanning Electron Microscopy and immunocytochemical staining of focal contact points. Chick embryo organotypic culture also revealed strong adhesion of endothelial cells expanding on the multifunctional silk-peptide coating. These results demonstrated that silk functionalized with TiBP and RGD represents a promising approach to modify cell-biomaterial interfaces, opening new perspectives for implantable medical devices, especially when reendothelialization is required. PMID:22975628

Novel β-TCP Coated Titanium Nanofiber Surface for Enhanced Bone Growth.

PubMed

Lim, Hyun-Pil; Park, Sang-Won; Yun, Kwi-Dug; Park, Chan; Ji, Min-Kyung; Oh, Gye-Jeong; Lee, Jong-Tak; Lee, Kwangmin

2018-02-01

In this study, we examined the effect of β-tricalcium phosphate (β-TCP) coating on alkali-treated CP Grade II titanium surface via RF magnetron sputtering on osteoblast like cell (MC3T3-E1) viability and bone formation in rat tibia. The specimens were divided into three groups; commercially pure titanium (control group), alkali-treated titanium with nanofiber structure (NF group) and β-TCP coating on alkali-treated titanium with nanofiber structure (TNF group). The surface characteristics of specimens were observed under a field emission scanning electron microscope (FE-SEM), and contact angle was measured. The cell viability was assessed in vitro after 1 day, 3 days and 7 days. Implants of 2.0 mm diameter and 5.0 mm length were inserted into the tibia of rats. After 4 wks, the histomorphometric analysis was performed. Group NF and group TNF showed improved hydrophilicity of Ti. Group TNF showed significantly higher cell viability (P < 0.05) after 7 days. The bone to implant contact (BIC) ratio of the control group, NF group, and TNF group were 32.3%, 35.5%, and 63.9%, respectively. The study results suggested that β-TCP coated alkali-treated titanium surface via RF magnetron sputtering might be effective in implant dentistry due to enhanced hydrophilicity, improved cell response, and better osseointegration.

Parameters for calcium metabolism in women with polycystic ovary syndrome who undergo clomiphene citrate stimulation: a prospective cohort study.

PubMed

Ott, J; Wattar, L; Kurz, C; Seemann, R; Huber, J C; Mayerhofer, K; Vytiska-Binstorfer, E

2012-05-01

To evaluate whether parameters for calcium metabolism were associated with characteristics of polycystic ovary syndrome (PCOS). A prospective cohort study. Ninety-one anovulatory, infertile women with PCOS patients underwent clomiphene citrate (CC) stimulation. Main outcome measures were parathyroid hormone (PTH); 25-hydroxyvitamin D3 (25OHD3); serum levels of calcium, phosphorus, magnesium, albumin, and total protein; the serum calcium-phosphorus product; LH; FSH; sexual hormone binding globulin; testosterone; and androstenedione. PTH correlated inversely with serum calcium (r=-0.235; P=0.004) and 25OHD3 (r=-0.664; P<0.001), whereas positive correlations were found between PTH and body mass index (BMI; r=0.270; P=0.010) and between PTH and testosterone (r=0.347; P=0.001). After stimulation with 50 mg CC, 57.1% (52/91) developed a follicle, whereas 26.4% (24/91) became pregnant. In a multivariate model to predict both follicle development and pregnancy, BMI and 25OHD3 deficiency were significant predictive parameters. 25OHD3 deficiency was an independent predictive parameter of CC stimulation outcome, in terms of follicle development and pregnancy. Our results suggest a substantial role of vitamin D in PCOS and infertility treatment in these patients.

Heritability of markers of bone metabolism

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Zwart, S. R.; Hargens, A. R.

