The increase in bone mineral density by bisphosphonate with active vitamin D analog is associated with the serum calcium level within the reference interval in postmenopausal osteoporosis

Objectives: To examine the factors associated with increase in lumbar spine bone mineral density (LS-BMD) by bisphosphonates (BPs) with active vitamin D analog (aVD).

Methods: Two independent postmenopausal osteoporotic patients treated by BPs with aVD for 24 months (Study 1: n?=?93, Study 2: n?=?99) were retrospectively analyzed.

Results: In Study 1, LS-BMD of the patients significantly increased for 24 m (5.4%, p?r²: 0.088, p?=?.02). While average sCa of the patients was 9.2?mg/dL before treatment, it increased time-dependently to 9.6?mg/dL for 24 m by treatment. As each patient had their LS-BMD five times during the study, there were four instances of %LS-BMD in each patient, resulting in 372 instances of %LS-BMD in Study 1. The smallest Akaike’s information criterion value for the most appropriate cut-off levels of sCa for %LS-BMD by treatment every 6 m was 9.3?mg/dL. The %LS-BMD by treatment for 6 m during 24 m period in patients with sCa ≥9.3?mg/dL (1.5%) was significantly higher than that in patients with sCa <9.3?mg/dL (0.8%, p?=?.038). The results of Study 2 were similar to those of Study 1, confirming the phenomena observed.

Conclusion: sCa was associated with an increased LS-BMD by BPs with aVD.     

Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds

In normal tissue repair, macrophages exhibit a pro-inflammatory phenotype (M1) at early stages and a pro-healing phenotype (M2) at later stages. We have previously shown that M1 macrophages initiate angiogenesis while M2 macrophages promote vessel maturation. Therefore, we reasoned that scaffolds that promote sequential M1 and M2 polarization of infiltrating macrophages should result in enhanced angiogenesis and healing. To this end, we first analyzed the in vitro kinetics of macrophage phenotype switch using flow cytometry, gene expression, and cytokine secretion analysis. Then, we designed scaffolds for bone regeneration based on modifications of decellularized bone for a short release of interferon-gamma (IFNg) to promote the M1 phenotype, followed by a more sustained release of interleukin-4 (IL4) to promote the M2 phenotype. To achieve this sequential release profile, IFNg was physically adsorbed onto the scaffolds, while IL4 was attached via biotin-streptavidin binding. Interestingly, despite the strong interactions between biotin and streptavidin, release studies showed that biotinylated IL4 was released over 6 days. These scaffolds promoted sequential M1 and M2 polarization of primary human macrophages as measured by gene expression of ten M1 and M2 markers and secretion of four cytokines, although the overlapping phases of IFNg and IL4 release tempered polarization to some extent. Murine subcutaneous implantation model showed increased vascularization in scaffolds releasing IFNg compared to controls. This study demonstrates that scaffolds for tissue engineering can be designed to harness the angiogenic behavior of host macrophages towards scaffold vascularization.     

The Myelodepletive Phenotype in Myelofibrosis: Clinical Relevance and Therapeutic Implication

Myelofibrosis (MF) is a BCR-ABL1⁻ myeloproliferative neoplasm that arises from hematopoietic stem and progenitor cells frequently harboring a somatic driver mutation in 1 of 3 genes: JAK2, CALR, or MPL. The pathologic features of this hematologic malignancy include myeloproliferation, diffuse bone marrow fibrosis, and overactivation of the JAK-STAT pathway, resulting in enhanced inflammatory cytokine release. The common clinical manifestations of MF include systemic symptoms, abnormal peripheral blood count levels, and splenomegaly. However, it has become increasingly appreciated that significant clinical heterogeneity exists among patients with MF. Two distinct MF clinical phenotypes include the myeloproliferative and myelodepletive phenotype, with peripheral blood counts being the main discerning feature. Patients with the myeloproliferative phenotype will present with elevated peripheral blood counts and often experience significant constitutional symptoms and progressive splenomegaly. In contrast, patients with the myelodepletive phenotype will have low peripheral blood counts and will frequently require transfusion support. Current frontline therapies for MF, include ruxolitinib and fedratinib, which can exacerbate cytopenias and thereby pose an impediment to effective treatment of the myelodepletive patient. The present review discusses the clinical and prognostic implications of the myelodepletive phenotype and the therapeutic options and limitations for this subset of patients, representing an unmet clinical need.     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

