Parathyroidectomy May Cause Remission of Uraemic Tumoral Calcinosis in Haemodialysis Patients

Few cases of uraemic tumoral calcinosis (UTC) have been reported. This study aimed to investigate the clinical efficacy of parathyroidectomy for UTC. Historical clinical data of patients with end-stage renal disease and UTC who underwent parathyroidectomy were analysed. Absorption of metastatic calcification was compared before and after operation. Changes in intact parathyroid hormone, serum calcium, phosphorus, and alkaline phosphatase levels were analysed before parathyroidectomy and at 1 week and 3, 6, and 12 months after parathyroidectomy. Eight patients met the enrolment criteria (men, 6; mean age, 38.6 SD 10.9 years). Uraemic tumoral calcinosis, which developed 2–8 years after dialysis began, was caused by secondary hyperparathyroidism. Massive calcium deposition was found in the shoulder (n = 6), hip (n = 3), and elbow (n = 2). Four patients had > 2 joints affected, and a single joint was involved for four patients. Seven patients had rapid remission (< 6 months) of the masses after parathyroidectomy. In one patient, the mass remained unabsorbed until 6 months postoperatively. Hypocalcaemia occurred in all patients where parathyroidectomy was successful, and calcium supplementation was required 1 year postoperatively. Serum intact parathyroid hormone levels on day 7 and at 3 and 6 months postoperatively decreased significantly from baseline and remained low 1 year postoperatively (22.015 SD33.134 pg/mL). Postoperative phosphorus levels were significantly lower than preoperative levels (p < 0.05), but no significant difference was found in alkaline phosphatase levels (p > 0.05). Parathyroidectomy has promising efficacy for UTC treatment and regulation of serum intact parathyroid hormone and phosphorus. Hypocalcaemia is a common complication after parathyroidectomy. Current Controlled Trials ChiCTR2000041311, date of registration: Dec. 23, 2020.

The Role of Neutrophil Elastase in Aortic Valve Calcification

Background: Calcific aortic valve disease (CAVD) is the most commonly valvular disease in the western countries initiated by inflammation and abnormal calcium deposition. Currently, there is no clinical drugs for CAVD. Neutrophil elastase(NE) plays a causal role in inflammation and participates actively in cardiovascular diseases. However, the effects of NE on valve calcification remains unclear. So we next explore whether it is involved in valve calcification and the molecular mechanisms involved.Methods: NE expression and activity in calcific aortic valve stenosis (CAVS) patients (n=58) and healthy patients (n=30) were measured by enzyme-linked immunosorbent assay (ELISA), western blot and immunohistochemistry (IHC). Porcine aortic valve interstitial cells (pVICs) were isolated and used in vitro expriments. The effects of NE on pVICs inflammation, apoptosis and calcification were detected by hochest 33258 staining, MTT assay, reverse transcription polymerase chain reaction (RT-PCR) and western blot. The effects of NE knockdown and NE activity inhibitor Alvelestat on pVICs inflammation, apoptosis and calcification under osteogenic medium induction were also detected by RT-PCR, western blot, alkaline phosphatase staining and alizarin red staining. Changes of Intracellular signaling pathways after NE treatment were measured by western blot.Results: The level and activity of NE were evaluated in patients with CAVS and calcified valve tissues. NE promoted inflammation, apoptosis and phenotype transition in pVICs in the presence or absence of osteogenic medium. Under osteogenic medium induction, NE silencing or NE inhibitor Alvelestat both suppressed the osteogenic differentiation of pVICs. Mechanically, NE played its role in promoting osteogenic differentiation of pVICs by activating the NF-κB and AKT signaling pathway.Conclusions: Collectively, NE is highly involved in the pathogenesis of valve calcification. Targeting NE such as Alvelestat may be a potential treatment for CAVD.

