Ventilator-induced diaphragm dysfunction: the clinical relevance of animal models

Experimental evidence suggests that controlled mechanical ventilation (CMV) can induce dysfunction of the diaphragm, resulting in an early-onset and progressive decrease in diaphragmatic force-generating capacity, called ventilator-induced diaphragmatic dysfunction (VIDD). The mechanisms of VIDD are not fully elucidated, but include muscle atrophy (resulting from lysosomal, calpain, caspase and proteasome activation), oxidative stress, structural injury (disrupted myofibrils, increased numbers of lipid vacuoles, and abnormally small and disrupted mitochondria), myofiber remodeling and mitochondrial dysfunction. The major clinical implication of the VIDD is to limit the use of CMV to the extent possible. Partial (assisted) modes of ventilatory support should be used whenever feasible, since these modes attenuate the deleterious effects of mechanical ventilation on respiratory muscles. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

益气补肾活血方对失用性骨质疏松模型大鼠BMD、BGP、BAP的影响

目的观察益气补肾活血方对失用性骨质疏松大鼠骨密度(BMD)、大鼠骨钙素(BGP)、大鼠骨特异性碱性磷酸酶(BAP)等指标的影响。方法将假手术大鼠作为空白对照组,大鼠右侧股骨骨折后石膏固定的方法建立废用性骨质疏松模型,分为益气补肾活血方组、钙尔奇组、模型对照组。灌胃给药60 d后,骨密度仪检测BMD、骨矿盐(BMC),ELISA法检测血清中BGP、BAP的含量。结果益气补肾活血方组与钙尔奇组全身及股骨BMD及BMC均显著高于模型对照组(P0.05),两组之间比较,差异无统计学意义(P0.05);模型对照组血清BGP最低,与其他组比较差异有统计学意义(P0.05);益气补肾活血方组与钙尔奇组均能降低血清中BAP含量,与模型对照组比较差异有统计学意义(P0.05)。结论益气补肾活血方能够有效防止失用性骨质疏松模型大鼠的骨量丢失,并能有效抑制骨吸收的发生,促进骨形成。     

Increased Osteoclast-Like Cells Formation in Long-Term Bone Marrow Cultures from Patients with a Spinal Cord Injury

Patients with a spinal cord section loose a significant amount of bone. After paraplegia, bone loss occurs below the lesional level and is the more dramatic in iliac bones and in the metaphyseal area of long bones. A peak of urinary calcium and hydroxyprolinuria is observed approximately 6 weeks after their lesion. To further understand the mechanisms underlying the bone damage, we used long-term bone marrow cultures to compare osteoclast-like (OCL-like) cell formation above and below the lesional level. Seven paraplegic, one quadriparetic, one quadriplegic patients and five normal subjects were investigated. Six weeks after their spinal cord section, the number of OCL-like cells formed in iliac bone marrow cultures was significantly greater than those formed in sternal bone marrow cultures for all paraplegic patients tested. No significant differences were seen between iliac and sternal bone marrow cultures for the quadriparetic, the quadriplegic patient, or for the five normal subjects. Conditioned media (CM) from iliac marrow of paraplegic patients increased OCL-like cell formation in normal bone marrow cultures. IL-1, TNF-alpha, IL-6, and PGE₂ were measured in the CM after 3 weeks of culture. IL-6 was found to be significantly higher in iliac CM compared with sternal CM in six out of seven paraplegic patients. In two patients, addition of an anti-IL-6 monoclonal antibody to the marrow cultures significantly decreased the number of OCL-like cells formed at 3 weeks. We conclude that paraplegia caused by a cord section locally induces an increase in the capacity of progenitors to form OCL-like cells in long-term bone marrow cultures. A locally increased IL-6 production in the marrow below the lesional level could be partly responsible for this observation. Received: 25 July 1997 / Accepted: 5 March 1998     