Low bone mineral density in ambulatory persons with cerebral palsy? A systematic review

Purpose: Non-ambulatory persons with cerebral palsy are prone to low bone mineral density. In ambulatory persons with cerebral palsy, bone mineral density deficits are expected to be small or absent, but a consensus conclusion is lacking. In this systematic review bone mineral density in ambulatory persons with cerebral palsy (Gross Motor Function Classification Scales I–III) was studied.

Materials and methods: Medline, Embase, and Web of Science were searched. According to international guidelines, low bone mineral density was defined as Z-score?≤??2.0. In addition, we focused on Z-score?≤??1.0 because this may indicate a tendency towards low bone mineral density.

Results: We included 16 studies, comprising 465 patients aged 1–65?years. Moderate and conflicting evidence for low bone mineral density (Z-score?≤??2.0) was found for several body parts (total proximal femur, total body, distal femur, lumbar spine) in children with Gross Motor Function Classification Scales II and III. We found no evidence for low bone mineral density in children with Gross Motor Function Classification Scale I or adults, although there was a tendency towards low bone mineral density (Z-score?≤??1.0) for several body parts.

Conclusions: Although more high-quality research is needed, results indicate that deficits in bone mineral density are not restricted to non-ambulatory people with cerebral palsy.

• Implications for Rehabilitation

• Although more high-quality research is needed, including adults and fracture risk assessment, the current study indicates that deficits in bone mineral density are not restricted to non-ambulatory people with CP.

• Health care professionals should be aware that optimal nutrition, supplements on indication, and an active lifestyle, preferably with weight-bearing activities, are important in ambulatory people with CP, also from a bone quality point-of-view.

• If indicated, medication and fall prevention training should be prescribed.

     

去势比格犬腹部脂肪与相关血清学指标及骨密度的变化关系

目的通过建立去势比格犬模型,观察绝经早期腹部脂肪变化规律,并通过对脂肪与骨代谢相关血清学指标的测量与分析,探讨脂肪及骨代谢的关键影响因素。方法选取6只成年雌性比格犬进行去势术,分别在术前、术后4个月、6个月、10个月进行腰椎定量CT(quantatitive computed tomography,QCT)腹部脂肪面积、骨密度(bone mineral density,BMD)、MRI腰椎骨髓脂肪含量及血清学指标的检测,比较不同时间各指标的变化趋势及关系。结果比格犬腹内脂肪面积(visceral fat area,VFA)、皮下脂肪面积(subcutaneous fat area,SFA)、腹部总脂肪面积(total fat area,TFA)在术后6个月、10个月均增加(P0.05),术后10个月VFA增加百分比均值为84.39%,且为三者中最大;术后比格犬BMD并未明显降低。体重、BMD、瘦素(leptin,LP)、VFA、高密度脂蛋白(high-density lipoprotein,HDL)与SFA相关。SFA、体重、低密度脂蛋白(low-density lipoprotein,LDL)、内脏脂肪素(visfatin,VFN)与BMD相关。结论去势比格犬模型可用于研究绝经后雌激素缺乏所引起的脂肪代谢变化,但短期内BMD并未明显丢失,骨、脂肪代谢之间存在交互作用。     

