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Calciphylaxis is a rare cutaneous vascular disease with clinical manifestations of intolerable pains, non-healing skin wounds, histologically characterized by calcification, fibrointimal hyperplasia, and thrombosis in microvessels. Currently, there are no approved guidelines for this disease. High prevalence of thrombophilias and hypercoagulable conditions in calciphylaxis patients have been recognized in recent years. Here, we report a case of uremic calciphylaxis patient whom was refractory to conventional treatments and then received a salvage strategyviahuman amnion-derived mesenchymal stem cell (hAMSC) intravenous combined with local application. In order to investigate the therapeutic mechanism of hMASCs from the novel perspective of hypercoagulability, coagulation-related indicators, wound status and quality of life were followed up. Improvement of hypercoagulable condition involving correction of platelet, D-dimer and plasminogen levels, skin regeneration and pain alleviation were revealed after hAMSC administration for one year. We propose that hypercoagulability is the therapeutic target of calciphylaxis patients which can be improved by hAMSC treatment.

IntroductionBlood bone metabolic biomarkers are non-invasive indexes for evaluating renal osteodystrophy (ROD). Here the relationships between blood bone metabolic biomarkers and anemia in chronic kidney disease (CKD) patients are investigated, the effects of parathyroidectomy (PTX) on above indices are analyzed.MethodsIn this cross-sectional study, 100 healthy controls and 239 CKD patients, including 46 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. A prospective study with 28 PTX patients was followed up. The degree of anemia was classified as mild, moderate, and severe based on the tertiles of hemoglobin (Hb) levels of the anemic CKD patients, with cutoff values of 83g/L and 102g/L. Bone metabolic biomarkers, including calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF23) and α-klotho were tested.ResultsThe mean eGFR in CKD patients was 25.74±35.99 ml/min/1.73 m2and 84.10% patients had anemia. The baseline Hb levels in the mild, moderate, and severe anemia subgroups were 110.86±5.99g/L, 92.71±5.96g/L and 67.38±10.56g/L, respectively. CKD patients had higher adjusted Ca, P, ALP, iPTH and FGF23 levels, and lower α-klotho levels than controls. Baseline adjusted Ca, P, iPTH and α-klotho levels were associated with Hb in CKD patients. Blood adjusted Ca, P, iPTH levels were correlated with anemia severity. After PTX (median interval: 6.88 months), anemia and high blood adjusted Ca, P, iPTH and FGF23 levels were ameliorated, while α-klotho levels increased.ConclusionsBlood adjusted Ca, P, iPTH and α-klotho levels were correlated with Hb in CKD patients, correcting ROD is supposed to be therapeutic targets for anemia.

Introduction Circulating intact parathyroid hormone (iPTH) levels include full-length (1-84) PTH and long C-PTH fragments, but primarily (7-84) PTH, which have been reported to have antagonistic effects on the bones and kidneys. However, their effects on the cardiovascular system remain unclear. In this study, the relationships between the plasma PTH fragments levels and heart rate variability (HRV) in stage 5 chronic kidney disease (CKD5) patients are explored. Furthermore, the effects of parathyroidectomy (PTX) on the above indices are investigated. Methods In this cross-sectional study, 164 healthy controls and 354 CKD5 patients, including 208 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. Circulating (7-84) PTH levels were calculated by subtracting plasma (1-84) PTH levels from iPTH levels. The HRV parameters were measured using a 24-hour Holter. Results The baseline levels of plasma iPTH, (1-84) PTH, and (7-84) PTH in the CKD5 patients were 930.40 (160.65, 1792.50) pg/mL, 448.60 (99.62, 850.45) pg/mL, and 468.20 (54.22, 922.55) pg/mL, respectively. In the CKD5 patients, plasma (1-84) PTH levels were independently correlated with the standard deviation of the normal-to-normal R-R intervals (SDNN) and the standard deviation of the five-minute average of the normal R-R intervals (SDANN). With a median follow up time of 6.50 months after PTX in the SHPT patients (n = 30), improved SDNN and SDANN markers were related with decreased (1-84) PTH levels. Furthermore, an improved SDNN was related with decreased (7-84) PTH levels. Conclusions The CKD5 patients’ baseline (1-84) PTH levels were correlated with the SDNN and SDANN. After PTX, an improved SDNN was related with decreased (1-84) PTH and (7-84) PTH levels, while improved SDANN was related with decreased (1-84) PTH levels. No antagonistic effects of (1-84) PTH and (7-84) PTH on HRV were found in the CKD5 patients.