2005-01-01

Several classic twin studies show genetic effects on markers of bone health, including bone mineral density and parathyroid hormone (PTH). This study was performed to assess the relative contribution of genetics to biochemical markers of bone metabolism. Fifteen sets of identical twins (8 male, 7 female) were housed in a clinical research center where diet was controlled (15% protein, 55% carbohydrate, 30% fat) for 3 consecutive days. Each day, 24-h urine pools were collected and N-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and serum PTH were measured. The broad-sense heritability factor (H2) is an estimation of the portion of the total variance of a given phenotype that is attributable to genetic variance. H2 was estimated from the correlation coefficient of the phenotype data. H2 for NTX was 94% for males and 80% for females, DPD was 88% for males and 97% for females, urinary calcium excretion was 97% for males and 90% for females, and PTH was 92% for males and 79% for females. Since environmental variability was minimized for the 3 days of data collection, these heritability factors are likely overestimated. Nonetheless, the data support the concept that PTH is a predominantly heritable trait, and suggest that NTX, DPD, and calcium excretion are as well. These biochemical data support the previously documented heritability of bone health.

Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression

NASA Technical Reports Server (NTRS)

Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

2002-01-01

A mechanism explaining the differential skeletal effects of intermittent and continuous elevation of serum parathyroid hormone (PTH) remains elusive. Intermittent PTH increases bone formation and bone mass and is being investigated as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by osteomalacia, focal bone resorption, and peritrabecular bone marrow fibrosis. Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. Many of the beneficial as well as detrimental effects of the hormone appear to be mediated by osteoblast-derived growth factors. This hypothesis was tested using cDNA microgene arrays to compare gene expression in tibia of rats treated with continuous and pulsatile administration of PTH. These treatments result in differential expression of many genes, including growth factors. One of the genes whose steady-state mRNA levels was increased by continuous but not pulsatile administration was platelet-derived growth factor-A (PDGF-A). Administration of a PDGF-A antagonist greatly reduced bone resorption, osteomalacia, and bone marrow fibrosis in a rat model for hyperparathyroidism, suggesting that PDGF-A is a causative agent for this disease. These findings suggest that profiling changes in gene expression can help identify the metabolic pathways responsible for the skeletal responses to the hormone.

Teriparatide promotes healing of critical size femur defect through accelerating angiogenesis and degradation of β-TCP in OVX osteoporotic rat model.

PubMed

Xie, Zhongjie; Weng, Sheji; Li, Hang; Yu, Xia; Lu, Shanshan; Huang, Kate; Wu, Zongyi; Bai, Bingli; Boodhun, Viraj; Yang, Lei

2017-12-01

Accumulating evidence suggests that early angiogenesis has an important effect on the healing of injury. Teriparatide (PTH) is extensively applied for its potent anabolic activity on bone, while little is known about its angiogenic ability which may facilitate new bone formation. In this study, we tested the angiogenic ability of PTH and its effect on degradation of β-tricalcium phosphate (β-TCP) in an ovariectomized (OVX) rat distal femoral metaphysis model. After successful establishment of the OVX model was confirmed, a critical size defect was drilled into each distal femur of the OVX rats. Afterwards all animals were randomly divided into three groups: control group, group β-TCP and group β-TCP+PTH, then rats of group β-TCP+PTH were injected Teriparatide (30 μg/kg) subcutaneous every other day. Four weeks after femur surgery, five specimens from each group were used for Microfil perfusion to reveal blood vessels in the bone defect. The residual rats were harvested for micro-computed tomography, histological analysis and immunochemistry. The results showed Teriparatide facilitated neovascularization, degradation of β-TCP and new bone formation in combination with β-TCP, which may be relevant to neovascularization in an early phase. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Ultrasonic effects on titanium tanning of leather.

PubMed

Peng, Biyu; Shi, Bi; Sun, Danhong; Chen, Yaowen; Shelly, Dennis C

2007-03-01

The effects of ultrasound on titanium tanning of leather were investigated. Either 20 or 40 kHz ultrasound was applied to the titanium tanning of pigskins. Five different treatment conditions were carried out and the effects were examined, such as leather shrinkage temperature (T(s)), titanium content and titanium distribution in the leather. Overall heat loading was carefully controlled. Results showed that 20 kHz ultrasound effectively improves titanium agent penetration into the hide and increases the leather's shrinkage temperature. Doubling the frequency to 40 kHz produced negligible enhancements. An impressive 105.6 degrees C T(s) was achieved using 20 kHz ultrasound pretreatment of the tanning liquor followed by 20 kHz ultrasound in the tanning mixture (liquor plus pigskins) in a special salt-free medium. Finally, using a unique ultrasonic tanning drum with 26.5 kHz ultrasound, the T(s) reached a record level of 106.5 degrees C, a value not achieved in conventional (no ultrasound) titanium tanning. The ultrasonic effects on titanium tanning of leather are judged to make a superior mineral tanned leather.

