Mechanical symptoms as an indication for knee arthroscopy in patients with degenerative meniscus tear: a prospective cohort study.

OBJECTIVE: According to prevailing consensus, patients with mechanical symptoms are those considered to most likely benefit from arthroscopic surgery. The aim of this study was to determine the value of using patients' pre-operative self-reports of mechanical symptoms as a justification surgery in patients with degenerative meniscus tear/knee disease. DESIGN: Pragmatic prospective cohort of 900 consecutive patients with symptomatic degenerative knee disease and meniscus tear undergoing arthroscopic partial meniscectomy (APM) was collected from one public orthopedic referral center specialized in arthroscopic surgery during 2007-2011. The patients' subjective satisfaction, self-rated improvement, change in Western Ontario Meniscal Evaluation Tool (WOMET) score, and patients' ratings of the knee using a numerical rating scale (NRS) was assessed at 1 year postoperatively. Multivariable regression models, adjusted for possible confounders and intermediates, were used to compare the outcomes in those with and without preoperative mechanical symptoms. RESULTS: The proportion of patients satisfied with their knee 12 months after arthroscopy was significantly lower among those with preoperative mechanical symptoms than among those without (61% vs 75%, multivariable adjusted risk ratio [RR] 0.84; 95% confidence interval [CI] 0.76, 0.92). Similarly, the proportion reporting improvement was lower (RR 0.91; 95% CI 0.85, 0.97). No statistically significant difference was found in change in WOMET or NRS between the two groups. Of those with preoperative mechanical symptoms, 47% reported persistent symptoms at 12 months postoperatively. CONCLUSIONS: Our observational data contradicts the current tenet of using patients' self-report of mechanical symptoms as a justification for performing arthroscopic surgery on patients with degenerative meniscus tear.

A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions.

Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. Surgically-injured rat skeletal muscles demonstrated the longitudinal process of muscle regeneration and fibrogenesis as stated by Myosin Heavy Chain developmental (MHCd) and collagen-I protein expression. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30% in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine.

Osteoporosis: the emperor has no clothes.

Current prevention strategies for low-trauma fractures amongst older persons depend on the notions that fractures are mainly caused by osteoporosis (pathophysiology), that patients at high risk can be identified (screening) and that the risk is amenable to bone-targeted pharmacotherapy (treatment). However, all these three notions can be disputed. PATHOPHYSIOLOGY: Most fracture patients have fallen, but actually do not have osteoporosis. A high likelihood of falling, in turn, is attributable to an ageing-related decline in physical functioning and general frailty. SCREENING: Currently available fracture risk prediction strategies including bone densitometry and multifactorial prediction tools are unable to identify a large proportion of patients who will sustain a fracture, whereas many of those with a high fracture risk score will not sustain a fracture. TREATMENT: The evidence for the viability of bone-targeted pharmacotherapy in preventing hip fracture and other clinical fragility fractures is mainly limited to women aged 65-80 years with osteoporosis, whereas the proof of hip fracture-preventing efficacy in women over 80 years of age and in men at all ages is meagre or absent. Further, the antihip fracture efficacy shown in clinical trials is absent in real-life studies. Many drugs for the treatment of osteoporosis have also been associated with increased risks of serious adverse events. There are also considerable uncertainties related to the efficacy of drug therapy in preventing clinical vertebral fractures, whereas the efficacy for preventing other fractures (relative risk reductions of 20-25%) remains moderate, particularly in terms of the low absolute risk reduction in fractures with this treatment.

3D visualization and quantification of rat cortical bone porosity using a desktop micro-CT system: a case study in the tibia.

Although micro-computed tomography (micro-CT) has become the gold standard for assessing the 3D structure of trabecular bone, its extension to cortical bone microstructure has been relatively limited. Desktop micro-CT has been employed to assess cortical bone porosity of humans, whereas that of smaller animals, such as mice and rats, has thus far only been imaged using synchrotron-based micro-CT. The goal of this study was to determine if it is possible to visualize and quantify rat cortical porosity using desktop micro-CT. Tibiae (n = 10) from 30-week-old female Sprague-Dawley rats were imaged with micro-CT (3 µm nominal resolution) and sequential ground sections were then prepared. Bland-Altman plots were constructed to compare per cent porosity and mean canal diameter from micro-CT (3D) versus histology (2D). The mean difference or bias (histology-micro-CT; ±95% confidence interval) for per cent porosity was found to be -0.15% (±2.57%), which was not significantly different from zero (P= 0.720). Canal diameter had a bias (±95% confidence interval) of -5.73 µm (±4.02 µm) which was found to be significantly different from zero (P < 0.001). The results indicated that cortical porosity in rat bone can indeed be visualized by desktop micro-CT. Quantitative assessment of per cent porosity provided unbiased results, whereas direct analysis of mean canal diameter was overestimated by micro-CT. Thus, although higher resolution, such as that available from synchrotron micro-CT, may ultimately be required for precise geometric measurements, desktop micro-CT--which is far more accessible--is capable of yielding comparable measures of porosity and holds great promise for assessment of the 3D arrangement of cortical porosity in the rat.

