End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under ...development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60-70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.
Background The management of chronic kidney disease–mineral and bone disorder requires the assessment of bone turnover, which most often is based on parathyroid hormone (PTH) concentration, the ...utility of which remains controversial. Study Design Cross-sectional retrospective diagnostic test study. Setting & Participants 492 dialysis patients from Brazil, Portugal, Turkey, and Venezuela with prior bone biopsy and stored (−20°C) serum. Index Tests Samples were analyzed for PTH (intact iPTH and whole PTH), bone-specific alkaline phosphatase (bALP), and amino-terminal propeptide of type 1 procollagen (P1NP). Reference Test Bone histomorphometric assessment of turnover (bone formation rate/bone surface BFR/BS) and receiver operating characteristic curves for discriminating diagnostic ability. Results The biomarkers iPTH and bALP or combinations thereof allowed discrimination of low from nonlow and high from nonhigh BFR/BS, with an area under the receiver operating characteristic curve > 0.70 but < 0.80. Using iPTH level, the best cutoff to discriminate low from nonlow BFR/BS was <103.8 pg/mL, and to discriminate high from nonhigh BFR/BS was >323.0 pg/mL. The best cutoff for bALP to discriminate low from nonlow BFR/BS was <33.1 U/L, and for high from nonhigh BFR/BS, 42.1 U/L. Using the KDIGO practice guideline PTH values of greater than 2 but less than 9 times the upper limit of normal, sensitivity and specificity of iPTH level to discriminate low from nonlow turnover bone disease were 65.7% and 65.3%, and to discriminate high from nonhigh were 37.0% and 85.8%, respectively. Limitations Cross-sectional design without consideration of therapy. Potential limited generalizability with samples from 4 countries. Conclusions The serum biomarkers iPTH, whole PTH, and bALP were able to discriminate low from nonlow BFR/BS, whereas iPTH and bALP were able to discriminate high from nonhigh BFR/BS. Prospective studies are required to determine whether evaluating trends in biomarker concentrations could guide therapeutic decisions.
Abstract Dipeptidyl peptidase 4 (DPP4) is a conserved exopeptidase with an important function in protein regulation. The activity of DPP4, an enzyme which can either be anchored to the plasma ...membrane or circulate free in the extracellular compartment, affects the glucose metabolism, cellular signaling, migration and differentiation, oxidative stress and the immune system. DPP4 is also expressed on the surface of osteoblasts, osteoclasts and osteocytes, and was found to play a role in collagen metabolism. Many substrates of DPP4 have an established role in bone metabolism, among which are incretins, gastrointestinal peptides and neuropeptides. In general, their effects favor bone formation, but some effects are complex and have not been completely elucidated. DPP4 and some of its substrates are known to interact with adipokines, playing an essential role in the energy metabolism.
The prolongation of the half-life of incretins through DPP4 inhibition led to the development of these inhibitors to improve glucose tolerance in diabetes. Current literature indicates that the inhibition of DPP4 activity might also result in a beneficial effect on the bone metabolism, but the long-term effect of DPP4 inhibition on fracture outcome has not been entirely established. Diabetic as well as postmenopausal osteoporosis is associated with an increased activity of DPP4, as well as a shift in the expression levels of DPP4 substrates, their receptors, and adipokines. The interactions between these factors and their relationship in bone metabolism
are
therefore an interesting field of study.
The use of geo-engineering materials to manage phosphorus in lakes has increased in recent years with aluminium and lanthanum based materials being most commonly applied. Hence the potential impact ...of the use of these compounds on human health is receiving growing interest. This review seeks to understand, evaluate and compare potential unintended consequences on human health and ecotoxicological risks associated with the use of lanthanum- and aluminium-based materials to modify chemical and ecological conditions in water bodies. In addition to their therapeutic use for the reduction of intestinal phosphate absorption in patients with impaired renal function, the phosphate binding capacity of aluminium and lanthanum also led to the development of materials used for water treatment. Although lanthanum and aluminium share physicochemical similarities and have many common applications, their uptake and kinetics within the human body and living organisms importantly differ from each other which is reflected in a different toxicity profile. Whilst a causal role in the development of neurological pathologies, skeletal lesions, hematopoietic disorders and respiratory effects has unequivocally been demonstrated with increased exposure to aluminium, studies until now have failed to find such a clear association after exposure to lanthanum although caution is warranted. Our review indicates that lanthanum and aluminium have a distinctly different profile with respect to their potential effects on human health. Regular monitoring of both aluminium and lanthanum concentrations in lanthanum-/aluminium-treated water by the responsible authorities is recommended to avoid acute accidental or chronic low level accumulation.
