Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1^asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1^asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1^asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1^asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Burosumab for the Treatment of Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..     

Predictors of clinical outcomes after non-operative management of symptomatic full-thickness rotator cuff tears

BACKGROUNDPrevious studies have shown that non-surgical management can be an effective treatment strategy for many patients with rotator cuff tears. Despite the prevalence of rotator cuff disease, few studies have examined the patient and tear related factors that predict outcomes of nonsurgical management in this cohort of patients.AIMTo identify factors that are associated with changes in patient reported outcomes over time in individuals with full-thickness rotator cuff tears treated without surgery. METHODSA cohort of 59 patients who underwent non-surgical management of full thickness rotator cuff tears with a minimum of 1-year follow-up were identified from our institutional registry. Patient demographics, comorbidities and tear characteristics were collected at initial presentation. Outcome measures were collected at baseline and at each clinical follow-up, which included Western Ontario Rotator Cuff (WORC) index, American Shoulder and Elbow Surgeons score, Visual Analog Scale for pain and Single Assessment Numerical Evaluation. Multi- and univariate regression analyses were used to determine the impact of each patient and tear related variable on final WORC scores and change in WORC scores throughout the study. RESULTSIn this non-surgical cohort, all patient-reported outcome measures significantly improved compared to baseline at 1 and 2-year follow-up. There was no significant difference in outcomes between 1 and 2 years. The average improvement surpassed the published minimal clinically important differences values for WORC, American Shoulder and Elbow Surgeons, Visual Analog Scale pain and Single Assessment Numerical Evaluation scores. Regression analysis identified female gender (β = - 19.88, P = 0.003), smoking (β = -29.98, P = 0.014) and significant subscapularis fatty infiltration (β = -15.35, P = 0.024) as predictors of less favorable WORC scores at 1 year, and female gender (β = -19.09, P = 0.015) alone as a predictor of lower WORC scores at 2 years. Patients with symptom duration greater than 1 year at presentation reported less improvement in WORC scores at 1-year follow-up (β = -14.63, P = 0.052) and patients with traumatic tears reported greater improvements in WORC scores at 2-year follow-up (β = 17.37, P = 0.031). CONCLUSIONPatients with full thickness rotator cuff tears can achieve and maintain clinically meaningful benefit from non-surgical management through 2-year follow-up. Female patients, smokers, and those with significant subscapularis fatty infiltration tend to have lower overall WORC scores at 1-year follow-up, and females also have lower WORC scores at 2-year follow-up. Patients presenting with symptoms greater than 1 year had less clinical improvement at 1-year follow-up, and those with traumatic tears had greater clinical improvement at 2-year follow-up.     

MAKO机器人辅助单髁置换手术的护理配合

机器人技术在微创领域的作用越来越突出,而高质量护理工作的配合可以保障机器人手术的安全、有效进行,且有利于患者术后稳定情绪和更好的恢复.为提升护理工作者对MAKO机器人辅助单髁置换手术的全面认识,优化护理工作的模式和流程,提高手术效率并改善患者术后恢复效果,本文在现有的相关文献资料基础上,结合北京大学人民医院11例行机器人单髁置换手术的实际工作体会,用理论联系实际,对术中的护理配合工作进行系统地分析.本团队认为,在机器人辅助单髁置换手术中,护理工作应在传统经验积累的基础上,进一步提高护理配合熟练程度.随着科技的进步,MAKO机器人辅助单髁置换手术的医护模式也将进一步的智能化和数字化.     

Timebanking and the co-production of preventive social care with adults; what can we learn from the challenges of implementing person-to-person timebanks in England?

This paper explores the potential contribution of timebanking, an innovative volunteering scheme, to the co-production of preventive social care with adults in England. Interest in volunteering in social care has increased as one proposed solution to the international crisis of a rising demand for services in juxtaposition with decreased resources. Volunteering has been particularly promoted in preventive services that prevent or delay care needs arising. Despite sustained interest in volunteering and co-production in social care, little is known about how theory translates into practice. Reporting implementation data from a Realistic Evaluation of six case studies in England, this paper explores one volunteering scheme, timebanking. The research explores how timebanks were working, what contribution they can make to adult social care, and whether they are an example of co-production. Data collected included interviews, focus groups or open question responses on surveys from 84 timebank members, and semi-structured interviews with 13 timebank staff. Each timebank was visited at least twice, and all timebank activity was analysed for a period of 12 months. Data were triangulated to improve reliability. The research found that in practice, timebanks were not working as described in theory, there were small numbers of person-to-person exchanges and some timebanks had abandoned this exchange model. Timebanks faced significant implementation challenges including managing risk and safeguarding and the associated bureaucracy, a paternalistic professional culture and the complexity of the timebank mechanism which required adequate resources. Lessons for timebanks are identified, as well as transferable lessons about co-production and volunteering in social care if such schemes are to be successful in the future.     