BACKGROUND AND AIMS Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported multidisciplinary regenerative treatment for rescuing a severe uremic calciphylaxis patient with human amnion-derived mesenchymal stem cells (hAMSCs). METHOD A 34-year-old uremic woman presented progressive skin ischaemia, large areas of painful malodorous ulcers and mummified legs. The patient was diagnosed as calciphylaxis based on clinical manifestations, laboratory examinations and skin pathological features. Because of her refractory to conventional therapy, treatment with hAMSCs was approved. HAMSCs were administered intravenously to the patient at a dose of 1.0 × 106 cells per kilogram of body weight, local intramuscular injection along the wound edge (2.0 × 104 cells/cm2) and external application of the cell culture supernatant on wound surfaces. RESULTS Following up 15 months regularly after hAMSCs treatment, the patient's blood biochemical, inflammatory, mineral and bone metabolic indices improved significantly, with immunoregulation effects, regeneration of skin and soft tissue. Besides, wound healing (Figure 1), pain status and quality of life, evaluated by Pain Visual Analog Scale, Bates-Jensen Wound Assessment and the wound-quality of life questionnaire were also improved significantly (Figure 2). CONCLUSION This case represented the new method of hAMSC regeneration therapy for uremic calciphylaxis with safety and effectiveness, which deserved further investigation. Before hAMSC treatment, the patient had irregular ulcers on the buttocks and lower extremities, some of which were crusted on the surface or had purulent fishy discharge. Skin and soft tissue necrosis can be seen at the ulcerated area of the buttocks, localized deep to the fascia, with purulent secretions on the surface and brown pigmentation of the skin at the edge of the ulcer (Figure 1A and B). Because of her worsening symptoms and signs refractory to conventional therapy, the patient was given intravenous and local intramuscular injections of hAMSCs, supplemented by application of hAMSC culture supernatant to the wound. After 4 months of treatment, the sacrococcygeal wound has reduced size and become shallow with less exudate, some new granulation tissue was visible. The infection was controlled with pain significantly reduced (Figure 1C). After 12 months, most of the sacrococcygeal wound had healed with only a few erosions (Figure1D). Fifteen months later, her skin scarring of the wound was healed without pain (Figure 1E). The pain Visual Analogue Scale (Figure 2A) showed that the pain was unbearable before treatment (10 points) and disappeared after 15 months of hAMSC treatment (0 point). BWAT (Figure 2B) showed that all the 13 indexes got 5 points (worst) before hAMSC treatment, with a total score of 65 points. After 15 months of hAMSC treatment, each index got 1 point (best), and the total score was 13 points. The Wound-QoL questionnaire (Figure 2C) showed that the 17 items were quantified as 4 points (very serious) before treatment, with a total score of 68 points. After 15 months of hAMSC treatment, the score was 0 (none at all), and the total score was 0.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. We reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers and mummified legs. Because of her rapid progression and refractory to conventional therapy, human amnion-derived mesenchymal stem cells (hAMSCs) treatment was approved. Establishment and release inspection of hAMSCs, efficacy and safety assessment including cytokines secretory ability, immunocompetence, tumorigenicity and genetics analysisin vitrowere introduced. We further performed acute and long-term hAMSC toxity evaluations in C57BL/6 mice/rats, abnormal immune response tests in C57BL/6 mice and tumorigenic tests in the neonatal NU nude mice. After pre-clinical research, she was treated by hAMSCs with intravenous and local intramuscular injection and external supernatants application to her ulcers. When followed up to 15 months, her blood-based markers of bone and mineral metabolism were improved, with regeneration of skin soft tissue and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1 month treatment showed vascular regeneration with mature non-calcified vessels within dermis and 20 months later re-epithelialization restored the integrity of damaged site. No infusion or local treatment related adverse events occurred. To the best of our knowledge, this is the first evidence for the clinical use of hAMSCs. These findings suggest hAMSCs warrant further investigation as a potential regenerative treatment for uremic calciphylaxis with effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multi-differentiation, re-epithelialization and restorage of integrity.

