Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone

Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65‐kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10^fl/fl mice (Mus musculus; C57BL/6) using the osteoblast‐specific Col1a1 2.3‐kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine‐aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral‐to‐matrix ratio and in crystal size as shown by Raman spectroscopy and small‐angle X‐ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild‐type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research.     

基于从筋治骨理论的康复锻炼对膝骨关节炎的疗效观察

目的:基于从筋治骨的中医理论,观察自主康复锻炼对膝骨性关节炎的有效性和安全性。方法:门诊收治90例膝骨关节炎患者,分为试验组45例和对照组45例。试验组男11例,女34例;年龄45~70岁,平均(55.47±8.66)岁;病程1周~5年,平均(6.66±7.96)周;对照组男11例,女34例;年龄48~67岁,平均(54.07±5.36)岁;病程1周~7年,平均(4.82±3.95)周。在股四头肌等长训练的基础上,试验组采用自主功能锻炼的干预方法 ,对照组则采用器械训练方法,共治疗2周。分别于治疗前、治疗后采用VAS、Lysholm评分和愈显率对两组临床疗效进行评价。结果:经过2周治疗,试验组的愈显率(86.67%)显著高于对照组(71.11%)。两组患者的VAS评分和Lysholm评分均较治疗前显著改善(P0.05),其中试验组均优于对照组(P0.05),两组均无严重不良事件。结论:自主功能锻炼联合股四头肌等长训练的康复方案对KOA临床疗效确切,且无严重不良反应发生。     

Lower cortisol response in high‐resilient caregivers of people with autism: the role of anger

Caring for an offspring with an autism spectrum disorder (ASD) has been related to high stress levels and health disturbances. However, a protective effect against these negative health outcomes has been described in high‐resilient caregivers. In this context, the main aim of the present study was to assess the association between resilient coping and cortisol response to acute stress in caregivers of people with ASD. Furthermore, the study aimed to explore the mediating role of anger in this association. We exposed 40 caregivers of people with ASD to an acute psychosocial stressor in the laboratory. Salivary cortisol samples were obtained before, during, and after the stressor. Resilient coping, anger, and socio‐demographic variables were also assessed. Resilient coping was negatively correlated with cortisol response. Specifically, cortisol release was lower in high‐resilient than low‐resilient caregivers. Anger was positively correlated with cortisol response, mediating the association with resilient coping. The observed associations of resilient coping and anger with cortisol response indicate that these variables may affect health outcomes, resilience being protective and anger harmful. Psychotherapeutic interventions focused on strengthening resilience and anger management could benefit caregivers, improving their health status and quality of life.     

Cognitive processing in the aftermath of relationship dissolution: Associations with concurrent and prospective distress and posttraumatic growth

Non‐marital romantic relationship dissolution is amongst the most stressful life events experienced by young adults. Yet, some individuals experience posttraumatic growth following relationship dissolution. Little is known about the specific and differential contribution of trait‐like and event‐specific cognitive processing styles to each of these outcomes. A longitudinal design was employed in which trait‐like (brooding and reflection) and dissolution‐specific (intrusive and deliberate) cognitive processing was examined as predictors of growth (Posttraumatic Growth Inventory) and distress (Breakup Distress Scale) following a recent relationship dissolution. Initially, 148 participants completed measures of trait‐like and dissolution‐specific cognitive processing, growth, and distress (T1). A subsample completed a seven‐month follow‐up (T2). Higher frequency of relationship‐dissolution intrusive thoughts predicted concurrent distress after accounting for brooding and relationship characteristics. Further, higher brooding and lower reflection predicted higher distress prospectively. Concurrent growth was predicted by both higher brooding and more deliberate relationship‐dissolution thoughts. Prospectively, T1 dissolution intrusive thoughts predicted higher T2 deliberate thoughts, and the interaction between these two constructs predicted higher T2 growth. Therefore, deliberately thinking of the dissolution was related to positive psychological outcomes. In contrast, intrusive dissolution cognitions and a tendency for brooding had a mixed (paradoxical) association with psychological adjustment.     