保留足趾的自体复合第2足趾关节移植治疗手指关节炎

目的 探讨保留足趾的自体复合第2足趾关节移植治疗手指关节炎的临床疗效.方法 2016年2月至2018年6月,共收治创伤性手指关节炎9例,其中男7例,女2例;年龄19~53岁,平均31.7岁;示指3例,中指6例;掌指关节(MP)关节炎4例,近侧指骨间关节(PIP)关节炎5例;均为创伤后继发的手指关节炎.采用游离带血供的自体复合第2足趾跖趾或趾骨间关节移植进行治疗,同时将受区废弃关节(7例)或切取自体髂骨移植(2例)修复供区骨缺损保留足趾长度,供区创面均直接关闭.术后观察手指和足趾骨折愈合情况、外形、移植关节活动度(ROM)、术后供区愈合情况和行走功能及相关并发症.结果 本组术后9例移植关节全部成活,1例足部供区行髂骨植骨微型钢板固定,术后1周伤口不愈合,考虑为内固定物排异反应,予拆除钢板改克氏针交叉固定,2周后创口顺利愈合.术后随访6~30个月,平均16.3个月.手指骨折平均愈合时间7~10周,平均8.3周,手指外观及功能良好.移植后的MP活动度为50°~75°,平均65.3°,PIP活动度为10°~85°,平均60.6°.根据中华医学会手外科学分会上肢部分功能评定试用标准评价手指功能:优5例,良3例,可1例,优良率为88.9%.足趾骨折平均愈合时间9~12周,平均10.2周,所有患者足趾外形良好,行走功能正常.2例取髂骨患者供区仅残留一条线形瘢痕,无疼痛、麻木等不适.结论 游离带血供的自体复合第2足趾关节移植治疗手指关节炎,同时应用受区废弃关节或切取自体髂骨移植修复供区骨缺损保留足趾,不仅能恢复手指关节的正常结构,使关节具有良好的功能,而且能保留足趾外形与功能,减少供区损伤,具有良好的治疗效果.     

Relationship between 3D lower limb bone morphology and 3D gait variables in children with uni and bilateral Cerebral Palsy

BackgroundMedical and surgical interventions to prevent or reduce bone deformities and improve gait in children with cerebral palsy (CP) are based on empirical evidence that there is a relationship between bone deformities and gait deviations.Research questionWhat is the relationship between tibial-femoral bone morphology and kinematic gait variables in ambulant children with CP?MethodsA retrospective analysis was conducted on data from 121 children with uni- (n = 64, mean age 9.9 (SD 3.4) years) and bi- lateral (n = 57, mean age 10.4 (SD 3.6) years) CP who had undergone 3D gait analysis and biplanar X-rays (EOS® system). The limbs were split as DIP (the more impaired limb of children with bilateral CP), HEMI (the impaired limb of unilateral CP) and REF (the unimpaired limb of unilateral CP). Multi-variable Linear Regressions were performed between 23 kinematic variables, the Gait Deviation Index (GDI) and a model composed of nine 3D bone variables for each limb type.ResultsWhen the whole sample was pooled, 72% of R² values were poor, 16% were fair, and 12% were moderate. Lower limb bone morphology models explained less than 1% of GDI variability. Correlations between tibial-femoral rotational parameters and hip rotation were mostly poor. Mean foot progression angle was the only kinematic parameter that was fairly to moderately correlated with bone variables in the 3 limb types. A tibial-femoral bone model explained 48% of the variability of mean foot progression angle in the REF limbs, 31% in the HEMI limbs and 25% in the DIP limbs.SignificanceTibial-femoral bone morphology was only weakly related to kinematic gait variables, in contrast with common clinical assumptions. These results suggest that factors other than bone morphology influence gait quality and thus a thorough clinical examination and gait analysis is required prior to making treatment decisions.     

Results From a Large,Multicenter, Retrospective Analysis On Radium223 Use in Metastatic Castration-resistant Prostate Cancer (mCRPC) in the Triveneto Italian Region

Background

Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting.

Clinical and subclinical cardiovascular disease in female SLE patients: Interplay between body mass index and bone mineral density

Background and aims

Since accelerated atherosclerosis has been reported in systemic lupus erythematosus (SLE), predictive biomarkers of cardiovascular disease (CVD) are needed. Among non-traditional risk factors, bone mineral density (BMD) has been related to CVD. However, its role in SLE remains controversial. This study aims to analyze the associations of subclinical atherosclerosis with traditional and non-traditional CV risk factors.