跟骨超声骨密度在足部废用性骨质疏松症诊断中的应用

目的 探讨足跟部骨定量超声（quantitative ultrasound, QUS）检查骨密度（bone mineral density, BMD）在诊断足部废用性骨质疏松症中的临床应用价值。方法 本研究对2016年6~12月于我院足踝外科门诊就诊的单足损伤后限制活动超过3个月以上的80例病人进行双足跟骨QUS检查和患足X线检查。其中男27例、女53例,年龄为18~59岁、平均（45.72±12.46）岁,右足损伤58例、左足损伤22例,平均制动或限制活动时间为（4.12±0.83）个月。BMD结果分别按照T值法和骨量丢失法进行分析,参照X线诊断标准对跟骨QUS诊断足部废用性骨质疏松症的敏感性进行评价。结果 将80例病人两侧跟骨BMD数值依据骨量丢失百分率法计算：诊断为骨质疏松者24例、骨量减少者10例,漏诊18例,无误诊,敏感度为57.1%。与T值法敏感性分析（14.3%）比较明显提高,差异具有统计学意义（u=6.9325,P＜0.05）。结论 骨量丢失法优于T值法,但QUS诊断足部废用性骨质疏松症的敏感性低于X线法,仅能作为足部废用性骨质疏松症的初筛方法。     

Recovery from a state of limb hypokinesia in the rat

Rehabilitation didn't get much attention in animal research as compared to disuse atrophy that has been widely investigated over the years. We therefore performed a combined morphometrical and biochemical study on the effect of recovery from hind-limb immobilization on the tibia and the serum of rats. The experiments were carried out on 42 young Sprague-Dawley male rats. In one group of 32 rats the left hind-limb was immobilized for 2 weeks and then remobilized for another 2 weeks. Another group of 10 rats served as controls. Total body weight was partially restored. Tibia weight (fresh, dry and ash) showed on the other hand no tendency to improve. Serum triglycerides, urea, creatinine, albumin and calcium that were found to be reduced during immobilization returned to normal values during the rehabilitation period. Serum phosphorus that remained normal during limb disuse rose to above normal values in the remobilization phase. Serum alanine aminotransferase levels changed from low to normal. Serum alkaline phosphatase showed a rebound phenomenon from low to above-normal. Both muscle aspartate aminotransferase and bone alkaline phosphatase that were low during immobilization returned to normal in response to rehabilitation. We conclude that biochemical alterations are fast and tend to become fully corrected. Overcoming weight loss is a much slower process and it is unclear whether weight ever returns to pre-atrophic values.     

Four days of muscle disuse impairs single fiber contractile function in young and old healthy men

The purpose of the study was to investigate the effects of 4 days of disuse (knee brace) on contractile function of isolated vastus lateralis fibers (n = 486) from 11 young (24.3 ± 0.9 yrs) and 11 old (67.2 ± 1.0 yrs) healthy men having comparable levels of physical activity. Prior to disuse single fiber specific force (maximal Ca^2 +-activated force per cross-sectional area) was lower in MHC I vs. IIa fibers (p < 0.05) both in young (44%) and old (32%), and specific force of MHC IIa fibers was lower in old vs. young (19%, p < 0.05). Further, Ca^2 + sensitivity was higher in MHC I vs. IIa fibers (p < 0.05) in both age groups. Following disuse single fiber specific force decreased (p < 0.05) in MHC I fibers in young (− 19%) and old (− 17%), and in MHC IIa fibers in young (− 21%) but not in old (− 11%; ns). The extent of these decreases did not differ between young and old. Ca^2 + sensitivity decreased (p < 0.05) in MHC I fibers in old (− 0.11 pCa units) but not in young (− 0.08 pCa units; ns). The extent of these decreases was greater in old vs. young (p < 0.05). In conclusion, 4 days of lower limb disuse led to marked impairments in single muscle fiber specific force independently of age, while changes in Ca^2 + sensitivity were dependent on age and MHC isoform composition. The present findings stress the importance of determining and implementing effective preventive and rehabilitative approaches for old individuals exposed to as little as 4 days of disuse.     

Ineffectiveness of calcitonin on a local-disuse osteoporosis in the sheep: A histomorphometric study