Treatment of keloid scars with intralesional triamcinolone and 5-fluorouracil injections - a randomized controlled trial.

Keloids have high recurrence rates. Current first-line therapy is triamcinolone (TAC) injection, but it has been suggested that approximately 50% of keloids are steroid resistant. We compared the efficacy of intralesional 5-fluorouracil (5-FU) and triamcinalone injections in a double-blind randomized controlled trial. Forty-three patients with 50 keloid scars were treated with either intralesional TAC or 5-FU-injections over 6 months. There was no statistically significant difference in the remission rate at 6 months between the 5-FU and TAC groups (46% vs 60%, respectively). Local adverse effects were higher in the TAC group compared to the 5-FU group. Occurrence of skin atrophy in TAC group was 44% and in the 5-FU group 8% (p < 0.05). Also the occurrence of telangiectasia in the TAC group was 50% and in the 5-FU 21% (p < 0.05). Vascularity of the keloids, assessed by spectral imaging and immunohistochemical staining for blood vessels, after treatment decreased in the TAC group, but not in the 5-FU group (p < 0.05). Fibroblast proliferation evaluated by Ki-67 staining significantly decreased in the TAC group (p < 0.05) but increased in the 5-FU group (p < 0.05). TAC and 5-FU injections did not differ in their clinical effectivity in this randomized study, but 5-FU injections lead to increased proliferation rate and did not affect vascular density in histological assessment. Due to the greater number of adverse effects observed after TAC treatment, 5-FU injections may be preferable for cosmetically sensitive skin areas.

A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families.

Children with type 1 diabetes (T1D) susceptibility HLA genotypes are shown to have an increased birthweight. We investigated to what extent T1D-predisposing HLA haplotypes were associated with increased birthweight. A total of 1255 Finnish children comprising those with T1D and their non-diabetic siblings were investigated. A total of 342 children and their non-diabetic parents were HLA genotyped. Birthweight data were obtained from the national Medical Birth Registry. The population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 was associated with high birthweight (P=0.0280) in families with a diabetic offspring. Other T1D-predisposing HLA haplotypes showed nonsignificant tendency with high birthweight. More infants with a birthweight >or=4000 g were born in families with a T1D offspring than in the general Finnish population (P=0.0139). The previously observed direct association between birthweight and T1D risk may be mediated through the modulating effects that T1D susceptibility HLA genes have on weight. High birthweight and subsequent weight gain may accelerate the ongoing pancreatic autoimmune process in genetically susceptible individuals. The high proportion of infants having a birthweight >or=4000 g in families with a diabetic offspring raises a concern of potential adverse health outcomes that high birthweight can have.

On-chip integrated vertically aligned carbon nanotube based super- and pseudocapacitors.

On-chip energy storage and management will have transformative impacts in developing advanced electronic platforms with built-in energy needs for operation of integrated circuits driving a microprocessor. Though success in growing stand-alone energy storage elements such as electrochemical capacitors (super and pseusocapacitors) on a variety of substrates is a promising step towards this direction. In this work, on-chip energy storage is demonstrated using architectures of highly aligned vertical carbon nanotubes (CNTs) acting as supercapacitors, capable of providing large device capacitances. The efficiency of these structures is further increased by incorporating electrochemically active nanoparticles such as MnOx to form pseudocapacitive architectures thus enhancing device capacitance areal specific capacitance of 37 mF/cm2. The demonstrated on-chip integration is up and down-scalable, compatible with standard CMOS processes, and offers lightweight energy storage what is vital for portable and autonomous device operation with numerous advantages as compared to electronics built from discrete components.

In vitro evaluation of the effect of cyclodextrin complexation on pulmonary deposition of a peptide, cyclosporin A.