UV photofunctionalization promotes nano-biomimetic apatite deposition on titanium

PubMed Central

Saita, Makiko; Ikeda, Takayuki; Yamada, Masahiro; Kimoto, Katsuhiko; Lee, Masaichi Chang-Il; Ogawa, Takahiro

2016-01-01

Background Although biomimetic apatite coating is a promising way to provide titanium with osteoconductivity, the efficiency and quality of deposition is often poor. Most titanium implants have microscale surface morphology, and an addition of nanoscale features while preserving the micromorphology may provide further biological benefit. Here, we examined the effect of ultraviolet (UV) light treatment of titanium, or photofunctionalization, on the efficacy of biomimetic apatite deposition on titanium and its biological capability. Methods and results Micro-roughed titanium disks were prepared by acid-etching with sulfuric acid. Micro-roughened disks with or without photofunctionalization (20-minute exposure to UV light) were immersed in simulated body fluid (SBF) for 1 or 5 days. Photofunctionalized titanium disks were superhydrophilic and did not form surface air bubbles when immersed in SBF, whereas non-photofunctionalized disks were hydrophobic and largely covered with air bubbles during immersion. An apatite-related signal was observed by X-ray diffraction on photofunctionalized titanium after 1 day of SBF immersion, which was equivalent to the one observed after 5 days of immersion of control titanium. Scanning electron microscopy revealed nodular apatite deposition in the valleys and at the inclines of micro-roughened structures without affecting the existing micro-configuration. Micro-roughened titanium and apatite-deposited titanium surfaces had similar roughness values. The attachment, spreading, settling, proliferation, and alkaline phosphate activity of bone marrow-derived osteoblasts were promoted on apatite-coated titanium with photofunctionalization. Conclusion UV-photofunctionalization of titanium enabled faster deposition of nanoscale biomimetic apatite, resulting in the improved biological capability compared to the similarly prepared apatite-deposited titanium without photofunctionalization. Photofunctionalization-assisted biomimetic apatite deposition may be a novel method to effectively enhance micro-roughened titanium surfaces without altering their microscale morphology. PMID:26834469

Supplemental vitamin D and calcium in the management of African Americans with heart failure having hypovitaminosis D.

PubMed

Zia, Ayhan A; Komolafe, Babatunde O; Moten, Marriyam; Ahokas, Robert A; McGee, Jesse E; William Rosenberg, E; Bhattacharya, Syamal K; Weber, Karl T

2011-02-01

A dyshomeostasis of macro- and micronutrients, including vitamin D and oxidative stress, are common pathophysiologic features in patients with congestive heart failure (CHF). In African Americans (AA) with CHF, reductions in plasma 25(OH)D are of moderate-to-marked severity (<20 ng/mL) and may be accompanied by ionized hypocalcemia with compensatory increases in serum parathyroid hormone (PTH). The management of hypovitaminosis D in AA with CHF has not been established. Herein, a 14-week regimen: an initial 8 weeks of oral ergocalciferol (50,000 IU once weekly); followed by a 6-week maintenance phase of cholecalciferol (1400 IU daily); and a CaCO₃ (1000 mg daily) supplement given throughout was designed and tested. Fourteen AA patients having a dilated (idiopathic) cardiomyopathy with reduced ejection fraction (EF, <35%) were enrolled: all completed the initial 8-week course; and 12 complied with the full 14 weeks. At baseline, 8 and/or 14 weeks, serum 25(OH)D and PTH; serum 8-isoprostane, a biomarker of lipid peroxidation, and echocardiographic EF were monitored. Reduced 25(OH)D at entry (14.4 ± 1.3 ng/mL) was improved (P < 0.05) in all patients at 8 weeks (30.7 ± 3.2 ng/mL) and sustained (P < 0.05) at 14 weeks (30.9 ± 2.8 ng/mL). Serum PTH, abnormally increased in 5 patients at baseline (104.8 ± 8.2 pg/mL), was reduced at 8 and 14 weeks (74.4 ± 18.3 and 73.8 ± 13.0 pg/mL, respectively). Plasma 8-isoprostane at entry (136.1 ± 8.8 pg/mL) was reduced at 14 weeks (117.8 ± 7.8 pg/mL; P < 0.05), whereas baseline EF (24.3 ± 1.7%) was improved (31.3 ± 4.3%; P < 0.05). Thus, the 14-week course of supplemental vitamin D and CaCO₃ led to healthy 25(OH)D levels in AA with heart failure having vitamin D deficiency of moderate-to-marked severity. Albeit a small patient population, the findings suggest that this regimen may attenuate the accompanying secondary hyperparathyroidism and oxidative stress and improve ventricular function.

