Neuroma morphology: A macroscopic classification system.

INTRODUCTION/AIMS: Neuromas come in different shapes and sizes; yet the correlation between neuroma morphology and symptomatology is unknown. Therefore, we aim to investigate macroscopic traits of excised human neuromas and assess the validity of a morphological classification system and its potential clinical implications. METHODS: End-neuroma specimens were collected from prospectively enrolled patients undergoing symptomatic neuroma surgery. Protocolized images of the specimens were obtained intraoperatively. Pain data (Numeric rating scale, 0-10) were prospectively collected during preoperative interview, patient demographic and comorbidity factors were collected from chart review. A morphological classification is proposed, and the inter-rater reliability (IRR) was assessed. Distribution of neuroma morphology with patient factors, was described. RESULTS: Forty-five terminal neuroma specimens from 27 patients were included. Residual limb patients comprised 93% of the population, of which 2 were upper (8.0%) and 23 (92.0%) were lower extremity residual limb patients. The proposed morphological classification, consisting of three groups (bulbous, fusiform, atypical), demonstrated a strong IRR (Cohen's kappa = 0.8). Atypical neuromas demonstrated higher preoperative pain, compared with bulbous and fusiform. Atypical morphology was more prevalent in patients with diabetes and peripheral vascular disease. DISCUSSION: A validated morphological classification of neuroma is introduced. These findings may assist surgeons and researchers with better understanding of symptomatic neuroma development and their clinical implications. The potential relationship of neuroma morphology with the vascular and metabolic microenvironment requires further investigation.

Neuroma Analysis in Humans: Standardizing Sample Collection and Documentation.

INTRODUCTION: The biology of symptomatic neuromas is poorly understood, particularly the factors causing pain in human neuromas. Pain presence varies among and within individuals, with some having painful and nonpainful neuromas. To bridge these knowledge gaps, our group developed a protocol for assessing neuroma pain and collecting tissue for molecular analysis. This manuscript outlines our workflow and challenges and aims to inspire other centers to share their experiences with these tissues. METHODS: For every included patient and collected nerve or bone tissue specimens, we perform a detailed chart review and a multifaceted analysis of pain and pain perception immediately before surgery. We collect patient-reported outcome measures (PROMs) on pain, function, and mental well-being outcomes at preoperative assessment and at the 6-month follow-up postoperatively. Before surgery, the patient is assessed once again to obtain an immediate preoperative pain status and identify potential differences in pain intensity of different neuromas. Intraoperatively, specimens are obtained and their gross anatomical features are recorded, after which they are stored in paraformaldehyde or frozen for later sample analyses. Postoperatively, patients are contacted to obtain additional postoperative PROMs. RESULTS: A total of 220 specimens of nerve tissue have been successfully obtained from 83 limbs, comprising 95 specimens of neuromas and 125 specimens of nerves located proximal to the neuromas or from controls. CONCLUSIONS: Our approach outlines the methods combining specimen collection and examination, including both macroscopic and molecular biological features, with PROMs, encompassing physical and psychological aspects, along with clinical metadata obtained through clinical teams and chart review.

Evaluation of MRI features of neuromas in oncological amputees, and the relation to pain.

OBJECTIVE: The impact of time on neuroma growth and morphology on pain intensity is unknown. This study aims to assess magnetic resonance imaging (MRI) differences between symptomatic and non-symptomatic neuromas in oncological amputees, and whether time influences MRI-detected neuroma dimensions and their association with pain. MATERIAL AND METHODS: Oncological patients who underwent traditional extremity amputation were included. Post-amputation MRIs were assessed before decision for neuroma surgery. Chart review was performed for residual limb pain (numeric rating scale, 0-10) and the presence of neuropathic symptoms. Neuromas were classified as symptomatic or non-symptomatic, with neuroma size expressed as radiological neuroma-to-nerve-ratio (NNR). RESULTS: Among 78 neuromas in 60 patients, the median NNR was 2.0, and 56 neuromas (71.8%) were symptomatic with a median pain score of 3.5. NNR showed no association with symptomatology or pain intensity but correlated with a longer time-to-neuroma-excision interval and a smaller nerve caliber. Symptomatic neuromas were associated with lower extremity amputation, T2 heterogeneity, and the presence of heterotopic ossification. Lower extremity amputation, T2 heterogeneity, perineural edema, and presence of heterotopic ossification were associated with more painful neuromas. CONCLUSION: MRI features associated with symptomatic neuromas and pain intensity were identified. Awareness of the potential clinical significance of these imaging features may help in the interpretation of MRI exams and may aid clinicians in patient selection for neuroma surgery in oncological amputees.