Tolerance of Vascularized Islet‐Kidney Transplants in Rhesus Monkeys

We previously reported that transplantation (Tx) of prevascularized donor islets as composite islet‐kidneys (IK) reversed diabetic hyperglycemia in both miniature swine and baboons. In order to enhance this strategy's potential clinical applicability, we have now combined this approach with hematopoietic stem cell (HSC) Tx in an attempt to induce tolerance in nonhuman primates. IKs were prepared by isolating islets from 70% partial pancreatectomies and injecting them beneath the autologous renal capsule of five rhesus monkey donors at least 3 months before allogeneic IK Tx. HSC Tx was performed after mobilization and leukapheresis of the donors and conditioning of the recipients with total body irradiation, T cell depletion, and cyclosporine. One IK was harvested for histologic analysis and four were transplanted into diabetic recipients. IK Tx was performed either 20–22 (n = 3) or 208 (n = 1) days after HSC Tx. All animals accepted IKs without rejection. All recipients required >20 U/day insulin before IK Tx to maintain <200 mg/dL, whereas after IK Tx, three animals required minimal doses of insulin (1–3 U/day) and one animal was insulin free. These results constitute a proof‐of‐principle that this IK tolerance strategy may provide a cure for both end‐stage renal disease and diabetes without the need for immunosuppression.     

Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized‐Controlled MECANO Trial

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open‐label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor‐specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.     

The First 2 Years of Activity of a Specialized Organ Procurement Center: Report of an Innovative Approach to Improve Organ Donation

The number of patients requiring organ transplants continues to outgrow the number of organs donated each year. In an attempt to improve the organ donation process and increase the number of organs available, we created a specialized multidisciplinary team within a specialized organ procurement center (OPC) with dedicated intensive care unit (ICU) beds and operating rooms. The OPC was staffed with ICU nurses, operating room nurses, organ donor management ICU physicians, and multidisciplinary staff. All organ donors within a designated geographic area were transferred to and managed within the OPC. During the first 2 years of operation, 126 patients were referred to the OPC. The OPC was in use for a total of 3527 h and involved 253 health workers. We retrieved 173 kidneys, 95 lungs, 68 livers, 37 hearts, and 13 pancreases for a total of 386 organs offered for transplantation. This translates to a total of 124.6 persons transplanted per million population, which compares most favorably to recently published numbers in developed countries. The OPC clearly demonstrates potential to increase the number of deceased donor organs available for transplant. Further studies are warranted to better understand the exact influence of the different components of the OPC on organ procurement.     

Impact of Calcium and Two Doses of Vitamin D on Bone Metabolism in the Elderly: A Randomized Controlled Trial

The optimal dose of vitamin D to optimize bone metabolism in the elderly is unclear. We tested the hypothesis that vitamin D, at a dose higher than recommended by the Institute of Medicine (IOM), has a beneficial effect on bone remodeling and mass. In this double‐blind trial we randomized 257 overweight elderly subjects to receive 1000 mg of elemental calcium citrate/day, and the daily equivalent of 3750 IU/day or 600 IU/day of vitamin D3 for 1 year. The subjects’ mean age was 71 ± 4 years, body mass index 30 ± 4 kg/m², 55% were women, and 222 completed the 12‐month follow‐up. Mean serum 25 hydroxyvitamin D (25OHD) was 20 ng/mL, and rose to 26 ng/mL in the low‐dose arm, and 36 ng/mL in the high‐dose arm, at 1 year (p < 0.05). Plasma parathyroid hormone, osteocalcin, and C‐terminal telopeptide (Cross Laps) levels decreased significantly by 20% to 22% in both arms, but there were no differences between the two groups for any variable, at 6 or 12 months, with the exception of serum calcitriol, which was higher in the high‐dose group at 12 months. Bone mineral density (BMD) increased significantly at the total hip and lumbar spine, but not the femoral neck, in both study arms, whereas subtotal body BMD increased in the high‐dose group only, at 1 year. However, there were no significant differences in percent change BMD between the two study arms at any skeletal site. Subjects with serum 25OHD <20 ng/mL and PTH level >76 pg/mL showed a trend for higher BMD increments at all skeletal sites, in the high‐dose group, that reached significance at the hip. Adverse events were comparable in the two study arms. This controlled trial shows little additional benefit in vitamin D supplementation at a dose exceeding the IOM recommendation of 600 IU/day on BMD and bone markers, in overweight elderly individuals. © 2017 American Society for Bone and Mineral Research.