Study on slag forming mechanism of hot metal containing titanium in converter

NASA Astrophysics Data System (ADS)

Wang, H. B.; Lv, Y. C.; Qin, L. Y.; Liu, Y.; Ma, C. W.; Kong, X. T.

2017-09-01

The use of titanium containing molten iron can expand the sources of raw materials, reduce the cost, but the process produce serious foaming slag, low dephosphorization proportion and the consumption of lime is high. The technicians have improved the operation process through experiments and solved the problem of efficient and smooth blowing of hot metal containing titanium. Through mine phase composition analysis of slag using SEM and EDS, the distribution of titanium and the regularity of phosphorus retention are found, and measures to prevent phosphorus recovery in the later stage of converter are put forward.

Machinability of an experimental Ti-Ag alloy in terms of tool life in a dental CAD/CAM system.

PubMed

Inagaki, Ryoichi; Kikuchi, Masafumi; Takahashi, Masatoshi; Takada, Yukyo; Sasaki, Keiichi

2015-01-01

Titanium is difficult to machine because of its intrinsic properties. In a previous study, the machinability of titanium was improved by alloying with silver. This study aimed to evaluate the durability of tungsten carbide burs after the fabrication of frameworks using a Ti-20%Ag alloy and titanium with a computer-aided design and computer-aided manufacturing system. There was a significant difference in attrition area ratio between the two metals. Compared with titanium, the ratio of the area of attrition of machining burs was significantly lower for the experimental Ti-20%Ag alloy. The difference in the area of attrition for titanium and Ti-20%Ag became remarkable with increasing number of machining operations. The results show that the same burs can be used for a longer time with Ti-20%Ag than with pure titanium. Therefore, in terms of tool life, the machinability of the Ti-20%Ag alloy is superior to that of titanium.

Cytocompatibility of Direct Laser Interference-patterned Titanium Surfaces for Implants.

PubMed

Hartjen, Philip; Nada, Ola; Silva, Thiago Gundelwein; Precht, Clarissa; Henningsen, Anders; Holthaus, Marzellus GROßE; Gulow, Nikolai; Friedrich, Reinhard E; Hanken, Henning; Heiland, Max; Zwahr, Christoph; Smeets, Ralf; Jung, Ole

2017-01-01

In an effort to generate titanium surfaces for implants with improved osseointegration, we used direct laser interference patterning (DLIP) to modify the surface of pure titanium grade 4 of four different structures. We assessed in vitro cytoxicity and cell attachment, as well as the viability and proliferation of cells cultured directly on the surfaces. Attachment of the cells to the modified surfaces was comparably good compared to that of cells on grit-blasted and acid-etched reference titanium surfaces. In concordance with this, viability and proliferation of the cells directly cultured on the specimens were similar on all the titanium surfaces, regardless of the laser modification, indicating good cytocompatibility. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Biomineralized diamond-like carbon films with incorporated titanium dioxide nanoparticles improved bioactivity properties and reduced biofilm formation.