Polystyrene microplastic-induced extracellular vesicles cause kidney-related effects in the crosstalk between tubular cells and fibroblasts.

Plastic waste accumulation and its degradation into microplastics (MPs) and nanoplastics (NPs) pose environmental concerns. Previous studies have indicated that polystyrene (PS)-MPs harm living animals. Extracellular vesicles (EVs) are associated with metabolic reprogramming and mitochondrial dysfunction in various kidney diseases. In this article, we evaluated how PS-MPs affected tubular cells and fibroblasts. The results demonstrated that PS-MPs increased EV production in human tubular cells and caused endoplasmic reticulum (ER) stress-related proteins without inducing inflammation-related proteins in human tubular cells. The uptake of PS-MPs and incubation with the conditioned medium of PS-MPs induced reactive oxygen species (ROS) production and ER stress-related proteins in fibroblast cells. The fibroblast cells treated with the conditioned medium of PS-MPs also increased the expression of fibrosis-related proteins. Our findings suggested that the expression of EV-related markers increased in tubular cells via Beclin 1 after PS-MP treatment. In addition, PS-MPs induced ROS production in vitro and in vivo. We found that PS-MPs also altered the expression of EV markers in urine, and CD63 expression was also increased in vitro and in vivo after PS-MP treatment. In conclusion, PS-MP-induced EVs lead to ER stress-related proteins, ROS production and fibrosis-related proteins in tubular cells and fibroblasts.

Does coracoclavicular augmentation additional to hook plate fixation provide benefits in acute unstable acromioclavicular dislocation? A meta-analysis.

BACKGROUND: Acromioclavicular joint (ACJ) dislocation is a common shoulder injury. In treating acute unstable ACJ dislocation, a hook plate (HP) is a straightforward and popular option for ensuring proper reduction and rigid fixation while promoting AC and coracoclavicular (CC) ligament healing. Surgeons typically remove the HP to prevent subacromial impingement and acromial osteolysis; however, concerns about redislocation after implant removal remain. Therefore, additional CC augmentation may be helpful in combination with HP fixation. The aim of this meta-analysis is to compare the outcomes and complications of HP fixation with or without additional CC augmentation for acute unstable ACJ dislocation. METHODS: We searched the PubMed, EMBASE, and Web of Science databases for relevant case-control studies. The primary outcomes were patient-reported outcome measures; the secondary outcomes were pain measured using a visual analog scale (VAS), CC distance (CCD), and complications. Continuous data were assessed using weighted standardized mean differences (SMDs) with 95% confidence intervals (CIs), and dichotomous data were evaluated with Mantel-Haenszel odds ratio (ORs) with 95% CIs. RESULTS: We analyzed one randomized control trial and four case-control studies comparing HP fixation with or without CC augmentation. A total of 474 patients with Rockwood type III or V ACJ dislocation were included. We found no differences in Constant-Murley score (SMD, - 0.58, 95% CI - 1.41 to 0.26; P = 0.18), American Shoulder and Elbow Surgeons score (SMD, 0.21, 95% CI - 0.10 to 0.52; P = 0.19), University of California at Los Angeles shoulder rating scale score (SMD, - 0.02, 95% CI - 1.27 to 1.23; P = 0.97), or VAS pain score (SMD, 0.36, 95% CI - 0.16 to 0.88; P = 0.17) between groups. The CC augmentation group had lower odds of osteolysis (OR, 0.27, 95% CI 0.10 to 0.74; P = 0.01) and a shorter CCD (SMD, - 0.29, 95% CI - 0.57 to - 0.01; P = 0.04). CONCLUSION: HP fixation with CC augmentation is preferable for acute unstable ACJ dislocations. Although CC augmentation did not provide additional benefits related to functional outcomes or pain, it resulted in greater reduction maintenance after implant removal and a 73% lower risk of acromial osteolysis. TRIAL REGISTRATION: PROSPERO ( CRD42021271118 ).

Extracorporeal Shock Wave Therapy Shows Superiority Over Injections for Pain Relief and Grip Strength Recovery in Lateral Epicondylitis: A Systematic Review and Network Meta-analysis.