•Geo-engineering materials containing La and Al used to manage P in lakes.•Potential impact of the use of these compounds on human health is of interest.•La and Al uptake, kinetics and toxicity profile differ within the humans and organisms.•Monitoring of La and Al is recommended to avoid acute and chronic exposure.
Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation ...(L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.
The objectives of this study were to assess the factors which contribute to individuals’ health motivation to address hearing loss and to gather baseline data that could then be used to measure the ...impact of an awareness campaign. An online questionnaire with 13 closed set questions was completed by 100 subjects in each country including Austria, Germany, France, Sweden, and the United Kingdom. The questionnaire was based around the Health Belief Model, which describes how, in order to take action to address a medical problem, the individual must perceive that the condition presents a threat to their well-being that exceeds any barriers to treatment. Good hearing was regarded as being important in all countries. There was agreement that the main sign of hearing loss was turning up the TV or radio. In most countries, hearing aids were thought to be not particularly visible, not require much maintenance, a hindrance while doing sport, and must be removed before bed. Perceptions of hearing implants were that they were permanently fitted, not externally visible, and do not need to be removed before bed. Medical issues were mostly researched through a doctor and then via the Internet. In this sample, there was a good understanding of the consequences and signs of hearing loss, but although hearing implants were viewed as being different to hearing aids, there was little understanding that the external speech processor was similar to a hearing aid in its physical characteristics. When actions were taken, the key professionals consulted about hearing problems were the general practitioner and ear, nose, and throat specialist.
Background and Purpose
No therapy is approved for vascular calcification or calcific uraemic arteriolopathy (calciphylaxis), which increases mortality and morbidity in patients undergoing dialysis. ...Deposition of hydroxyapatite (HAP) crystals in arterial walls is the common pathophysiologic mechanism. The mechanism of action of SNF472 to reduce HAP deposition in arterial walls was investigated.
Experimental Approach
We examined SNF472 binding features (affinity, release kinetics and antagonism type) for HAP crystals in vitro, inhibition of calcification in excised vascular smooth muscle cells from rats and bone parameters in osteoblasts from dogs and rats.
Key Results
SNF472 bound to HAP with affinity (KD) of 1–10 μM and saturated HAP at 7.6 μM. SNF472 binding was fast (80% within 5 min) and insurmountable. SNF472 inhibited HAP crystal formation from 3.8 μM, with complete inhibition at 30.4 μM. SNF472 chelated free calcium with an EC50 of 539 μM. Chelation of free calcium was imperceptible for SNF472 1–10 μM in physiological calcium concentrations. The lowest concentration tested in vascular smooth muscle cells, 1 μM inhibited calcification by 67%. SNF472 showed no deleterious effects on bone mineralization in dogs or in rat osteoblasts.
Conclusion and Implications
These experiments show that SNF472 binds to HAP and inhibits further HAP crystallization. The EC50 for chelation of free calcium is 50‐fold greater than a maximally effective SNF472 dose, supporting the selectivity of SNF472 for HAP. These findings indicate that SNF472 may have a future role in the treatment of vascular calcification and calcific uraemic arteriolopathy in patients undergoing dialysis.