PubMed

Lopes, F S; Oliveira, J R; Milani, J; Oliveira, L D; Machado, J P B; Trava-Airoldi, V J; Lobo, A O; Marciano, F R

2017-12-01

Recently, the development of coatings to protect biomedical alloys from oxidation, passivation and to reduce the ability for a bacterial biofilm to form after implantation has emerged. Diamond-like carbon films are commonly used for implanted medical due to their physical and chemical characteristics, showing good interactions with the biological environment. However, these properties can be significantly improved when titanium dioxide nanoparticles are included, especially to enhance the bactericidal properties of the films. So far, the deposition of hydroxyapatite on the film surface has been studied in order to improve biocompatibility and bioactive behavior. Herein, we developed a new route to obtain a homogeneous and crystalline apatite coating on diamond-like carbon films grown on 304 biomedical stainless steel and evaluated its antibacterial effect. For this purpose, films containing two different concentrations of titanium dioxide (0.1 and 0.3g/L) were obtained by chemical vapor deposition. To obtain the apatite layer, the samples were soaked in simulated body fluid solution for up to 21days. The antibacterial activity of the films was evaluated by bacterial eradication tests using Staphylococcus aureus biofilm. Scanning electron microscopy, X-ray diffraction, Raman scattering spectroscopy, and goniometry showed that homogeneous, crystalline, and hydrophilic apatite films were formed independently of the titanium dioxide concentration. Interestingly, the diamond-like films containing titanium dioxide and hydroxyapatite reduced the biofilm formation compared to controls. A synergism between hydroxyapatite and titanium dioxide that provided an antimicrobial effect against opportunistic pathogens was clearly observed. Copyright © 2017 Elsevier B.V. All rights reserved.

Photofunctionalization and non-thermal plasma activation of titanium surfaces.

PubMed

Henningsen, Anders; Smeets, Ralf; Hartjen, Philip; Heinrich, Oliver; Heuberger, Roman; Heiland, Max; Precht, Clarissa; Cacaci, Claudio

2018-03-01

The aim of this study was to compare UV light and non-thermal plasma (NTP) treatment regarding the improvement of physical material characteristics and cell reaction on titanium surfaces in vitro after short-term functionalization. Moderately rough (Ra 1.8-2.0 μm) sandblasted and acid-etched titanium disks were treated by UV light (0.05 mW/cm 2 at λ = 360 nm and 2 mW/cm 2 at λ = 250 nm) or by NTP (24 W, -0.5 mbar) of argon or oxygen for 12 min each. Surface structure was investigated by scanning electron microscopy, confocal microscopy and X-ray photoelectron spectroscopy (XPS). Hydrophilicity was assessed by dynamic contact angle measurement. Cell attachment, viability, cell proliferation and cytotoxicity were assessed in vitro using murine osteoblast-like cells. UV irradiation or NTP treatment of titanium surfaces did not alter the surface structure. XPS analysis revealed a significantly increased oxidation of the surface and a decrease of carbon after the use of either method. NTP and UV light led to a significant better cell attachment of murine osteoblasts; significantly more osteoblasts grew on the treated surfaces at each time point (p < 0.001). UV light as well as NTP modified the surface of titanium and significantly improved the conditions for murine osteoblast cells in vitro. However, results indicate a slight advantage for NTP of argon and oxygen in a short time interval of surface functionalization compared to UV. UV light and NTP are able to improve surface conditions of dental implants made of titanium.

An application of eddy current damping effect on single point diamond turning of titanium alloys

NASA Astrophysics Data System (ADS)

Yip, W. S.; To, S.

2017-11-01

Titanium alloys Ti6Al4V (TC4) have been popularly applied in many industries. They have superior material properties including an excellent strength-to-weight ratio and corrosion resistance. However, they are regarded as difficult to cut materials; serious tool wear, a high level of cutting vibration and low surface integrity are always involved in machining processes especially in ultra-precision machining (UPM). In this paper, a novel hybrid machining technology using an eddy current damping effect is firstly introduced in UPM to suppress machining vibration and improve the machining performance of titanium alloys. A magnetic field was superimposed on samples during single point diamond turning (SPDT) by exposing the samples in between two permanent magnets. When the titanium alloys were rotated within a magnetic field in the SPDT, an eddy current was generated through a stationary magnetic field inside the titanium alloys. An eddy current generated its own magnetic field with the opposite direction of the external magnetic field leading a repulsive force, compensating for the machining vibration induced by the turning process. The experimental results showed a remarkable improvement in cutting force variation, a significant reduction in adhesive tool wear and an extreme long chip formation in comparison to normal SPDT of titanium alloys, suggesting the enhancement of the machinability of titanium alloys using an eddy current damping effect. An eddy current damping effect was firstly introduced in the area of UPM to deliver the results of outstanding machining performance.