The effect of hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD) complexation on in vitro pulmonary deposition of a cyclic peptide cyclosporin A (CsA) was studied. In addition, the effect of storage (32 days, 40 degrees C, 75% RH) on CsA/HP-alpha-CD complexes was studied. The complexation of CsA with CDs was evaluated by a phase-solubility method. Solid CsA/HP-alpha-CD complexes were prepared by freeze drying. Three inhalation formulations were prepared: CsA/lactose reference formulation (LF) (drug:carrier 1:364, w/w), CsA/HP-alpha-CD complex formulation (CDF) (drug:CD 1:269, w/w) and CsA/HP-alpha-CD complex/lactose formulation (CDLF) (complex:carrier 100:114, w/w). The inhalation studies were performed in vitro using Andersen Sampler (Ph. Eur.) and Taifun multi-dose dry powder inhalers (DPIs). Before the storage, the respirable fraction value (RF%) of CsA was 19.8+/-0.7%, 33.0+/-7.0% and 34.6+/-1.1% (mean+/-S.D., n=4 x 20) with LF, CDF and CDLF, respectively. When exposed to moisture (storage in a permeable polystyrene tube), the RF% values of CsA from formulations containing CsA/HP-alpha-CD complexes were lower than before the storage. However, when stored in the Taifun DPI, the RF% value of CsA from any of the formulations did not decrease. In conclusion, an acceptable RF% value of a peptide CsA from freeze-dried, simply micronized CsA/HP-alpha-CD complex powder was achieved before and after storage in the DPI.

Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands.

Since the discovery of the cannabinoid CB2 receptor in 1993, there has been a growing interest to clarify the importance of this G-protein coupled receptor (GPCR) for human physiology, and to investigate it as a possible target for current and future drug development. Several mutation studies have examined the receptor activation and structure of the receptor binding cavity. Additionally, 3D models for the CB2 receptor have been constructed to aid in perceiving important ligand-receptor interactions. In recent years, many research groups have succeeded in synthesizing new CB2 selective ligands. This review focuses on (i) important features for ligand recognition and/or receptor activation at CB2, derived from mutation and modeling studies, and (ii) recent advances in the field of CB2 selective ligands.

Reduced bone mineral density in men with a previous femur fracture.

This study determined the areal bone mineral density (BMD) from the lumbar spine (L2-4), right distal radius and ulna, and the femoral neck, trochanter area of the femur, distal femur, patella, proximal tibia, and calcaneus of both extremities in 29 men who had a femur shaft fracture 10 years earlier. For evaluation of the patients' BMDs in the spine and distal forearm, 29 age-, weight-, and height-matched normal men were also measured. Compared with normal men (mean +/- SD = 1.123 +/- 0.153), the spinal BMDs of the patients were significantly (p = 0.0054) lower (1.018 +/- 0.119, -9.3%). Distal radius and distal ulna showed no significant group differences. In patients, the mean BMD of the injured extremity (compared with the uninjured side) was significantly lower in the distal femur (-6.8%; p = 0.0000), patella (-5.4%; p = 0.0000), proximal tibia (-4.7%; p = 0.0000), and calcaneus (-2.2%; p = 0.0259). In the proximal femur, this value was at the same level (femoral neck 1.3%, NS) or higher (trochanter area 6.3%, p = 0.0002) than that in the uninjured extremity. The relative BMDs of the injured extremity did not associate with the fracture type, fracture location, age, muscle strength, follow-up time, or non-weight-bearing time but showed significant (r = 0.33-0.64) positive correlation with low pain assessment and high functional scores of the injured extremity.(ABSTRACT TRUNCATED AT 250 WORDS)

Inaccuracies inherent in patient-specific dual-energy X-ray absorptiometry bone mineral density measurements: comprehensive phantom-based evaluation.

An extensive series of dual-energy X-ray absorptiometry (DXA) scans and dual polyenergetic X-ray simulation studies of 150 different phantom arrays were carried out to evaluate quantitatively the extent of systematic inaccuracies inherent in DXA in vivo bone mineral density (BMD). These measurements are particularly relevant to lumbar vertebral and proximal femoral sites. The phantoms were specially fabricated near perfect absorptiometric representations of bone material, red marrow (RM) and yellow marrow (YM), and extraosseous mixtures of fat (F) and lean muscle that spanned the full range of soft tissue anthropometrics encountered clinically. In each case, the DXA-measured BMD values obtained using Hologic, Lunar, and Norland densitometers were found to be virtually the same and to be in excellent agreement with the corresponding quantitative simulation study BMD results. Comparisons of the known phantom BMD values and DXA-measured BMD in each case allowed the BMD inaccuracies to be evaluated. These present findings show that these ubiquitous inaccuracies in DXA BMD methodology are of in vivo soft tissue anthropometric genesis. It is found that patient-specific DXA-measured in vivo BMD inaccuracies as high as 20% or more can be readily anticipated clinically, particularly in cases of osteopenic, osteoporotic, and elderly patients. As these inaccuracies exceed considerably DXA precision errors, they may compromise patient-specific evaluations of fracture risk and, in prospective studies, mask or exaggerate clinically significant true changes in BMD. It is concluded that the magnitudes and variability of inherent inaccuracies in DXA-measured in vivo BMD underscore the need for prudence and circumspection in interpretations and assessments of DXA-based clinical studies.