PURPOSE: To examine the efficacy of extracorporeal shock wave therapy (ESWT) and injection therapies by synthesizing direct and indirect evidence for all pairs of competing therapies for lateral epicondylitis. METHODS: PubMed, EMBASE, and Web of Science databases were searched for all appropriate randomized controlled trials (RCTs), assessing the effect of ESWT or injection therapies. The primary outcome was short-term (≤3 months) and medium-term (>3 months but ≤12 months) pain, while the secondary outcomes were grip strength and patient-reported outcome measures. All outcomes were assessed using standardized mean differences (SMDs) with 95% confidence intervals (CIs) and were ranked using surface under the cumulative ranking curve (SUCRA) probabilities to determine a hierarchy of treatments. Sensitivity analysis was performed to eliminate potential therapeutic effects of normal saline (NS) and exclude trials that included patients with acute lateral epicondylitis (LE). RESULTS: 40 RCTs were included to evaluate ESWT and five different injection therapies, including corticosteroids (CSs), autologous whole blood, platelet-rich plasma (PRP), botulinum toxin A (BoNT-A), and dextrose prolotherapy (DPT). DPT (-.78 [-1.34 to -.21]), ESWT (.57 [-.89 to -.25]), PRP (-.48 [-.85 to -.11]), and BoNT-A (-.43 [-.84 to -.02]) outperformed placebo for short-term pain relief; ESWT (-.44 [-.85 to -.04]) outperformed placebo for medium-term pain relief. DPT was ranked as the most optimal short-term and medium-term pain reliever (SUCRA, 87.3% and 98.6%, respectively). ESWT was ranked as the most optimal short-term and medium-term grip strength recovery (SUCRA; 79.4% and 86.4%, respectively). CONCLUSIONS: DPT and ESWT were the best two treatment options for pain control and ESWT was the best treatment option for grip strength recovery. CSs were not recommended for the treatment of LE. More evidence is required to confirm the superiority in pain control of DPT among all these treatment options on LE. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I randomized controlled trials.

Perspective Adjunctive Therapies for COVID-19: Beyond Antiviral Therapy.

The coronavirus disease 2019 (COVID-19) pandemic is the largest health crisis ever faced worldwide. It has resulted in great health and economic costs because no effective treatment is currently available. Since infected persons vary in presentation from healthy asymptomatic mild symptoms to those who need intensive care support and eventually succumb to the disease, this illness is considered to depend primarily on individual immunity. Demographic distribution and disease severity in several regions of the world vary; therefore, it is believed that natural inherent immunity provided through dietary sources and traditional medicines could play an important role in infection prevention and disease progression. People can boost their immunity to prevent them from infection after COVID-19 exposure and can reduce their inflammatory reactions to protect their organ deterioration in case suffering from the disease. Some drugs with in-situ immunomodulatory and anti-inflammatory activity are also identified as adjunctive therapy in the COVID-19 era. This review discusses the importance of COVID-19 interactions with immune cells and inflammatory cells; and further emphasizes the possible pathways related with traditional herbs, medications and nutritional products. We believe that such pathophysiological pathway approach treatment is rational and important for future development of new therapeutic agents for prevention or cure of COVID-19 infection.

Toxic Effects of Indoxyl Sulfate on Osteoclastogenesis and Osteoblastogenesis.

Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.

Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and ß-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin-angiotensin-aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill's causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.

Biocompatibility and Biological Performance Evaluation of Additive-Manufactured Bioabsorbable Iron-Based Porous Suture Anchor in a Rabbit Model.

This study evaluated the biocompatibility and biological performance of novel additive-manufactured bioabsorbable iron-based porous suture anchors (iron_SAs). Two types of bioabsorbable iron_SAs, with double- and triple-helical structures (iron_SA_2_helix and iron_SA_3_helix, respectively), were compared with the synthetic polymer-based bioabsorbable suture anchor (polymer_SAs). An in vitro mechanical test, MTT assay, and scanning electron microscope (SEM) analysis were performed. An in vivo animal study was also performed. The three types of suture anchors were randomly implanted in the outer cortex of the lateral femoral condyle. The ultimate in vitro pullout strength of the iron_SA_3_helix group was significantly higher than the iron_SA_2_helix and polymer_SA groups. The MTT assay findings demonstrated no significant cytotoxicity, and the SEM analysis showed cells attachment on implant surface. The ultimate failure load of the iron_SA_3_helix group was significantly higher than that of the polymer_SA group. The micro-CT analysis indicated the iron_SA_3_helix group showed a higher bone volume fraction (BV/TV) after surgery. Moreover, both iron SAs underwent degradation with time. Iron_SAs with triple-helical threads and a porous structure demonstrated better mechanical strength and high biocompatibility after short-term implantation. The combined advantages of the mechanical superiority of the iron metal and the possibility of absorption after implantation make the iron_SA a suitable candidate for further development.