Effects of sandblasting and silica-coating procedures on pure titanium.

PubMed

Kern, M; Thompson, V P

1994-10-01

Silica coating titanium improves chemomechanical bonding. Sandblasting is recommended as a pretreatment to thermal silica coating (Silicoater MD) or as part of a tribochemical silica coating process (Rocatec). This study evaluated the effects of sandblasting and coating techniques on volume loss, surface morphology and composition changes in pure titanium. Volume loss of titanium was similar to values reported for base alloys and does not seem to be critical for the clinical fit of restorations. Embedded alumina particles were found in the titanium after sandblasting and the alumina content increased to a range of 27.5-39.3 wt% as measured by EDS. Following tribochemical silica coating, a layer of small silica particles remained on the surface, increasing the silica content to a range of 17.9-19.5 wt%. Ultrasonic cleaning removed loose alumina or silica particles from the surface, resulting in only slight decreases in alumina or silica contents, suggesting firm attachment of most of the alumina and silica to the titanium surface. Silica content following thermal silica coating treatment increased only slightly from the sandblasted specimen to 1.4 wt%. The silica layer employed by these silica coating methods differs widely in both morphology and thickness. These results provide a basis for explanation of adhesive failure modes in bond strength tests and for developing methods to optimize resin bonding. Clinically, ultrasonic cleaning of sandblasted and tribochemically silica coated titanium should improve resin bonding as loose surface particles are removed without relevant changes in composition.

Calcium and vitamin D supplementation maintains parathyroid hormone and improves bone density during initial military training: a randomized, double-blind, placebo controlled trial.

PubMed

Gaffney-Stomberg, Erin; Lutz, Laura J; Rood, Jennifer C; Cable, Sonya J; Pasiakos, Stefan M; Young, Andrew J; McClung, James P

2014-11-01

Calcium and vitamin D are essential nutrients for bone health. Periods of activity with repetitive mechanical loading, such as military training, may result in increases in parathyroid hormone (PTH), a key regulator of Ca metabolism, and may be linked to the development of stress fractures. Previous studies indicate that consumption of a Ca and vitamin D supplement may reduce stress fracture risk in female military personnel during initial military training, but circulating markers of Ca and bone metabolism and measures of bone density and strength have not been determined. This randomized, double-blind, placebo-controlled trial sought to determine the effects of providing supplemental Ca and vitamin D (Ca+Vit D, 2000mg and 1000IU/d, respectively), delivered as 2 snack bars per day throughout 9weeks of Army initial military training (or basic combat training, BCT) on PTH, vitamin D status, and measures of bone density and strength in personnel undergoing BCT, as well as independent effects of BCT on bone parameters. A total of 156 men and 87 women enrolled in Army BCT (Fort Sill, OK; 34.7°N latitude) volunteered for this study. Anthropometric, biochemical, and dietary intake data were collected pre- and post-BCT. In addition, peripheral quantitative computed tomography was utilized to assess tibia bone density and strength in a subset of volunteers (n=46). Consumption of supplemental Ca+Vit D increased circulating ionized Ca (group-by-time, P=0.022), maintained PTH (group-by-time, P=0.032), and increased the osteoprotegerin:RANKL ratio (group-by-time, P=0.006). Consistent with the biochemical markers, Ca+Vit D improved vBMD (group-by-time, P=0.024) at the 4% site and cortical BMC (group-by-time, P=0.028) and thickness (group-by-time, P=0.013) at the 14% site compared to placebo. These data demonstrate the benefit of supplemental Ca and vitamin D for maintaining bone health during periods of elevated bone turnover, such as initial military training. This trial was registered with ClincialTrials.gov, NCT01617109. Published by Elsevier Inc.