Overexpression of Rice Gene Lsi1 (Low Silicon Gene 1) Enhances The Plant-Microbe Interaction Resulting In Improved Chilling Tolerance

Chilling is an environmental phenomenon that hampers the plant growth. Related studies are mainly on based on the aerial plant parts. While, below ground to rhizosphere microbiome have been neglected under low temperature stress. The overexpression of Lsi1 in Dular significantly enhances its proline concentration compared with wild type Dular. This overexpression phenomenon maintains the osmotic balance of cells through influx of Ca2+, K+, H+ and efflux of Na+. The calcium deposition and the activity of plasma membrane H+-ATPase determined in root tip was consistent with the obtained ion flux results. In addition, the high-throughput sequencing results showed significant variation among identified 84 genera in different rhizocompartments (rhizosphere, rhizoplane and endosphere). The identified bacteria were associated with photosynthesis, energy metabolism, nitrogen fixation and defense, which were significantly increased in overexpressed plant. While, the number of pathogenic microorganisms associating were significantly reduced. Our findings suggests that the stability of ion balance in overexpressed plant roots affects the structure of microbial community in soil. To conclude, the over expression of Lsi1 gene enhanced cold tolerance of rice and its underlying mechanisms were comprehensively analyzed which can further impart its role in the stress tolerant rice plants.

CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma

Background Calcification of adamantinomatous craniopharyngioma (ACP) often causes problems with tumor resection, leading to a high incidence of deadly complications and tumor recurrence. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are 2 key enzymes that regulate histone acetylation and play important roles in tumor development. However, the roles of HAT and HDAC in the calcification and osteoblastic differentiation of ACP are not known. Methods In this study, primary cells were isolated from ACP tissues, and calcification was induced with bone morphogenetic protein 2 (Bmp2). HDAC3 expression was assessed in 12 tissue samples by Western blotting and immunohistochemistry. ACP calcification was assessed by Alizarin red staining. A luciferase reporter assay was performed to examine the interaction between miR-181b and the 3’-untranslated region of the polycomb chromobox 4 (CBX4) gene. Results Our results showed that the expression of HDAC3 was increased in the calcified ACP samples, but inhibition of HDAC3 promoted ACP cell calcification and osteoblastic differentiation. Mechanistically, HDAC3 nuclear translocation was suppressed by Bmp2, leading to Runx2 protein expression and Osterix, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP) mRNA expression. In addition, this process was suppressed by CBX4, which stabilized the nuclear localization of HDAC3. miR-181b, the expression of which was increased in Bmp2-induced ACP cells, directly targeted and decreased CBX4 expression and inhibited the nuclear localization of HDAC3. Conclusions Our results demonstrate that Bmp2 increases miR-181b levels to directly target and inhibit CBX4 expression, leading to a reduction in the CBX4-dependent regulation of HDAC3 nuclear translocation, which results in Runx2 activation/osteoblastic differentiation and calcium deposition in ACP. Further studies targeting these cascades may contribute to therapeutic interventions used for recurrent ACP.

HISTOMORPHOLOGICAL FINDINGS AND CLINICO-RADIOLOGICAL CORRELATION OF INTESTINAL ATRESIA AT A TERTIARY CARE CENTRE

Background: An atresia is a congenital defect of a hollow viscus that results in complete obstruction of the lumen. Intestinal atresia is one of the most frequent causes of bowel obstruction in the newborn and can occur at any point in the gastrointestinal tract. This study was undertaken to study the histomorphological findings of intestinal atresia and to correlate it with different subtypes and clinico-radiological feature. Material and methods: This was a prospective observational study conducted in 24 months on the resected gastrointestinal tract of 40 neonatal intestinal obstruction cases admitted in Pediatric surgery ward received in the Department of Pathology, Indira Gandhi Institute of Medical Sciences, Patna. Control Group- A total of 5 cases of vitello-intestinal duct patency were taken as control and compared with the study group. Results: With respect to total 40 cases, there were six, i.e. 15.0% female babies and 34, i.e. 85.0% male babies studied. Out of that, 15 i.e. 37.50% were full term and 25, i.e. 62.5% were premature. Mucosa showed oedema, ulceration and flattening in 9 cases. Apart from flattening and oedema, mucosa was denuded at some places and also showed congestion and extravasated blood in 6 cases each. Abnormal villus configuration, calcium deposition in 4 cases each and hypertrophied mucosa were found in 3 cases. Luminal narrowing, loss of mucosa, duplication of mucosa and gangrenewere found in one case each. Sub mucosal changes showed congestion in 33 cases, oedema in 15, Fibrosis in 4, thickened submucosa in 2 cases and dilated irregular branching blood vessels, extravasted blood, calcification in 1 case each. Muscularispropria having changes i.e. thinning in 16 cases, congestion, hypertrophy in 4 cases each, focal loss in 3 cases, calcification in 2 cases and thinning in 2 cases. Similarly, histopathological changes in serosa shows serositis in 16 cases, congestion in 11 cases and thinning in 3 cases. Oedema and congestion were present in 2 cases, hypertrophy and calcification in 1 case each. Conclusion:In this study spectrum of histomorphological changes in the atretic segment has been described. Histomorphological changes at atretic segment can be valuable to surgeons in deciding the type of surgery and minimizing the postoperative intestinal dysmotility, which remains the most common complication of intestinal atresia.