Comparative effectiveness of various treatment strategies for trigger finger by pairwise meta-analysis.

OBJECTIVE: To compare the efficacy of various strategies in the treatment of trigger finger. DATA SOURCES: A systematic literature search for randomized controlled trials to compare treatments for trigger finger was conducted through three online databases, Pubmed, Embase and Cochrane Library, from their inception dates to 22 May 2020. METHODS: Relative risk (RR) with 95% confidence interval (CI) was used to evaluate the effect sizes in success rate for included articles. RESULTS: Sixteen articles (n = 1185) were included in our meta-analysis. The results showed that the efficacy of steroid injection was significantly better than the placebo group at short-term follow-ups (RR = 19.00, 95% CI = 1.17-309.77 for one-week; RR = 3.70, 95% CI = 3.70, 95% CI = 1.61-8.53 for one-month), and then became non-significant at four months (RR = 3.21, 95% CI = 0.88-11.79). There was no significant difference in success rate between steroid injection and nonsteroidal anti-inflammatory drug injection, and between open surgery and percutaneous release at all the follow-ups. Only surgical treatment had significantly better efficacy in success rate than steroid injection at all follow-ups (RR = 0.48, 95% CI = 0.34-0.66 for one-month; RR = 0.87, 95% CI = 0.80-0.96 for three-month; RR = 0.58, 95% CI = 0.48-0.68 for six-month; RR = 0.38, 95% CI = 0.20-0.72 for 12-month). CONCLUSION: There were no differences in efficacy between steroid injection and shockwave or nonsteroidal anti-inflammatory drug injection. The surgical treatments had the best efficacy among these treatments.

Sirtuin-1 and Its Relevance in Vascular Calcification.

Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of ß-catenin that, following the facilitation of ß-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.

The Role of Vitamin D in Modulating Mesenchymal Stem Cells and Endothelial Progenitor Cells for Vascular Calcification.

Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem cells and endothelial progenitor cells in vascular calcification. Mesenchymal stem cells reside in the bone marrow and the adventitial layer of arteries. Endothelial progenitor cells that originate from the bone marrow are an important mechanism for repairing injured endothelial cells. Mesenchymal stem cells may differentiate osteogenically by inflammation or by specific stimuli, which can activate calcification. However, the bioactive substances secreted from mesenchymal stem cells have been shown to mitigate vascular calcification by suppressing inflammation, bone morphogenetic protein 2, and the Wingless-INT signal. Vitamin D deficiency may contribute to vascular calcification. Vitamin D supplement has been used to modulate the osteoblastic differentiation of mesenchymal stem cells and to lessen vascular injury by stimulating adhesion and migration of endothelial progenitor cells. This narrative review clarifies the role of mesenchymal stem cells and the possible role of vitamin D in the mechanisms of vascular calcification.

Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway.

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 µM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients.

Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease.

Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce the mortality rates among patients with CKD. Nontraditional factors related to mineral and vitamin-D metabolic disorders provide some explanation for the increased CVD risk. Non-dialyzable toxins, indoxyl sulfate (IS) and p-cresol sulfate (PCS)-produced in the liver by colonic microorganisms-cause kidney and vascular dysfunction. Plasma trimethylamine-N-oxide (TMAO)-a gut microbe-dependent metabolite of dietary L-carnitine and choline-is elevated in CKD and related to vascular disease, resulting in poorer long-term survival. Therefore, the modulation of colonic flora can improve prospects for patients with CKD. Managing metabolic syndrome, anemia, and abnormal mineral metabolism is recommended for the prevention of CVD in patients with CKD. Considering nontraditional risk factors, the use of resveratrol (RSV), a nutraceutical, can be helpful for patients with CVD and CKD. This paper discusses the beneficial effects of RSV on biologic, pathophysiological and clinical responses, including improvements in intestinal epithelial integrity, modulation of the intestinal microbiota and reduction in hepatic synthesis of IS, PCS and TMAO in patients with CVD and CKD.

Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor.

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.