Maximizing PTH Anabolic Osteoporosis Therapy

DTIC Science & Technology

2014-09-01

PTH- stimulated addition of trabecular bone at 3 weeks of hor- mone treatment, and that Nmp4 has a profound regulatory role in BM population dynamics...Qin L, LJ Raggatt, and Partridge. (2004). Parathyroid hor- mone : a double-edged sword for bone metabolism. Trends Endocrinol Metab 15:60–65. 14. Kular...parathyroid hor- mone administration is due to the stimulation of prolifera- tion and differentiation of osteoprogenitor cells in BM. Bone 15:717–723. 16

Dissecting the Roles of Brain Injury and Combat-Related Stress in Post-Traumatic Headache

DTIC Science & Technology

2015-10-01

were the major goals of the project? Post-traumatic headache (PTH) is an epidemic in our military personnel. It is a chronic, migraine -like...and affective processing that lead to PTH. Cortical spreading depression (CSD) is the physiological correlate of the migraine aura, but it also...paradigm. NTG infusion triggers migraine without aura in human migraineurs and reduced mechanical allodynia threshold in rodents. This enables 11

Band Excitation Kelvin probe force microscopy utilizing photothermal excitation

DOE PAGES

Collins, Liam; Jesse, Stephen; Balke, Nina; ...

2015-03-13

A multifrequency open loop Kelvin probe force microscopy (KPFM) approach utilizing photothermal as opposed to electrical excitation is developed. Photothermal band excitation (PthBE)-KPFM is implemented here in a grid mode on a model test sample comprising a metal-insulator junction with local charge-patterned regions. Unlike the previously described open loop BE-KPFM, which relies on capacitive actuation of the cantilever, photothermal actuation is shown to be highly sensitive to the electrostatic force gradient even at biases close to the contact potential difference (CPD). PthBE-KPFM is further shown to provide a more localized measurement of true CPD in comparison to the gold standardmore » ambient KPFM approach, amplitude modulated KPFM. In conclusion, PthBE-KPFM data contain information relating to local dielectric properties and electronic dissipation between tip and sample unattainable using conventional single frequency KPFM approaches.« less

Factors predictive of critical value of hypocalcemia after total parathyroidectomy without autotransplantation in patients with secondary hyperparathyroidism.

PubMed

Yang, Meng; Zhang, Ling; Huang, Linping; Sun, Xiaoliang; Ji, Haoyang; Lu, Yao

2016-09-01

Severe hypocalcemia is the most dangerous complication occurring after total parathyroidectomy without autotransplantation (TPTX) for secondary hyperparathyroidism (SHPT). We aim to identify the prevalence and potential risk factors of very severe hypocalcemia in patients with SHPT undergoing TPTX. From April 2012 to August 2015, 157 patients with SHPT undergoing TPTX were reviewed. The critical value of hypocalcemia (CVH) was postoperative serum Ca(2+) levels of ≤1.5 mmol/L. Univariate analysis showed that patients in the CVH group were significantly younger than those in the non-CVH group. Sex ratio was significantly different between the two groups. The CVH group had significantly higher levels of preoperative PTH and ALP. Male sex and preoperative levels of PTH and ALP were significant independent risk factors by logistic regression analysis. Male sex, preoperative PTH and ALP were significantly associated with CVH in patients with SHPT undergoing TPTX.

The pleiotropic effects of paricalcitol: Beyond bone-mineral metabolism.

PubMed

Egido, Jesús; Martínez-Castelao, Alberto; Bover, Jordi; Praga, Manuel; Torregrosa, José Vicente; Fernández-Giráldez, Elvira; Solozábal, Carlos

2016-01-01

Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease (CKD) that is characterised by elevated parathyroid hormone (PTH) levels and a series of bone-mineral metabolism anomalies. In patients with SHPT, treatment with paricalcitol, a selective vitamin D receptor activator, has been shown to reduce PTH levels with minimal serum calcium and phosphorus variations. The classic effect of paricalcitol is that of a mediator in mineral and bone homeostasis. However, recent studies have suggested that the benefits of treatment with paricalcitol go beyond PTH reduction and, for instance, it has a positive effect on cardiovascular disease and survival. The objective of this study is to review the most significant studies on the so-called pleiotropic effects of paricalcitol treatment in patients with CKD. Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.