MOTS-c accelerates bone fracture healing by stimulating osteogenesis of bone marrow mesenchymal stem cells via positively regulating FOXF1 to activate the TGF-ß pathway.

The article "MOTS-c accelerates bone fracture healing by stimulating osteogenesis of bone marrow mesenchymal stem cells via positively regulating FOXF1 to activate the TGF-ß pathway, by F.-B. Weng, L.-F. Zhu, J.-X. Zhou, Y. Shan, Z.-G. Tian, L.-W. Yang, published in Eur Rev Med Pharmacol Sci 2019; 23 (24): 10623-10630-DOI: 10.26355/eurrev_201912_19759-PMID: 31858528" has been withdrawn from the authors due to inaccuracies during the process of organizing the images. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19759.

MOTS-c accelerates bone fracture healing by stimulating osteogenesis of bone marrow mesenchymal stem cells via positively regulating FOXF1 to activate the TGF-ß pathway.

OBJECTIVE: To elucidate the function of MOTS-c in accelerating bone fracture healing by inducing BMSCs differentiation into osteoblasts, as well as its potential mechanism. MATERIALS AND METHODS: Primary BMSCs were extracted from rats and induced for osteogenesis. The highest dose of MOTS-c that did not affect BMSCs proliferation was determined by CCK-8 assay. After 7-day osteogenesis, the relative levels of ALP, Bglap, and Runx2 in MOTS-c-treated BMSCs influenced by FOXF1 were examined. ALP staining and alizarin red S staining in BMSCs were performed as well. The interaction between FOXF1 and TGF-ß was analyzed by ChIP assay. At last, rescue experiments were performed to uncover the role of FOXF1/TGF-ß axis in MOTS-c-induced osteogenesis. RESULTS: 1 µM MOTS-c was the highest dose that did not affect BMSCs proliferation. MOTS-c treatment upregulated the relative levels of ALP, Bglap, and Runx2, and stimulated mineralization ability in BMSCs, which were attenuated by the silence of FOXF1. TGF-ß was proved to interact with FOXF1, and its level was positively mediated by FOXF1. The silence of FOXF1 attenuated the accelerated osteogenesis and TGF-ß upregulation in BMSCs because of MOTS-c induction, and these trends were further reversed by the overexpression of TGF-ß. CONCLUSIONS: MOTS-c treatment markedly induces osteogenesis in BMSCs. During MOTS-c-induced osteogenic progression, the upregulated FOXF1 triggers the activation of TGF-ß pathway, thus accelerating bone fracture healing.

MicroRNA-222 contributed to cell proliferation, invasion and migration via regulating YWHAG in osteosarcoma.

OBJECTIVE: The aim of this study was to investigate the role of microRNA-222 (miR-222) in osteosarcoma (OS), and to further explore the potential molecular mechanism. PATIENTS AND METHODS: We measured the level of miR-222 in OS tissues and cell lines using quantitative Real-time polymerase chain reaction. Synthesized miR-222 mimics or inhibitors were obtained to up-regulate or down-regulate the expression of miR-222 in U2OS or Saos2 cells. Cell counting kit-8 (CCK8) and colony formation assay were employed to detect the ability of cell proliferation, and transwell assay was used to confirm the ability of cell invasion. Furthermore, luciferase assay and Western blot were applied to verify the target of miR-222 in OS. RESULTS: The level of miR-222 in OS tumor tissue samples was significantly lower than that in normal group. Over-expression of miR-222 decreased cell proliferation and invasion in U2OS cells while knockdown of miR-222 promoted cell growth and metastasis in Saos2 cells. Furthermore, YWHAG was found to be a candidate target of miR-222 using several databases. Elevated level of miR-222 inhibited YWHAG expression while reduced miR-222 promoted YWHAG expression. Also, up-regulation of YWHAG restored the inhibiting effect of miR-222 mimics. CONCLUSIONS: We identified for the first time that the expression level of miR-222 was reduced in OS tissues as well as in OS cell lines. miR-222 could inhibit cell proliferation and invasion via down-regulating YWHAG. These data could provide a potential target for the biological treatment of OS.

