A CD11d Monoclonal Antibody Treatment Reduces Tissue Injury and Improves Neurological Outcome after Fluid Percussion Brain Injury in Rats

Abstract Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of anti-CD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2?h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24- to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24?h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI.     

Anti-CD44 Antibody Treatment Lowers Hyperglycemia and Improves Insulin Resistance,Adipose Inflammation,and Hepatic Steatosis in Diet-Induced Obese Mice

Type 2 diabetes (T2D) is a metabolic disease affecting >370 million people worldwide. It is characterized by obesity-induced insulin resistance, and growing evidence has indicated that this causative link between obesity and insulin resistance is associated with visceral adipose tissue inflammation. However, using anti-inflammatory drugs to treat insulin resistance and T2D is not a common practice. We recently applied a bioinformatics methodology to open public data and found that CD44 plays a critical role in the development of adipose tissue inflammation and insulin resistance. In this report, we examined the role of CD44 in T2D by administering daily injections of anti-CD44 monoclonal antibody (mAb) in a high-fat–diet mouse model. Four weeks of therapy with CD44 mAb suppressed visceral adipose tissue inflammation compared with controls and reduced fasting blood glucose levels, weight gain, liver steatosis, and insulin resistance to levels comparable to or better than therapy with the drugs metformin and pioglitazone. These findings suggest that CD44 mAb may be useful as a prototype drug for therapy of T2D by breaking the links between obesity and insulin resistance.     

Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap–/– Mice,a Model of Recessive Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is characterized by low bone mass, poor bone quality, and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin‐neutralizing antibodies (Scl‐Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl‐Ab treatment has not been studied in models of recessive OI. Cartilage‐associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1‐week‐old and 6‐week‐old Crtap^–/– mice with Scl‐Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of “pediatric” and “young adult” recessive OI. Vehicle‐treated Crtap^–/– and wild‐type (WT) mice served as controls. Compared with control Crtap^–/– mice, micro–computed tomography (μCT) analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl‐Ab–treated Crtap^–/– mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl‐Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl‐Ab improved parameters of whole‐bone strength in Crtap^–/– mice, with more robust effects in the week 6 to 12 cohort, but did not affect the increased bone brittleness. Additionally, Scl‐Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6 to 12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl‐Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen posttranslational modification. © 2015 American Society for Bone and Mineral Research.     

加速康复外科理念在脊柱骨折围手术期中的应用研究

目的:探讨加速康复外科理念(ERAS)在脊柱骨折围手术期中的应用。方法:选取天津市天津医院脊柱外科收治的100例接受脊柱手术治疗脊柱骨折的患者,其中50例接受ERAS计划的患者为ERAS组,50例在实施ERAS计划之前接受手术的回顾性队列患者为对照组,比较两组患者术后疼痛评分(VAS评分)、阿片类药物消耗量、住院时间、术后30 d并发症和30 d再住院率。结果: ERAS组术后VAS评分为术后第1天(6.80±1.90)分,第2天(6.50±2.10)分,第3天(5.80±1.60)分,出院时(3.80±1.10)分和术后1个月(3.20±1.30)分均低于对照组,差异有统计学意义(P<0.05);术前,ERAS组与对照组阿片类药物消耗量差异无统计学意义(P>0.05),ERAS组阿片类药物消耗量术后第1天(12.50±3.90)片,第2天(10.50±3.70)片,第3天(8.70±3.10)片均低于对照组,差异有统计学意义(P<0.05);ERAS组平均住院时间为(3.90±1.62) d小于对照组(7.14±3.45) d,差异有统计学意义(P<0.05);术后30 d并发症发生率,对照组(30%)高于ERAS组(12%),差异有统计学意义(P=0.03);两组30 d再住院率差异无统计学意义(P=0.37)。结论: ERAS可显著加快脊柱骨折患者术后恢复,让更多的脊柱外科患者受益,值得推广应用。     

Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice

X-linked hypophosphatemia (XLH), caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D-resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostin's role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or sclerostin antibody (Scl-Ab) twice weekly, beginning at 4 weeks of age and euthanized at 8 weeks of age. Scl-Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild-type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl-Ab treatment in both sexes. This short-term treatment study suggests that Scl-Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH. © 2019 American Society for Bone and Mineral Research.     

体内埋置光纤介导的光生物调节对脊髓损伤后小鼠继发性炎症反应和功能恢复的影响

目的 研究体内埋置光纤介导的光生物调节对脊髓损伤小鼠组织修复和运动功能恢复的影响。方法 构建小鼠T9节段钳夹损伤及光生物调节治疗模型,将小鼠随机分为假手术（Sham）组、脊髓损伤（SCI）组、光生物调节治疗（SCI+PBM）组。用实时荧光定量PCR（qPCR）和酶联免疫吸附测定（ELISA）法检测损伤区炎症因子的表达情况。免疫荧光染色及原位末端标记（TUNEL）法观察损伤区神经元存活和轴突再生情况。采用巴索小鼠量表（Basso mouse scale,BMS）及足印记评估脊髓损伤小鼠后肢运动功能恢复情况。结果 与SCI组比较,SCI+PBM组小鼠损伤区的白细胞介素-1α（interleukin-1α,IL-1α）、白细胞介素-1β（interleukin-1β,IL-1β）和肿瘤坏死因子-α（tumor necrosis factor-α,TNF-α）的表达水平显著降低（P＜0.01）,总凋亡和神经元凋亡百分比显著降低（P＜0.001）,轴突到损伤中心的距离显著缩小（P＜0.001）,BMS评分和足印记步长明显优于SCI组（P＜0.01）。结论 体内埋置光纤介导的光生物调节可抑制小鼠脊髓损伤区继发性炎症反应,促进损伤区神经元存活及轴突再生,并最终促使损伤小鼠后肢运动功能的恢复。     