Osteoclast-Released Wnt-10b Underlies Cinacalcet Related Bone Improvement in Chronic Kidney Disease.

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/ß-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.

Endothelial Progenitor Cells Predict Long-Term Mortality in Hemodialysis Patients.

BACKGROUND: The endothelial progenitor cells (EPCs) dysfunction is a critical event in the initiation of atherosclerotic plaque development and the level of circulating EPCs can be considered a biomarker of cardiovascular events. The level and functional change in EPCs has been investigated in hemodialysis patients, but the effect of absolute number of EPCs on risk of death has not yet been explored. We hypothesized that the number of EPCs predicted death from cardiovascular and all-cause mortality in hemodialysis patients. METHODS: We evaluate the association between endothelial progenitor cells and clinical outcome in 154 patients on maintenance hemodialysis. The blood sample was drawn at the time of patient enrollment and EPCs were identified by flow cytometry using triple staining for CD34/CD133/KDR. RESULTS: The median duration of follow-up was 4.19 years. There were 79 (51.3%) deaths during the follow-up period, 41 of whom died due to a confirmed cardiovascular cause. The cumulative survival was greater in the high-EPC group than the low-EPC group for all-cause and cardiovascular mortality. Decreased EPCs levels were associated with a significant increase in the risk of cardiovascular and all-cause mortality after adjusting for age, gender, current smokers, diabetes mellitus, and hypertension. CONCLUSIONS: The level of circulating EPCs independently predicts the clinical outcome in patients on maintenance hemodialysis. Thus, the EPCs levels may be a useful predictive tool for evaluating the risk of death in maintenance hemodialysis patients.

Vascular calcification and renal bone disorders.

At the early stage of chronic kidney disease (CKD), the systemic mineral metabolism and bone composition start to change. This alteration is known as chronic kidney disease-mineral bone disorder (CKD-MBD). It is well known that the bone turnover disorder is the most common complication of CKD-MBD. Besides, CKD patients usually suffer from vascular calcification (VC), which is highly associated with mortality. Many factors regulate the VC mechanism, which include imbalances in serum calcium and phosphate, systemic inflammation, RANK/RANKL/OPG triad, aldosterone, microRNAs, osteogenic transdifferentiation, and effects of vitamins. These factors have roles in both promoting and inhibiting VC. Patients with CKD usually have bone turnover problems. Patients with high bone turnover have increase of calcium and phosphate release from the bone. By contrast, when bone turnover is low, serum calcium and phosphate levels are frequently maintained at high levels because the reservoir functions of bone decrease. Both of these conditions will increase the possibility of VC. In addition, the calcified vessel may secrete FGF23 and Wnt inhibitors such as sclerostin, DKK-1, and secreted frizzled-related protein to prevent further VC. However, all of them may fight back the inhibition of bone formation resulting in fragile bone. There are several ways to treat VC depending on the bone turnover status of the individual. The main goals of therapy are to maintain normal bone turnover and protect against VC.

Long-term and short-term effects of hemodialysis on liver function evaluated using the galactose single-point test.

AIM: The galactose single-point (GSP) test assesses functioning liver mass by measuring the galactose concentration in the blood 1 hour after its administration. The purpose of this study was to investigate the impact of hemodialysis (HD) on short-term and long-term liver function by use of GSP test. METHODS: Seventy-four patients on maintenance HD (46 males and 28 females, 60.38 ± 11.86 years) with a mean time on HD of 60.77 ± 48.31 months were studied. The GSP values were compared in two groups: (1) before and after single session HD, and (2) after one year of maintenance HD. RESULTS: Among the 74 HD patient, only the post-HD Cr levels and years on dialysis were significantly correlated with GSP values (r = 0.280, P < 0.05 and r = -0.240, P < 0.05, resp.). 14 of 74 patients were selected for GSP evaluation before and after a single HD session, and the hepatic clearance of galactose was similar (pre-HD 410 ± 254 g/mL, post-HD 439 ± 298 g/mL, P = 0.49). GSP values decreased from 420.20 ± 175.26 g/mL to 383.40 ± 153.97 g/mL after 1 year maintenance HD in other 15 patients (mean difference: 19.00 ± 37.66 g/mL, P < 0.05). CONCLUSIONS: Patients on maintenance HD for several years may experience improvement of their liver function. However, a single HD session does not affect liver function significantly as assessed by the GSP test. Since the metabolism of galactose is dependent on liver blood flow and hepatic functional mass, further studies are needed.