Pathogenesis and Molecular Immune Mechanism of Calcified Aortic Valve Disease

Calcified aortic valve disease (CAVD) was previously regarded as a passive process associated with valve degeneration and calcium deposition. However, recent studies have shown that the occurrence of CAVD is an active process involving complex changes such as endothelial injury, chronic inflammation, matrix remodeling, and neovascularization. CAVD is the ectopic accumulation of calcium nodules on the surface of the aortic valve, which leads to aortic valve thickening, functional stenosis, and ultimately hemodynamic disorders. CAVD has become an important cause of death from cardiovascular disease. The discovery of therapeutic targets to delay or block the progression of CAVD and the clinical application of transcatheter aortic valve implantation (TAVI) provide new ideas for the prevention and treatment of CAVD. This article summarizes the pathogenesis of CAVD and provides insight into the future directions of CAVD diagnosis and treatment.

IL-18-Mediated SLC7A5 Overexpression Enhances Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells via the c-MYC Pathway

Objective: To investigate the role of IL-18 in the regulation of osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs).Methods: To assess whether IL-18 affects the osteogenic differentiation of hBMSCs through the c-MYC/SLC7A5 axis, IL-18 dose-response and time-course experiments were performed to evaluate its impact on osteogenic differentiation. To confirm osteogenic differentiation, alizarin red staining calcium measurement were performed. RT-qPCR and western blotting were used to determine the expression levels of bone-specific markers ALP, RUNX2, and BMP2, as well as those of SLC7A5 and c-MYC. Furthermore, SLC7A5 and c-MYC expression was evaluated via immunofluorescence. To elucidate the roles of SLC7A5 and c-MYC in osteoblast differentiation, cells were transfected with SLC7A5 or c-MYC siRNAs, or treated with the SLC7A5-specific inhibitor JPH203 and c-MYC-specific inhibitor 10058-F4, and the expression of SLC7A5, c-MYC, and bone-specific markers ALP, RUNX2, and BMP2 was assessed.Results: Our results demonstrated that IL-18 increased calcium deposition in hBMSCs, and upregulated the expression of SLC7A5, c-MYC, ALP, RUNX2, and BMP2. Silencing of SLC7A5 or c-MYC using siRNA reduced the expression of ALP, RUNX2, and BMP2, while IL-18 treatment partially reversed the inhibitory effect of siRNA. Similar results were obtained by treating hBMSCs with SLC7A5 and c-MYC specific inhibitors, leading to significant reduction of the osteogenesis effect of IL-18 on hBMSCs.Conclusion: In conclusion, our results indicate that IL-18 promotes the osteogenic differentiation of hBMSCs via the SLC7A5/c-MYC pathway and, therefore, may play an important role in fracture healing. These findings will provide new treatment strategies for delayed fracture healing after splenectomy.