Local immobilization is a good model for studying disuse-induced bone loss and to appreciate the effects of drugs, especially preventive action of antiresorptive therapy. In fact, increased osteoclastic activity is the main point of such a bone loss. The effect of salmon calcitonin was investigated on immobilization-induced osteoporosis in the sheep. Twenty-four nonovariectomized, adult, female, Welsh mountain sheep were submitted, by an external fixator procedure, to hock joint immobilization from the tibia to the the metatarsus for 12 weeks. The sheep were randomized into two groups receiving either an injection of placebo or salmon calcitonin (100 IU) three times per week, for 12 weeks. Histomorphometric analysis was performed on pre-and posttherapeutic transiliac bone biopsies, and on immobilized (left) and nonimmobilized calcanei removed after sacrifice. Results showed a 29% significant decrease of cancellous bone volume in the placebo group due to a significant reduced trabecular thickness when we compared immobilized versus nonimmobilized calcaneus. This structural adaptation appeared to be the consequence of an overall increased bone turnover. In the calcitonin group, same changes were observed, with a 23% reduction of bone mass in the immobilized calcaneus. By comparing calcitonin with placebo groups in both left and right calcanei, no difference was found. On the other hand, a significant increase of mineralization parameters in the iliac crest was only observed in the calcitonin group. In conclusion, salmon calcitonin, at a dose of 100 IU/day three times a week, was ineffective in preventing local disuse osteoporosis in this sheep model.This work was presented as a poster at the annual meeting of the American Society for Bone and Mineral Research, in Tampa, Florida, 1993.     

Forearm bone mineral density in patients with rheumatoid arthritis

 The aims of the present study were to determine whether patients with rheumatoid arthritis (RA) show significantly lower forearm bone mineral density (BMD) than sex- and age-matched healthy controls, and to identify significant factors that are associated with their BMD loss. One hundred eighty-four patients with RA and 185 sex- and age-matched healthy controls were enrolled in the study: 71 men 37–68 years of age (RA, 31; controls, 40), 129 premenopausal women 30–48 years of age (RA, 67; controls, 62), and 169 postmenopausal women 48–69 years of age (RA, 86; controls, 83). The correlation of forearm BMD, measured by dual energy X-ray absorptiometry with anatomic grade in the wrist, functional class, duration of disease, steroid use, modified health assessment questionnaire (HAQ) score for the upper and lower extremities, levels of serum C-reactive protein and rheumatoid factor, erythrocyte sedimentation rate, and years since menopause (YSM) were examined by multiple regression analysis. In men with RA, no clinical factors were significantly correlated with forearm BMD, and the BMD did not differ significantly from that in controls (0.329 ± 0.060 [mean ± SD] vs. 0.351 ± 0.069 g/cm²). In premenopausal women with RA, the HAQ score for the upper extremities was positively correlated with forearm BMD (P < 0.05), but the BMD did not differ significantly from that in controls (0.298 ± 0.085 vs. 0.324 ± 0.088 g/cm²); in postmenopausal women with RA, YSM and anatomic grade in the wrist were negatively correlated with forearm BMD (P < 0.01 and P < 0.05), and the BMD was significantly lower than in controls (0.192 ± 0.063 vs. 0.223 ± 0.076 g/cm², P < 0.01). These findings suggest that forearm BMD loss in patients with RA may be accelerated in women after menopause, and that YSM and disuse of the wrist may be significant determinants of their forearm BMD loss. Received: February 18, 2002/ Accepted: May 23, 2002     

Prevention of ligament and meniscus atrophy by active joint motion in a non-weight-bearing model

This study describes the effect of active joint motion on the maintenance of ligament and meniscus mass in a non-weight-bearing model of disuse. Denervation and fixation models of immobilization have shown that resorption of isotope and atrophy of mass occurred for hard tissue (bone) and soft tissues (ligament, tendon, or meniscus). A unilateral ankle disarticulation model of disuse that maintains active knee motion without weight bearing was studied for 8 weeks in dogs that were chronically prelabeled with three different isotopes. The effects of non-weight-bearing without denervation or fixation were analyzed for the resorption of isotopes, and net atrophy of bone mass (femur or tibia) and soft-tissue mass (collateral or cruciate ligaments, menisci). A large and similar loss of all three isotopes, as well as collagen and calcium mass occurred for whole femur and tibia; this indicated that mass loss was equivalent to bone resorption and suggests little replacement with new bone. No loss of isotope or mass per whole tissue occurred for the collateral and cruciate ligaments or menisci. The strength of the femur-anterior cruciate ligament-tibia complex was analyzed by a tensile failure test when a fast rate of deformation was applied; the results did not differ qualitatively or quantitatively between control and experimental limbs. The absence of weight bearing for 8 weeks resulted in marked bone atrophy without resorption or atrophy of soft tissues, or decrease of the mechanical strength for the femur-ligament-tibia complex.