肝衰竭肝细胞移植治疗时的"种子细胞"

目前,对肝衰竭治疗主要依赖于原位肝移植,但这一治疗手段因存在多方面的困难而难以广泛开展。肝细胞移植的出现以其独特的优点将成为原位肝移植的辅助治疗甚至会替代原位肝移植。但是,肝细胞移植时最佳细胞来源的选择又成为我们面临的一个紧迫的课题,现用于研究的细胞来源多为骨髓干细胞(包括间充质干细胞和造血干细胞)、脐血干细胞及胚胎干细胞等,且在实验研究方面都取得了不同程度的研究进展。通过对这几种细胞分化为肝细胞的实验研究进展作综述,为肝细胞移植时“种子细胞”的选择打下理论基础。     

NCL-5D3: a new monoclonal antibody recognizing low molecular weight cytokeratins effective for immunohistochemistry using fixed paraffin-embedded tissue

Production of a new monoclonal antibody designated NCL-5D3 is described. The antibody recognizes several low molecular weight cytokeratins, in particular cytokeratin Moll number 8 as determined by immunoblotting studies, and is highly effective for immunocytochemistry using routinely processed paraffin-embedded material. Staining is enhanced by prior treatment of the sections with trypsin. Assessment using a wide variety of normal and neoplastic tissue indicates reactivity with all tissues of simple or glandular epithelial origin, and in addition with many squamous carcinomas. Thus the antibody should prove of value in diagnostic histopathology.     

TIPE2 Ki67在子宫内膜癌组织中的表达及对预后的评估价值

目的 探讨肿瘤坏死因子诱导蛋白8样蛋白2(TIPE2)、细胞增殖核抗原Ki67在子宫内膜癌组织中的表达及对患者预后的评估价值。方法 选取2018年1月至2020年1月河北工程大学附属医院妇科收治的子宫内膜癌患者120例作为观察组,另选取同期收治的非子宫内膜癌患者130例作为对照组,所有入组患者均接受手术治疗。回顾性收集患者的临床及病理资料,比较两组患者子宫内膜组织中TIPE2、Ki67的表达水平。同时定期对观察组患者进行随访,分析患者2年生存情况,通过Cox比例风险回归模型分析子宫内膜癌患者预后的影响因素。结果 观察组、对照组子宫内膜组织中TIPE2阳性率分别为28.33%、71.54%。与对照组相比,观察组子宫内膜组织TIPE2阳性率降低（P<0.05）;观察组、对照组子宫内膜组织中Ki67阳性率分别为33.33%、5.38%。观察组子宫内膜组织Ki67阳性率高于对照组（P<0.05）。对120例子宫内膜癌患者随访2年,至随访结束,93例患者存活,生存率77.50%。Cox模型分析结果显示,TIPE2阴性（HR=3.736,95%CI=1.016～13.157）为子宫内膜...     

功能性消化不良患者胃排空功能与症状分型的关系

目的　通过 99m Tc植酸钠固体餐检测胃排空 ,了解功能性消化不良 (functional dyspepsia,FD)患者各临床亚型胃运动的情况 .方法　 99m Tc植酸钠标记固体餐 ,对 30例 FD患者 (其中溃疡样型 10例 ,动力障碍型 10例 ,非特异型 10例 )及 10名健康对照者进行了核素检测分析 .结果　运动障碍样型及非特异型 FD患者胃半排空时间延迟 (87± 2 8min,89± 2 6 min vs6 1± 9min,P<0 .0 5 ) ,2 h胃排空率明显减少(6 3.0± 11.5 % ,5 7.7± 15 .5 % vs87.0± 10 .3% ,P<0 .0 1) ,而溃疡样型 FD与正常人比无差异 (P>0 .0 5 ) .结论　胃排空延迟在运动障碍样型及非特异型 FD病因中占重要地位 ,FD三个临床亚型之间发病机制既相同又略有不同 ;FD患者中有症状与胃排空之间存在不一致现象 ,所以核素胃排空检查在 FD胃运动功能的判定及指导治疗上有重要意义 .     

脐血造血干细胞移植对肿瘤化疗病人骨髓功能的影响

1目的　探讨脐血造血干细胞移植对因化疗所致骨髓功能抑制的恶性肿瘤病人骨髓造血功能重建的临床意义。 2方法　从健康人脐血中纯化制备造血干细胞 ,每例病人每天静脉输注 2× 10 9个造血干细胞 ,连续5 d.以治疗前后自身对照进行疗效评价。 3结果　治疗前白细胞计数为 (2 .78± 1.72 )× 10 9/ L,治疗后第 7天为(4.5 5± 1.0 1)× 10 9/ L,两组比较有显著性差异 (F=18.5 0 ,q=6 .95 ,P<0 .0 1) ;治疗前血红蛋白含量为 (12 1.5 6±11.2 7) g/ L,治疗后第 14天为 (130 .72± 12 .5 8) g/ L,治疗前后比较差异有极显著意义 (F=14.0 2 ,q=4.90 ,P<0 .0 1) ,且治疗后第 2 1天比治疗后第 7天增高 (F=14.0 2 ,q=6 .2 6 ,P<0 .0 1) ;治疗前血小板计数为 (192 .38±18.2 1)× 10 9/ L,治疗后第 2 1天为 (2 0 1.5 7± 17.86 )× 10 9/ L,治疗前后比较差异有极显著意义 (F=9.0 1,q=3.99,P<0 .0 1)。 4结论　脐血造血干细胞移植对于重建或改善骨髓造血功能有一定疗效。提升白细胞速度较血红蛋白及血小板为快。