Icariin and Icariside II Reciprocally Stimulate Osteogenesis and Inhibit Adipogenesis of Multipotential Stromal Cells through ERK Signaling

Herba Epimedii is a famous Chinese herbal medicine for treating bone diseases. Icariin and icariside II, the main chemical constituents, have attracted great attention from scientists for their potential as antiosteoporosis agents. Our study aimed to evaluate their effects on the lineage commitment of multipotential stromal cells (MSCs). The osteogenesis and adipogenesis of MSCs were assessed by ALP activity, calcium deposition, and adipocyte formation. The expression profiles and levels of osteogenic and adipogenic specific genes were evaluated by cDNA microarray and quantitative real-time PCR. The involvement of extracellular signal-regulated kinase (ERK) signaling was studied by enzyme-linked immunosorbent assay. Icariin and icariside II significantly increased ALP activity and mineralization during osteogenic differentiation of MSCs. Runx2, Col1, and Bmp2 were upregulated in the presence of icariin and icariside II. Meanwhile, they downregulated Pparg, Adipsin, and Cebpb expression during adipogenic differentiation. cDNA microarray revealed 57 differentially expressed genes during lineage commitment of MSCs. In addition, icariin and icariside II enhanced the phosphorylation of ERK, and the above biological effects were blocked by ERK inhibitor U0126. Icariin and icariside II may drive the final lineage commitment of MSCs towards osteogenesis and inhibit adipogenesis through the ERK signaling pathway. Both of them exert multiple osteoprotective effects and deserve more attention for their medicinal and healthcare prospects.

Micro-CT Study of Mongolian Gerbil Humeral Bone After Prolonged Spaceflight Based on a New Algorithm for Delimitation of Long-Bone Regions

The Mongolian gerbil displays unique physiological and anatomical features that make this species an attractive object for biological experiments in space. However, until recently, the Mongolian gerbil has remained a novel, mostly unstudied animal model in investigating bone loss in weightlessness (G0). After 12 days of orbital Foton-M3 mission, the humerus of Mongolian gerbils has been studied here via micro-computed tomography (micro-CT) to quantify bone morphometric parameters. The samples from the flight group, delayed synchronous ground-control group, and basal control group were investigated, and main morphometric parameters were reported in the article. The accurate selection of a region of interest is an essential step for a correct assessment of bone parameters. We proposed a new, easy and efficient method for delimiting the bone’s basic regions in the humerus. It is based on quantitative estimation of X-ray attenuation in the cortical bone as a function of humerus bone length. The micro-CT analysis of the basic bone regions revealed a difference in bone morphometric parameters between the flight and control gerbils. The most significant bone loss was observed in the cortical part of the proximal humeral zone in the flight group. No statistically significant changes of volume fraction in the cancellous tissue of proximal and distal epiphyses and metaphyses were observed. A statistically significant increase in both cancellous bone volume and bone X-ray attenuation in the flight group was detected in the proximal part of the diaphyses. We assume that enhanced calcium deposition in the diaphyseal cancellous tissue occurred due to a bone response to G0 conditions.

Vascular Stiffness in Aging and Disease

The goal of this review is to provide further understanding of increased vascular stiffness with aging, and how it contributes to the adverse effects of major human diseases. Differences in stiffness down the aortic tree are discussed, a topic requiring further research, because most prior work only examined one location in the aorta. It is also important to understand the divergent effects of increased aortic stiffness between males and females, principally due to the protective role of female sex hormones prior to menopause. Another goal is to review human and non-human primate data and contrast them with data in rodents. This is particularly important for understanding sex differences in vascular stiffness with aging as well as the changes in vascular stiffness before and after menopause in females, as this is controversial. This area of research necessitates studies in humans and non-human primates, since rodents do not go through menopause. The most important mechanism studied as a cause of age-related increases in vascular stiffness is an alteration in the vascular extracellular matrix resulting from an increase in collagen and decrease in elastin. However, there are other mechanisms mediating increased vascular stiffness, such as collagen and elastin disarray, calcium deposition, endothelial dysfunction, and the number of vascular smooth muscle cells (VSMCs). Populations with increased longevity, who live in areas called “Blue Zones,” are also discussed as they provide additional insights into mechanisms that protect against age-related increases in vascular stiffness. Such increases in vascular stiffness are important in mediating the adverse effects of major cardiovascular diseases, including atherosclerosis, hypertension and diabetes, but require further research into their mechanisms and treatment.