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Short-term administration of glucocorticoids (GCs) impairs muscle insulin sensitivity at least in part via the reduction of undercarboxylated osteocalcin (ucOC). However, whether ucOC treatment reverses the GC-induced muscle insulin resistance remains unclear. To test the hypothesis that ucOC directly ameliorates impaired insulin-stimulated glucose uptake (ISGU) induced by short-term GC administration in mice muscle and to identify the molecular mechanisms, mice were implanted with placebo or corticosterone (CS) slow-release pellets. Two days post-surgery, insulin-tolerance tests (ITTs) were performed. On day 3, serum was collected and extensor digitorum longus (EDL) and soleus muscles were isolated and treated ex vivo with vehicle, ucOC (30 ng/mL), insulin (60 µU/mL), or both. Circulating hormone levels, muscle glucose uptake, and muscle signaling proteins were assessed. CS administration reduced both serum osteocalcin and ucOC levels, whole-body insulin sensitivity, and muscle ISGU in EDL. Ex vivo ucOC treatment restored ISGU in CS-affected muscle, without increasing non-insulin-stimulated glucose uptake. In CS-affected EDL muscle, ucOC enhanced insulin action on phosphorylated (p-)protein kinase B (Akt)^Ser473and the p-extracellular signal-regulated kinase isoform 2 (ERK2)^{Thr202/Tyr204}/total (t)ERK2 ratio, which correlated with ISGU. In CS-affected soleus muscle, ucOC enhanced insulin action on p-mammalian target of rapamycin (mTOR)^Ser2481, the p-mTOR^Ser2481/tmTOR ratio, p-Akt substrate of 160kD (AS160)^Thr642, and p-protein kinase C (PKC) (pan)^Thr410, which correlated with ISGU. Furthermore, p-PKC (pan)^Thr410 correlated with p-Akt^Ser473 and p-AS160^Thr642. ucOC exerts direct insulin-sensitizing effects on CS-affected mouse muscle, likely through an enhancement in activity of key proteins involved in both insulin and ucOC signaling pathways. Furthermore, these effects are muscle type-dependent. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.     

Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFβ antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.     

多节段腰椎融合术的应用价值

目的：比较３节段以下和３节段以上腰椎融合术病人的融合率及临床疗效,以确定多节段腰椎融合术的临床应用价值。方法：回顾两组因退行性腰椎病变而接受融合醉的病人（第１组为３节段以下;第２组为３节段及３节段以上）,通过动力Ｘ线侧位片、病历复习、病人回访及信访评价融合率和临床疗效。结果：第１线及第２组的融合率分别是９６％和７８％,临床疗效优良率分别是８９％和６３％。而第２组病人中５０岁以下年龄组融合率是８７％,临床疗效优良率是８７％。结论：３节段及３节段以上腰椎融合术融合率低且临床疗效不佳。术前全面仔细的临床及影像学检查,融合节段的正确和慎重选择是取得满意疗效的关键。多节段融合术尤其在高龄病人应持慎重态度。     

CD HORIZON 前路内固定系统治疗退行性腰椎管狭窄症

目的探讨CD HORIZON前路内固定系统治疗退行性腰椎管狭窄症的应用价值。方法对21例退行性腰椎管狭窄症患者经从前路行椎管扩大减压植骨、CD HORIZON内固定术，术后经3～30个月，平均9个月的随访。结果17例术前腰痛、间歇跛行症状完全消除，下肢乏力基本消除，术后1个月戴腰围行走800～1500m，2例术前双下肢肌力0级，术后2个月恢复至4级。手术优良率90．5％。结论前路CD HORIZON系统治疗退行性腰椎管狭窄症可以达到有限化的椎管扩大、融合和固定，不过多干扰脊髓，临床效果满意。     

RAGE Deficiency Improves Postinjury Sciatic Nerve Regeneration in Type 1 Diabetic Mice