Objective Persistent secondary hyperparathyroidism (SHPT) may occur because of residual cervicothoracic parathyroids in parathyroidectomy (PTX) patients with chronic kidney disease. We prospectively compared the predictive values of intraoperative plasma (1-84) parathyroid hormone (PTH) and intact PTH (iPTH) levels to improve the safety and efficacy of PTX. Methods We included 100 healthy controls, 162 stage 5 chronic kidney disease patients without SHPT, and 214 patients who underwent PTX because of SHPT. Plasma iPTH and (1-84) PTH levels were measured before incision (io-iPTH0 and io-[1-84]PTH0, respectively) and 10 minutes (io-iPTH10 and io-[1-84]PTH10, respectively) and 20 minutes (io-iPTH20 and io-[1-84]PTH20, respectively) after removing all parathyroids. The percentage reduction of iPTH and (1-84) PTH at 10 minutes (io-iPTH10% and io-[1-84]PTH10%, respectively) and 20 minutes (io-iPTH20%, and io-[1-84]PTH20%, respectively) was calculated. iPTH and (1-84) PTH were measured using second- and third-generation PTH assays, respectively. Results Compared with the controls and non-PTX patients, the PTX group had more obvious mineral metabolism disorders. There were 187 successful PTXs, 19 patients with persistent SHPT, and 8 patients lost to follow-up. The receiver operating characteristic curves revealed that io-(1-84)PTH10% >86.6% and io-(1-84)PTH20% >87.5% suggested successful PTX. The sensitivity of io-iPTH20% and io-(1-84)PTH20% were higher than those at the timepoint of 10 minutes. Moreover, the specificity and sensitivity of the (1-84) PTH reduction percentage were superior to that of iPTH. Conclusion Intraoperative reduction percentages of plasma (1-84) PTH levels are superior to iPTH for accurately predicting successful PTX, especially at 20 minutes after all cervicothoracic parathyroids had been resected.

Human babesiosis, a worldwide emerging tick-borne disease, is caused by the intraerythrocytic apicomplexan parasite, babesia. In recent years, the number of infected patients globally has continued to rise, and thus human babesiosis poses a significant public health threat. Therefore, stronger initiatives should be undertaken to prevent further spread and development of this disease. In the present review, we summarize the epidemiology of reported human babesiosis cases in China from 1993 until now. The data show that Babesia microti is the dominant species causing human babesiosis in China and has led to more than 100 human infections thus far, where Babesia crassa-like is the second-most common. Moreover, Guangxi province is the second-most infected area after the Heilongjiang province. We also review the babesia life cycle, manifestation, diagnosis, and treatment. Additionally, we discuss babesiosis prevention strategies to raise public awareness, and also provide suggestions for improved babesiosis control.

Babesia microti, an intraerythrocytic protozoa, can cause an emerging tick-borne disease-Human babesiosis. The parasite can successfully invade host red blood cells owing to the assistance of molecules expressed by babesia. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the housekeeping intracellular glycolytic enzyme, can also be expressed in the external of cells, where contributes to binding to several molecules such as plasminogen and actin. In the present study, we identified B. microti GAPDH (BmGAPDH) and generated the recombinant BmGAPDH (rBmGAPDH) via an E. coli expression system. Furthermore, we confirmed its catalytic dehydration activity in vitro. Moreover, we also demonstrated that rBmGAPDH could bind to human plasminogen and mouse α-actin. In addition, we demonstrated that rBmGAPDH could recognize anti-B. microti mouse serum. In conclusion, BmGAPDH is a multifunctional glycolytic enzyme, which can bind to host plasminogen and α-actin.

Quinacrine (QC), a synthetic antimalarial drug, was consistently used worldwide to combat malaria during the last century. Interestingly, later studies revealed that it also displays various additional properties, specifically antitumor activity. QC's antitumor activity occurs via a variety of pathways, including DNA intercalation, angiogenesis inhibition, signal transduction regulation, cell cycle arrest and autophagy induction. In combination with traditional therapies such as chemotherapy and radiotherapy, QC has also displayed synergistic effects against tumors, which may open promising therapeutic avenues. However, the breadth and complexity of its antitumor mechanisms have not yet been fully elucidated. In this review, we have systematically categorized QC's reported antitumor mechanisms from recent studies, to enable a deeper understanding of its antitumor activity.