There are 466 million people living with a disabling hearing loss and the challenges of managing this public health crisis cannot be underestimated. Yet, adult utilization of cochlear implants is ...poor with less than 10% of suitable candidates receiving one. The aim of this study was to investigate the awareness levels regarding cochlear implants in older adults after a digital campaign to raise awareness of cochlear implantation in this population. To address the lack of awareness of the cochlear implants in the general population, adverts were placed in online medical magazines and mainstream newspapers. Data were collected in 400 subjects via an online market research questionnaire, in Germany, Austria, Sweden, and the United Kingdom, and compared with baseline data collected in a previous study. Median click rates were in line with expectations for the medical industry and approximately 22 000 individuals clicked through to the cochlear implant Web site. However, there were few significant differences between the 2 sets of data. The Internet was consulted as much as the doctor for medical information in Germany, Austria, and Sweden. The study reinforces the importance of the Internet in accessing information about health, including hearing loss. The click through rates shows that there is interest in learning about cochlear implants. Further work is needed to assess the impact of this type of campaign on individuals who have already been identified as hearing impaired.
Accelerated intimal and medial calcification and sclerosis accompany the increased cardiovascular mortality of dialysis patients, but the pathomechanisms initiating microcalcifications of the media ...are largely unknown. In this study, we systematically investigated the ultrastructural properties of medial calcifications from patients with uremia. We collected iliac artery segments from 30 dialysis patients before kidney transplantation and studied them by radiography, microcomputed tomography, light microscopy, and transmission electron microscopy including electron energy loss spectrometry, energy dispersive spectroscopy, and electron diffraction. In addition, we performed synchrotron x-ray analyses and immunogold labeling to detect inhibitors of calcification. Von Kossa staining revealed calcification of 53% of the arteries. The diameter of these microcalcifications ranged from 20 to 500 nm, with a core-shell structure consisting of up to three layers (subshells). Many of the calcifications consisted of 2- to 10-nm nanocrystals and showed a hydroxyapatite and whitlockite crystalline structure and mineral phase. Immunogold labeling of calcification foci revealed the calcification inhibitors fetuin-A, osteopontin, and matrix gla protein. These observations suggest that uremic microcalcifications originate from nanocrystals, are chemically diverse, and intimately associate with proteinaceous inhibitors of calcification. Furthermore, considering the core-shell structure of the calcifications, apoptotic bodies or matrix vesicles may serve as a calcification nidus.
Arterial medial calcification (AMC) is the deposition of calcium phosphate in the arteries. AMC is widely thought to share similarities with physiological bone formation; however, emerging evidence ...suggests several key differences between these processes. N‐acetylcysteine (NAC) displays antioxidant properties and can generate hydrogen sulphide (H2S) and glutathione (GSH) from its deacetylation to l‐cysteine. This study found that NAC exerts divergent effects in vitro, increasing osteoblast differentiation and bone formation by up to 5.5‐fold but reducing vascular smooth muscle cell (VSMC) calcification and cell death by up to 80%. In vivo, NAC reduced AMC in a site‐specific manner by 25% but had no effect on the bone. The actions of l‐cysteine and H2S mimicked those of NAC; however, the effects of H2S were much less efficacious than NAC and l‐cysteine. Pharmacological inhibition of H2S‐generating enzymes did not alter the actions of NAC or l‐cysteine; endogenous production of H2S was also unaffected. In contrast, NAC and l‐cysteine increased GSH levels in calcifying VSMCs and osteoblasts by up to 3‐fold. This suggests that the beneficial actions of NAC are likely to be mediated via the breakdown of l‐cysteine and the subsequent GSH generation. Together, these data show that while the molecular mechanisms driving the actions of NAC appear similar, the downstream effects on cell function differ significantly between osteoblasts and calcifying VSMCs. The ability of NAC to exert these differential actions further supports the notion that there are differences between the development of pathological AMC and physiological bone formation. NAC could represent a therapeutic option for treating AMC without exerting negative effects on bone.
This study found that N‐acetylcysteine (NAC) exerts divergent effects in vitro, increasing osteoblast differentiation and bone formation but reducing vascular smooth muscle cell calcification and death. These data show that whilst the molecular mechanisms driving the actions of NAC appear similar, the downstream effects on cell function differ significantly between osteoblasts and calcifying vascular smooth muscle cells. The ability of NAC to exert these differential actions further supports the notion that there are differences between the development of pathological arterial medial calcification and physiological bone formation.
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