Associations between Deceased-Donor Urine MCP-1 and Kidney Transplant Outcomes.

INTRODUCTION: Existing methods to predict recipient allograft function during deceased-donor kidney procurement are imprecise. Understanding the potential renal reparative role for monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in macrophage recruitment after injury, might help predict allograft outcomes. METHODS: We conducted a sub-study of the multicenter prospective Deceased Donor Study cohort, which evaluated deceased kidney donors from five organ procurement organizations from May 2010 to December 2013. We measured urine MCP-1 (uMCP-1) concentrations from donor samples collected at nephrectomy to determine associations with donor acute kidney injury (AKI), recipient delayed graft function (DGF), 6-month estimated GFR (eGFR), and graft failure. We also assessed perfusate MCP-1 concentrations from pumped kidneys for associations with DGF and 6-month eGFR. RESULTS: AKI occurred in 111 (9%) donors. Median (interquartile range) uMCP-1 concentration was higher in donors with AKI compared to donors without AKI (1.35 [0.41-3.93] ng/ml vs. 0.32 [0.11-0.80] ng/ml, p<0.001). DGF occurred in 756 (31%) recipients, but uMCP-1 was not independently associated with DGF. Higher donor uMCP-1 concentrations were independently associated with higher 6-month eGFR in those without DGF [0.77 (0.10, 1.45) ml/min/1.73m2 per doubling of uMCP1]. However, there were no independent associations between uMCP-1 and graft failure over a median follow-up of about 2 years. Lastly, perfusate MCP-1 concentrations significantly increased during pump perfusion but were not associated with DGF or 6-month eGFR. CONCLUSION: Donor uMCP-1 concentrations were modestly associated with higher recipient 6-month eGFR in those without DGF. However, the results suggest that donor uMCP-1 has minimal clinical utility given no associations with graft failure.

Characteristics and Evaluation of Geographically Distant vs Geographically Nearby Living Kidney Donors.

BACKGROUND: Living donor kidney transplant (LDKT) can be impeded by multiple barriers. One possible barrier to LDKT is a large physical distance between the living donor's home residence and the procuring transplant center. METHODS: We performed a retrospective, single-center study of living kidney donors in the United States who were geographically distant (residing ≥150 miles) from our transplant center. Each distant donor was matched to 4 geographically nearby donors (<150 miles from our center) as controls. RESULTS: From 2007 to 2010, of 429 live kidney donors, 55 (12.8%) were geographically distant. Black donors composed a higher proportion of geographically distant vs nearby donors (34.6% vs 15.5%), whereas Hispanic and Asian donors composed a lower proportion (P = .001). Distant vs nearby donors had similar median times from donor referral to actual donation (165 vs 161 days, P = .81). The geographically distant donors lived a median of 703 miles (25% to 75% range, 244 to 1072) from our center and 21.2 miles (25% to 75% range, 9.8 to 49.7) from the nearest kidney transplant center. The proportion of geographically distant donors who had their physician evaluation (21.6%), psychosocial evaluation (21.6%), or computed tomography angiogram (29.4%) performed close to home, rather than at our center, was low. CONCLUSIONS: Many geographically distant donors live close to transplant centers other than the procuring transplant center, but few of these donors perform parts of their donor evaluation at these closer centers. Black donors comprise a large proportion of geographically distant donors. The evaluation of geographically distant donors, especially among minorities, warrants further study.

Associations of Perfusate Biomarkers and Pump Parameters With Delayed Graft Function and Deceased Donor Kidney Allograft Function.

