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OBJECTIVES: Muscular forces are an important determinant of bone strength, but bone may also adapt to non-muscular loading. We tested the hypothesis that loads associated with childhood gymnastics yield high arm bone mass (BMC), bone size and bone strength, independent of arm lean mass (FFM) and muscle cross-sectional area (CSA). METHODS: Total body DXA and distal radius pQCT scans were performed on 33 post-menarcheal girls (19 ex/gymnasts, 14 non-gymnasts). Physical activity and calcium intake were assessed by questionnaire. For the non-dominant arm, pQCT measured bone strength indices and bone CSA (total, cortical) (4%, 33% sites); DXA measured arm FFM, arm BMC and skull BMC. Multiple regression analyses assessed gymnastic exposure, arm FFM, gynecological age and stature as predictors of bone parameters. RESULTS: Bone outcomes at loaded upper extremity sites were 10-42% greater in ex/gymnasts than non-gymnasts. Gymnastic exposure remained a consistent, significant predictor of upper extremity skeletal parameters after accounting for the effects of muscle parameters, gynecological age and height. CONCLUSIONS: Considering the effects of either arm FFM or muscle CSA, indices of bone mass, geometry and theoretical strength are disproportionately elevated after gymnastic exposure. Thus, non-muscular loading may be a distinct and important determinant of human skeletal structure.

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Alendronate (ALN) and other bisphosphonates have been used successfully in pediatric patients with osteopenia secondary to connective tissue diseases. Loss of growth in height has not been reported, but concerns remain regarding the effect of these potent antiresorptive agents when used in children and adolescents. High-dose methotrexate (MTX) and other chemotherapy drugs have been implicated in osteoporosis and a high fracture incidence in survivors of childhood cancers and are also associated with osteopenia in adult animals. The effect of high dose MTX on bone density during rapid skeletal growth, however, has not been widely studied, nor has the potentially therapeutic effect of bisphosphonates in this setting. We examined the effects of ALN and MTX administration, alone and in combination, on bone density, morphology, mechanical strength, and longitudinal growth in normal growing rats. Sprague-Dawley rats were given ALN once weekly (0.3 mg/kg) from 5 to 11 weeks of age, with and without a course of methotrexate (MTX) given daily in weeks 1 and 3 (0.75 mg/kg/day). Twenty-four animals were randomly divided into four groups: Control (vehicle), ALN alone, ALN + MTX, and MTX alone. After 6 weeks, the femora, tibiae, and lumbar spine were studied by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, mechanical strength testing, microradiography, light microscopy, and by determination of ash weights and bone lengths. ALN treatment increased bone mineral density (BMD) by 23% to 68%. The largest increases in the femur occurred in the distal third where endochondral bone growth was greatest and included large increases in trabecular bone and total cross-sectional area. ALN + MTX produced similar effects to ALN alone. MTX only reduced BMD by 8% in the vertebrae, but not significantly at other sites. MTX also led to femoral length reductions of 2.9%. The small reductions in BMD due to MTX were overwhelmed by the increases due to ALN, whereas the length loss was unaffected. Transverse density banding corresponding to weekly ALN administrations were clearly evident radiographically throughout the growing skeleton, likely due to decreased resorption and possibly increased mineralization in the bands. ALN or ALN + MTX treatment also led to increases in mechanical strength in the femora. Although MTX administration during growth leads to some BMD reduction, ALN given with MTX eliminates this reduction and in fact bone density and strength increase above control levels.

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PURPOSE: To determine if pentoxifylline, interleukin 1alpha, selenium and misoprostol can minimize damage to physeal longitudinal growth during single radiation dose exposure in an animal model. MATERIALS AND METHODS: Eighty-seven weanling Sprague-Dawley rats were randomized into 15 drug/dose groups. All groups received a single 17.5-Gy gamma-irradiation exposure to the right knee, the left limb serving as an internal control. Pentoxifylline was injected 30 min before exposure, sodium selenite and interleukin 1alpha 24 h before exposure and misoprostol 2 h before exposure. Positive controls received 17.5 Gy. At 6 weeks, animals were sacrificed, the hind limb lengths were measured and detailed histomorphometric analysis was performed. RESULTS: Statistically significant reductions (p < or = 0.03) in mean limb length discrepancy compared with irradiation alone were seen following administration of pentoxifylline (50 mg kg(-1)), interleukin 1alpha (15 mcg kg(-1)), selenium (5 mg kg(-1)) and misoprostol (20 mg kg(-1)). Histomorphometric endpoints and growth rate remained altered at 6 weeks despite treatment, but length discrepancy reduction was highly correlated with the appearance of regenerative clones. CONCLUSIONS: Each drug reduced the amount of anticipated growth arrest in the animal model and some compared favourably in magnitude with that previously demonstrated for the established radioprotectant drug amifostine. Restoration of growth appears related to appearance of regenerative clones.