Expression of osteocalcin in the patella of experimentally immobilized and remobilized rats.

The exact mechanisms by which mechanical loading-unloading affects bone tissue are mostly unknown. Recently, osteocalcin, a direct product of osteoblasts, has been shown to reflect the activity of the mineralization phase of the newly formed bone matrix, and therefore, the in situ detection of osteocalcin could be used for studying the effects of physical activity-inactivity on the osteoblast function or bone formation in the target bone. In this study, the effect of various loading states (immobilization and three forms of subsequent remobilization) on the in situ expression of osteocalcin in the rat patellas and their osteotendinous junctions was studied immunohistochemically using a polyclonal rat antiosteocalcin as the primary antibody. Following immobilization for 3 weeks, the immunoreactivity of osteocalcin was markedly decreased or was completely absent in all the patellar areas which normally show intense reaction as a sign of mineralization of the newly formed bone, that is, in the subperiosteal and subchondral regions, in the osteoid tissue that lies on the surface of the trabecular bone, and around the cortical lacunae. The same was true in the mineralized fibrocartilage zone of the osteotendinous junction of the quadriceps tendon. Free remobilization for 8 weeks (free cage activity) could not improve the situation, but after intensified remobilization of the same duration (low and especially high intensity treadmill running) high osteocalcin expression was observed in the above-mentioned anatomic sites. These findings indicate that formation of new bone tissue is rapidly regulated by the loading states of the bone. Higher than normal activity seems to be needed to restore the bone formation from the disuseinduced depression to normal.

Randomized controlled study of effects of sudden impact loading on rat femur.

Physical loading creating high peak strains on the skeleton at high strain rates is suggested to be the most effective type of activity in terms of bone mineral acquisition. This study assessed the effects of sudden impact loading on mineral and mechanical bone properties in 13-week-old Sprague-Dawley rats. The rats were randomly assigned as sedentary controls (SED, n = 10), control animals receiving low-intensity exercise (EX, n = 15), and experimental animals receiving low-intensity exercise combined with sudden impact-loading (EX + IMP, n = 15). In the EX group, the rats walked in a walking mill at a speed of 10 cm/s for 20 minutes/day, 5 days/week for 9 weeks. In the EX + IMP group, the program was identical to the EX group except for the additional sudden impacts administered to their skeleton during the walking exercise. At the start, there were 50 impacts per session, after which their number was gradually increased to 200 impacts per session by week 6 and then kept constant until the end of the experiment, week 9. These horizontally and vertically directed body impacts were produced by a custom-made walking mill equipped with computer-controlled high-pressure air cylinders. After sacrifice, both femora of each rat were removed and their dimensions, bone mineral content (BMC) by dual-energy X-ray absorptiometry, and mechanical properties by femoral shaft three-point bending and femoral neck compression were determined. The cortical wall thickness increased significantly in the EX and EX + IMP groups as compared with SEDs (+7.6%, p = 0.049 and +10%, p = 0.020, respectively). The EX + IMP group showed +9.0% (p = 0.046) higher cross-sectional moment of inertia values than the EX group. No significant intergroup differences were seen in the BMC values, while the breaking load of the femoral shaft (EX + IMP vs. SED +8.8%,p = 0.047) and femoral neck (EX + IMP vs. SED +14.1%, p = 0.013) was significantly enhanced by the impact loading. In conclusion, this study indicates that mechanical loading can substantially improve the mechanical characteristics of a rat femur without simultaneous gain in its mineral mass. If this is true in humans too, our finding gives an interesting perspective to the numerous longitudinal exercise studies (of women) in which the exercise-induced gains in bone mass and density have remained mild to moderate only.