Hypothermic machine perfusion (HMP) is increasingly used in deceased donor kidney transplantation, but controversy exists regarding the value of perfusion biomarkers and pump parameters for assessing organ quality. We prospectively determined associations between perfusate biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1, IL-18 and liver-type fatty acid-binding protein [L-FABP]) and pump parameters (resistance and flow) with outcomes of delayed graft function (DGF) and 6-mo estimated GFR (eGFR). DGF occurred in 230 of 671 (34%) recipients. Only 1-h flow was inversely associated with DGF. Higher NGAL or L-FABP concentrations and increased resistance were inversely associated with 6-mo eGFR, whereas higher flow was associated with higher adjusted 6-mo eGFR. Discarded kidneys had consistently higher median resistance and lower median flow than transplanted kidneys, but median perfusate biomarker concentrations were either lower or not significantly different in discarded compared with transplanted kidneys. Notably, most recipients of transplanted kidneys with isolated "undesirable" biomarker levels or HMP parameters experienced acceptable 6-mo allograft function, suggesting these characteristics should not be used in isolation for discard decisions. Additional studies must confirm the utility of combining HMP measurements with other characteristics to assess kidney quality.

Associations of deceased donor kidney injury with kidney discard and function after transplantation.

Deceased donor kidneys with acute kidney injury (AKI) are often discarded due to fear of poor outcomes. We performed a multicenter study to determine associations of AKI (increasing admission-to-terminal serum creatinine by AKI Network stages) with kidney discard, delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). In 1632 donors, kidney discard risk increased for AKI stages 1, 2 and 3 (compared to no AKI) with adjusted relative risks of 1.28 (1.08-1.52), 1.82 (1.45-2.30) and 2.74 (2.0-3.75), respectively. Adjusted relative risk for DGF also increased by donor AKI stage: 1.27 (1.09-1.49), 1.70 (1.37-2.12) and 2.25 (1.74-2.91), respectively. Six-month eGFR, however, was similar across AKI categories but was lower for recipients with DGF (48 [interquartile range: 31-61] vs. 58 [45-75] ml/min/1.73m(2) for no DGF, p < 0.001). There was significant favorable interaction between donor AKI and DGF such that 6-month eGFR was progressively better for DGF kidneys with increasing donor AKI (46 [29-60], 49 [32-64], 52 [36-59] and 58 [39-71] ml/min/1.73m(2) for no AKI, stage 1, 2 and 3, respectively; interaction p = 0.05). Donor AKI is associated with kidney discard and DGF, but given acceptable 6-month allograft function, clinicians should consider cautious expansion into this donor pool.

Effect of CeO2 and Y2O3 on microstructure, bioactivity and degradability of laser cladding CaO-SiO2 coating on titanium alloy.

To solve the lack of strength of bulk biomaterials for load-bearing applications and improve the bioactivity of titanium alloy (Ti-6Al-4V), CaO-SiO2 coatings on titanium alloy were fabricated by laser cladding technique. The effect of CeO2 and Y2O3 on microstructure and properties of laser cladding coating was analyzed. The cross-section microstructure of ceramic layer from top to bottom gradually changes from cellular-dendrite structure to compact cellular crystal. The addition of CeO2 or Y2O3 refines the microstructure of the ceramic layer in the upper and middle regions. The refining effect on the grain is related to the kinds of additives and their content. The coating is mainly composed of CaTiO3, CaO, α-Ca2(SiO4), SiO2 and TiO2. Y2O3 inhibits the formation of CaO. After soaking in simulated body fluid (SBF), the calcium phosphate layer is formed on the coating surface, indicating the coating has bioactivity. After soaking in Tris-HCl solution, the samples doped with CeO2 or Y2O3 present a lower weight loss, indicating the addition of CeO2 or Y2O3 improves the degradability of laser cladding sample.

Glutathione S-transferase iso-enzymes in perfusate from pumped kidneys are associated with delayed graft function.

Accurate and reliable assessment tools are needed in transplantation. The objective of this prospective, multi-center study was to determine the associations of the alpha and pi iso-enzymes of glutathione S-transferase (GST), measured from perfusate solution at the start and end (base and post) of kidney allograft machine perfusion, with subsequent delayed graft function (DGF). We also compared GST iso-enzyme perfusate levels from discarded versus transplanted kidneys. A total of 428 kidneys were linked to outcomes as recorded by the United Network of Organ Sharing. DGF, defined as any dialysis in the first week of transplant, occurred in 141 recipients (32%). Alpha- and pi-GST levels significantly increased during machine perfusion. The adjusted relative risks (95% confidence interval) of DGF with each log-unit increase in base and post pi-GST were 1.14 (1.0-1.3) and 1.36 (1.1-1.8), respectively. Alpha-GST was not independently associated with DGF. There were no significant differences in GST values between discarded and transplanted kidneys, though renal resistance was significantly higher in discarded kidneys. We found pi-GST at the end of machine perfusion to be independently associated with DGF. Further studies should elucidate the utility of GST for identifying injured kidneys with regard to organ allocation, discard and recipient management decisions.