Peripheral neuropathy and insensate limbs and digits cause significant morbidity in diabetic individuals. Previous studies showed that deletion of the receptor for advanced end-glycation products (RAGE) in mice was protective in long-term diabetic neuropathy. Here, we tested the hypothesis that RAGE suppresses effective axonal regeneration in superimposed acute peripheral nerve injury attributable to tissue-damaging inflammatory responses. We report that deletion of RAGE, particularly in diabetic mice, resulted in significantly higher myelinated fiber densities and conduction velocities consequent to acute sciatic nerve crush compared with wild-type control animals. Consistent with key roles for RAGE-dependent inflammation, reconstitution of diabetic wild-type mice with RAGE-null versus wild-type bone marrow resulted in significantly improved axonal regeneration and restoration of function. Diabetic RAGE-null mice displayed higher numbers of invading macrophages in the nerve segments postcrush compared with wild-type animals, and these macrophages in diabetic RAGE-null mice displayed greater M2 polarization. In vitro, treatment of wild-type bone marrow–derived macrophages with advanced glycation end products (AGEs), which accumulate in diabetic nerve tissue, increased M1 and decreased M2 gene expression in a RAGE-dependent manner. Blockade of RAGE may be beneficial in the acute complications of diabetic neuropathy, at least in part, via upregulation of regeneration signals.Diabetes leads to the development of multiple complications (1–3). Peripheral neuropathy affects 30–50% of all diabetic patients (4–6). Individuals with diabetes are more vulnerable to superimposed thermal and pressure injuries (7–10). Diabetic individuals exposed to either topical application of capsaicin or intracutaneous excision axotomy (punch skin biopsy) displayed a reduction in regenerative rate, even without evidence of neuropathy, and reduced axonal regenerative sprouting and blood vessel growth, respectively, compared with nondiabetic control subjects (11,12). Studies of diabetic animals reported a delay of axonal regeneration after acute sciatic nerve crush compared with nondiabetic mice (13). Evidence suggests that enhanced accumulation of advanced glycation end products (AGEs) may be an important contributing mechanism to the pathogenesis of diabetes complications (14,15). AGEs are a heterogeneous group of molecules that impact cellular properties and gene expression via specific receptors such as receptor for advanced end-glycation product (RAGE) (16–18). RAGE, a pattern recognition receptor, also interacts with multiple members of the proinflammatory S100/calgranulin family and with high-mobility group box 1 protein (HMGB1); both classes of molecules are implicated in inflammation and cellular migration (19,20). These non-AGE ligands may be released by dying cells, and evidence suggests that although RAGE is not intimately involved in innate immune responses, its upregulation and activation by these ligands contribute to sustained inflammation and suppression of repair (21,22).These considerations prompted us to hypothesize that RAGE action in superimposed acute injury to the peripheral nerve, particularly in diabetes, attenuates neurite outgrowth and axonal regeneration via tissue-damaging inflammatory mechanisms. We subjected wild-type (WT) and homozygous RAGE-null mice to acute sciatic nerve crush to dissect the specific contribution of bone marrow RAGE expression. We also subjected WT mice to lethal irradiation and performed reconstitution with bone marrow expressing or devoid of RAGE.     

Postoperative Enteral Nutrition Improves Survival After Orthotopic Small Bowel Transplantation in Mice

Background

The aim of this study was to assess the effect postoperative enteral nutrition support on the survival after orthotopic small bowel transplantation in mice.

Methods

A model of orthotopic small bowel transplantation used C57BL/6 mice as both donors and recipients.

Results

We demonstrated that postoperative ileus was the deciding complication after transplantation. Postoperative enteral nutritional support resolved this problem and significantly improved survival and growth rates after transplantation.

Conclusion

These data suggest the importance of routine nutritional support after orthotopic small bowel transplantation in mice.     

Recovery Off-Kinetics Following Exhaustive Upper Body Exercise in Spinal Cord Injury

Background:People with spinal cord injury (SCI) present with impaired autonomic control when the lesion is above T6. This could lead to delayed cardiorespiratory recovery following vigorous physical activity.Objectives:To characterize and compare gas exchange off-kinetics following exhaustive exercise in individuals with SCI and an apparently healthy control group.Methods:Participants were 19 individuals with SCI who presented with the inability to voluntarily lift their legs against gravity (age, 44.6 ± 14.2 years; AIS A, n = 5; AIS B, n = 7; AIS C, n = 7; paraplegia, n = 14; tetraplegia, n = 5) and 10 healthy comparisons (COM; age, 30.5 ± 5.3 years). All participants performed an arm ergometer cardiopulmonary exercise test (aCPET) to volitional exhaustion followed by a 10-minute passive recovery. O₂ uptake (V̇o₂) and CO₂ output (V̇co₂) off-kinetics was examined using a mono-exponential model in which tau off (τ_off) and mean response time (MRT) were determined. The off-kinetics transition constant (Kt_off) was calculated as ΔV̇o₂/MRT. Student t tests were used to compare SCI versus COM group means.Results:COM had a significantly higher relative peak V̇o₂ compared to SCI (1.70 ± 0.55 L/min vs 1.19 ± 0.51 L/min, p = .019). No difference was observed for τ_off between the groups, however Kt_off for both V̇o₂ and V̇co₂ was significantly lower in the SCI compared to the COM group.Conclusion:A reduced Kt_off during recovery may suggest inefficiencies in replenishing muscle ATP stores and lactate clearance in these participants with SCI. These findings may contribute to the observed lower cardiorespiratory fitness and greater fatigability typically reported in individuals with SCI.