Effects of free mobilization and low- to high-intensity treadmill running on the immobilization-induced bone loss in rats.

After an immobilization period of 3 weeks, the effects of free remobilization (8 weeks) as well as low- and high-intensity treadmill running on the bone mineral content (BMC) and density (BMD) of the hindlimbs of Sprague-Dawley rats (n = 70) were studied using a dual-energy x-ray absorptiometric scanner. In the low-intensity running program, the rats were allowed to move freely in the cage for 1 week, after which they started to run on a treadmill twice a day for 7 weeks. The speed of the treadmill was 20 cm/s, with an uphill inclination of 10 degrees. The running time was gradually increased from 20 minutes per session to 45 minutes per session. In the high-intensity group, the program was similar, with the exception that the speed of the treadmill was 30 cm/s, with an uphill inclination of 30 degrees. Immobilization for 3 weeks produced a significant BMC and BMD loss in the immobilized left femur and tibia (mean loss 9.6%, p < 0.001) but did not affect the right free limbs. Both low- and high-intensity running restored mineral content in the immobilized limb; however, an average 5% difference (p < 0.05) in mineral content of the right and left limb bones persisted. In the running groups, the values for the immobilized left limbs were at the same level or exceeded (range 3.8-11.6%, p < 0.05-0.01) and those of the free right limbs exclusively exceeded (range 5.3-15.9%, p < 0.05-0.01) the corresponding values of the age-matched control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of immobilization, three forms of remobilization, and subsequent deconditioning on bone mineral content and density in rat femora.

Disuse is associated with bone loss, which may not be recoverable. It is not known whether intensified remobilization is beneficial in restoring disuse-related bone loss nor if any such benefit would depend upon continuing mobilization for its maintenance. After an immobilization period of 3 weeks, the effects of free remobilization (11 weeks), and low-and high-intensity treadmill running (11 weeks) with and without subsequent deconditioning (18 weeks) on the bone mineral content (BMC) and density (BMD) of the hindlimb femora of Sprague-Dawley rats (n = 98) were studied using a dual-energy X-ray absorptiometric (DXA) scanner. Our hypothesis was that intensified remobilization is beneficial in restoring the BMC and BMD from disuse to normal while subsequent deconditioning is deleterious to these parameters. Immobilization for 3 weeks produced a significant BMC and BMD loss in the immobilized left femur (range -4.4 to -12.8%; p < 0.05-0.001). In the groups with free remobilization (free cage activity), the body weight-adjusted BMCs and BMDs always remained below those in the controls (range -2.3 to -12.1%; p values ranging from NS to < 0.01). Both low- and high-intensity running restored BMC and BMD in the immobilized limb, the effect being better in the latter group. In both of these groups, the values of the immobilized left limbs and those of the free right limbs exclusively exceeded the corresponding values of the age-matched control rats (left limb values 3.0-21.1% higher with p values ranging from NS to < 0.01; right limb values 7.9-21.4% higher with p < 0.05-0.01). However, after the deconditioning period of 18 weeks, the above described beneficial effects of low- and high-intensity running were lost, the left and right limb BMC and BMD values being lower than those in the age-matched controls (range -3.8 to -8.7%; p values ranging from NS to < 0.05). In conclusion, this study clearly indicates the need for greater than normal activity to restore the BMC and BMD after disuse to normal levels. However, the benefits of intensified remobilization are lost if the activity is terminated, and therefore, after immobilization and disuse, bone loading activities should be continued, perhaps indefinitely.

Dual-energy X-ray absorptiometry in predicting mechanical characteristics of rat femur.

Dual-energy X-ray absorptiometry (DXA), geometrical measurements, and mechanical testing of the rat femoral shaft and neck were performed on both femora of 51 Sprague-Dawley rats to: (i) determine the reproducibility of the DXA, geometrical, and biomechanical measurements of rat femora; (ii) determine linear and power-law (y=ax(b)) associations between the site-specific bone mineral variables and the actual mechanical characteristics of the given sites; (iii) develop, if sufficiently strong associations were found, appropriate prediction equations for the breaking load (F) and flexural rigidity (EI) of the femoral shaft and neck (only for F); and (iv) validate these equations in terms of accuracy of prediction. In the majority of the DXA measurements, the repeatability of the measurements was good, the CVrms varying between 1.2% and 3.9% in the bone mineral density (BMD) measurements and between 1.6% and 13.8% in the bone mineral content (BMC) measurements. DXA also proved accurate in length measurements of the rat femur (measurement error <1%). The manual (digimatic caliper-obtained) geometrical measurements of the rat femora were equally precise, the CVrms values varying between 0.2% and 5.0%. The repeatability of the biomechanical testings of these femora varied between 5.0% and 14.7%. Virtually all of the power-law and linear models explained more than 80% (at best 97%) of the variation in the F of the femoral shaft and neck, and the EI of the femoral shaft. Despite the high group-level correlations between the DXA-based predictions of bone strength and the actual breaking loads of the rat femora, and good precision of DXA, the ability of any DXA-based estimate to predict accurately the actual biomechanical characteristics of an individual bone remained relatively poor. In extreme cases, the prediction error could be tens of percent. Despite this we feel that bone strength-estimating equations can be used in the group-level analyses of experimental and clinical studies. Care must be taken, however, when choosing the most appropriate prediction method for a particular study.

Estrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading.

To first test the possible effect of gender on the responsiveness of growing rat skeleton to mechanical loading, 5-week-old littermates of 25 male and 25 female rats were subjected to either free-cage activity or treadmill training for a period of 14 weeks (experiment 1). Using peripheral quantitative computed tomography (pQCT) and mechanical testing of the femoral neck, we observed female rats exhibiting a clearly lower responsiveness to external loading than male rats (+3.0% vs +25% in cross-sectional area (CSA), +4.2% vs +27% in the bone mineral content (BMC), -0.6% vs +10% in volumetric bone mineral density (BMD), and +4.7% vs +28% in fracture strength (F(max)) of the femoral neck). Also, relative to the mechanical demands placed on the skeleton, the bones of the young female rats were considerably denser (>50%) than those of the males. In the subsequent experiment 2, we repeated the above-noted first experiment with 33-week-old rats and observed virtually identical exercise-induced benefits (+2.1% vs +10% in CSA, +3.4% vs +18% in BMC, +2.5% vs +23% in BMD, and -1.1% vs +27% in F(max) in females vs males, respectively) and the growth/puberty-related condensation of mineral into female bones. Finally, in experiment 3, 60 littermates of 3-week-old female rats were first subjected to sham operation or ovariectomy and then further randomized to exercise or control groups, respectively, to study whether the condensation of mineral into female bones and their lower responsiveness to loading were attributable to the effects of estrogen. At the end of the 16-week intervention, our pQCT and mechanical testing analysis showed not only the anticipated effect of reduced bone density in the ovariectomized rats ( approximately -20%) but also the hypothesized better responsiveness to mechanical loading in these estrogen-depleted rats (-3.5% vs +9.1% in CSA, -0.4% vs +12% in BMC, +4.4% vs +9.6% in BMD, and -4.2% vs +16% in F(max) in SHAM vs OVX, respectively). In conclusion, the results of our series of three experiments suggest that as such estrogen seems to have very little primary effect on the sensitivity of female bone to respond to external loading, but rather deposits extra stock of mineral into female bones in puberty. This estrogen-driven extra condensation of the female skeleton seems to persist into adulthood, simultaneously damping the responsiveness of the female skeleton to mechanical loading.

Integrin and dystrophin associated adhesion protein complexes during regeneration of shearing-type muscle injury.

In shearing injury both the myofibres and connective tissue framework are breached and the muscle tendon continuity is disrupted. During regeneration the firm myofibre to extracellular matrix (ECM) adhesion must be re-established. We have analysed the expression of selected molecules implementing this adhesion in regenerating myofibres 2-56 days after transection of rat soleus muscle using quantitative immunohistochemistry and Northern blotting. Beta1 integrin mRNA level and alpha7 integrin and vinculin immunoreactivities were transiently increased in both the intact and regenerating parts of the transected myofibres by day 5-7 with normalization by day 10-14. After day 14, alpha7 integrin and vinculin accumulated at the tips of the regenerating myofibres, indicating formation of new mini-myotendinous junctions (mMTJ). Immunoreactivities for dystrophin and associated proteins as well as merosin appeared in regenerating myotubes by day 3-4 reaching control levels by day 56. Our results suggest that integrin and dystrophin associated molecules are complementary in myofibre-ECM adhesion. During regeneration, ruptured myofibres temporarily reinforce their integrin mediated lateral adhesion until mMTJs are formed. Thereby the load on the newly formed scar and the risk of rerupture are reduced. Dystrophin associated molecules appear later and replace integrin on the lateral aspects, while both complexes are abundant at the mMTJs. These molecular events correspond to our previous results on tensile strength.