Carbachol excites sublaterodorsal nucleus neurons projecting to the spinal cord.

Considerable electrophysiological and pharmacological evidence has long suggested an important role for acetylcholine in the regulation of rapid-eye-movement (REM) sleep. For example, injection of the cholinergic agonist carbachol into the dorsomedial pons produces an REM sleep-like state with muscle atonia and cortical activation, both of which are cardinal features of REM sleep. Located within this region of the pons is the sublaterodorsal nucleus (SLD), a structure thought to be both necessary and sufficient for generating REM sleep muscle atonia. Subsets of glutamatergic SLD neurons potently contribute to motor inhibition during REM sleep through descending projections to motor-related glycinergic/GABAergic neurons in the spinal cord and ventromedial medulla. Prior electrophysiological and pharmacological studies examining the effects of acetylcholine on SLD neurons have, however, produced conflicting results. In the present study, we sought to clarify how acetylcholine influences the activity of spinally projecting SLD (SLDsp) neurons. We used retrograde tracing in combination with patch-clamp recordings and recorded pre- and postsynaptic effects of carbachol on SLDsp neurons. Carbachol acted presynaptically by increasing the frequency of glutamatergic miniature excitatory postsynaptic currents. We also found that carbachol directly excited SLDsp neurons by activating an Na(+)-Ca(2+) exchanger. Both pre- and postsynaptic effects were mediated by co-activation of M1 and M3 muscarinic receptors. These observations suggest that acetylcholine produces synergistic, excitatory pre- and postsynaptic responses on SLDsp neurons that, in turn, probably serve to promote muscle atonia during REM sleep.

Application of recA and rpoB sequence analysis on phylogeny and molecular identification of Geobacillus species.

AIMS: Some Geobacillus species have highly similar 16S rRNA gene sequences, making 16S rDNA sequence analysis-based identification problematic. To overcome this limitation, recA and rpoB sequence analysis was evaluated as an alternative for distinguishing Geobacillus species. METHODS AND RESULTS: The phylogram of 16S rRNA gene sequences inferred from the neighbour-joining method showed that nine clusters of Geobacillus species were characterized with bootstrap values >90%. The recA and rpoB sequences of 10 reference strains in clusters V, VIb and VIc were amplified and sequenced using consensus primers. Alignment of recA sequences in clusters V, VIb and VIc revealed three types of recA genes, consistent with the putative amino acid sequences and in vivo recA splicing analysis. The phylogram constructed from rpoB sequences showed more divergence than that constructed from 16S rRNA gene sequences. CONCLUSIONS: recA and rpoB sequence analysis differentiated closely-related Geobacillus species and provided direct evidence for reclassifying some species dubiously categorized as Geobacilli. Additionally, this study revealed three types of recA genes in the different Geobacillus species. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the advantage of recA and rpoB sequence analysis to supplement 16S rRNA gene sequence analysis for efficient and convenient determination of Geobacillus species.

Fatal graft-versus-host disease presenting as fever of unknown origin in a pancreas-after-kidney transplant recipient.

Acute graft-versus-host disease (GVHD) is a rare complication of pancreas transplantation. We describe a 54-year-old male with type 1 diabetes who received a zero-antigen mismatched pancreas-after-kidney transplant from a pancreas donor who was homozygous at the HLA-B, -Cw, -DR, and -DQ alleles. Starting on postoperative day (POD) #22, the patient developed persistent fevers. Workup was notable only for low-grade cytomegalovirus viremia, which was treated. The fevers eventually disappeared. On POD #106, the patient was noted to have a diffuse erythematous rash. A skin biopsy was consistent with GVHD. Short tandem repeat DNA analysis of both peripheral blood lymphocytes and skin demonstrated mixed chimerism, confirming the diagnosis of GHVD. Soon after diagnosis, the patient developed pancytopenia and fevers and died of multiorgan failure on POD #145. Transplant clinicians should consider GVHD as a possible, although admittedly rare, cause of fevers of unknown origin in recipients of pancreas transplants.

Renal transplantation in patients with pre-transplant donor-specific antibodies and negative flow cytometry crossmatches.

The clinical significance of pre-transplant donor-specific antibodies (DSA), despite negative cytotoxicity and flow cytometry crossmatches (FCXMs), is unknown. We performed a retrospective cohort study of 60 living donor renal transplant recipients, all with pre-transplant cytotoxicity and T-cell and B-cell FCXMs that were negative. Twenty recipients had pre-transplant DSA detected by enzyme-linked immunosorbent assays (ELISA) and/or microbead methods. Forty contemporaneous DSA-negative controls were selected. In the DSA-positive group, after a median follow-up of 8.2 months (25-75% range, 5.4-22.8 months), patient survival was 100% and allograft survival was 95.0%. Acute humoral rejection (AHR) developed in four patients (20.0%). Three of the AHR episodes occurred within the first month post-transplant. Median serum creatinine at last follow-up was 1.3 mg/dL (25-75% range, 1.0-1.6 mg/dL), versus 1.1 mg/dL (25-75% range, 0.9-1.4 mg/dL) in the DSA-negative controls (p = 0.29). Only one of the 40 controls developed AHR (2.5%). Pre-transplant DSA was associated with a significantly increased incidence of AHR (p = 0.02 by log-rank test). In conclusion, despite negative pre-transplant cytotoxicity and FCXMs, renal transplant recipients with pre-transplant DSA detected by solid-phase methods may have an increased incidence of AHR and require close monitoring post-transplant.

[Effects of qufengshi prescription on release of hydrogen peroxide and interleukin-1 from peritoneal macrophage in adjuvant arthritis rat].

OBJECTIVE: To study the mechanism of antiarthritis effects of Qufengshi Prescription. METHODS: Adjuvant arthritis (AA) was applied as pathological model of rheumatoid arthritis and prednisone was used as positive control. RESULTS: The Prescription at high and medium dosages significantly decreased the rising level of hydrogen peroxide and interleukin-1 in AA rats (P < 0.05), the potency being similar to prednisone. CONCLUSION: Qufengshi Prescription Could reduce the rising level of interleukin-1 and hydrogen peroxide in AA rats, which may be part of mechanism of the antiarthritis effect.

[Clinical anti-caries effect of dentifrice containing two fluorides]

Anti-caries effect of dentifrice containing sodium monofluorophophate and sodium fluoride was studied among 2-3 years OLD nursery children.After one year,both mean dft and dfs were very significantly lower than those of control groups.

[Comparative study on the pharmacokinetics of rifampicin between the old and middle-aged tuberculosis patients].

The pharmacokinetics of rifampicin was studied in 16 tuberculosis patients including the elderly (64.3 +/- 4.8 yrs, n = 8) and the middle-aged (35.9 +/- 7.6 yrs, n = 8). 450 mg of rifampicin (RFP) were given orally. The concentration of RFP was assayed by HPLC. The plasma concentration-time curves of both groups fitted to one-compartment model. Important parameters were taken: t 1/2 2.39 +/- 0.66, 3.84 +/- 1.91 h; Cmax: 14.56 +/- 6.45, 9.83 +/- 2.55 micrograms/ml; vd: 0.43 +/- 0.11, 0.67 +/- 0.15L/kg; CL: 0.14 +/- 0.03, 0.13 +/- 0.06 L.h-1/kg respectively. No significant difference was found between the old and middle aged TB patients on the pharmacokinetics of rifampicin (P greater than 0.05). We suggest that 450 mg/day of rifampicin taken orally are available for aging tuberculosis patients.