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Although PEMF's have been found to promote fracture healing and to modulate the activity of bone cells in vitro, effects on bone metabolism are largely unexplored. A bioassay using neonatal rat calvarial bone was used to determine the early effects of a pulsing electromagnetic field (PEMF) exposure in vivo and in vitro on bone metabolic calcium exchange. Bone discs taken from whole body exposed animals (0-4 hours) show a log exposure time-dependent average increase in net Ca uptake in the 0-50% range (r2 = 0.83). This increase could be detected immediately after exposure and also after 24 hours, but not 48 hours later. Animals given whole body PEMF exposure also showed a decrease in serum calcium and did not elevate serum Ca after administration of exogenous parathyroid hormone (PTH). Bone discs from untreated rats, exposed to PEMF for 15 minutes in vitro and then assayed, showed net Ca uptake increases of a similar magnitude and also were refractory to the Ca-releasing effect of PTH. Unexposed discs responded normally to PTH by decreasing net Ca uptake. Treatment of calvarial discs with calcitonin or acetazolamide, both of which inactivate osteoclasts, made the bone refractory to further increases in Ca uptake by PEMF. These results suggest that PEMF exposure produces PTH-refractory osteoclastics and has a relatively rapid effect on increasing net bone Ca uptake, putatively due to a decrease in PTH/paracrine-mediated bone resorption.

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The aim of this study was to determine the independent and combined effects of 100 mg/kg and 200 mg/kg doses of the radioprotectant amifostine and radiotherapy dose fractionation in preserving the integrity of or minimizing damage to the physis during high-dose radiation exposure in an animal model. Thirty-six weanling four-week-old male Sprague-Dawley rats were randomized into six study groups of six animals each. The distal femur and proximal tibia in the right leg of each animal was exposed to X-irradiation, with the contralateral left leg serving as the nonirradiated control. Three groups received a single 25 Gy radiotherapy dose: one group alone, a second group preceded by 100 mg/kg amifostine, and a third preceded by 200 mg/kg amifostine. Three groups received a total of 25 Gy in three equal fractions: one group alone, a second group preceded by 100 mg/kg amifostine, and a third preceded by 200 mg/kg amifostine. Fractionation of the 25 Gy radiation dose reduced the mean percent overall limb growth loss to 44.8%, a statistically significant reduction compared to a mean 58.8% reduced growth with the single 25 Gy dose. Addition of amifostine at 100 and 200 mg/kg before each of the three fractions of radiotherapy further decreased the mean percent overall limb growth loss to 35.2% and 28.5%, respectively, both statistically significant reductions beyond that achieved by fractionation alone.

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BACKGROUND: ACE inhibitors have shown beneficial results in several studies after myocardial infarction (MI). However, these studies have shown conflicting results about the ideal starting time of the ACE inhibitors administration after MI and the importance of infarct size. OBJECTIVES: This study was designed to assess the long-term effects of lisinopril on mortality, cardiac function, and ventricular fibrosis after MI, in rats. METHODS: Lisinopril (20 mg/kg/day) was given on day 1 or 21 days after coronary occlusion in small or large infarctions. RESULTS: The mortality rate was reduced by 39 % in early treatment and 30 % in delayed treatment in comparison to the untreated rats. Early treatment reduced cardiac dysfunction in small MIs; however, delayed treatment did not. No statistical difference was observed among the groups for large MIs. No statistical difference was observed among the groups with large or small MIs on myocardial hydroxyproline concentration. CONCLUSIONS: Both early and delayed treatments with lisinopril increased survival. Treatment exerts no marked effects on fibrosis; early treatment has exerted beneficial influences on cardiac function whereas delayed treatment had no consistent effects. The protective effect of lisinopril is detectable only in small (< 40 % of LV) MIs.

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PURPOSE: The purpose of this study was to determine the relative benefits of sparing longitudinal bone growth by fractionation alone compared to pretreatment with amifostine, a chemical that provides differential radioprotection of normal tissues. METHODS AND MATERIALS: Twenty-four weanling 4-week-old male Sprague-Dawley rats were randomized into 2 overall treatment groups: fractionation alone (n = 12) and amifostine pretreatment (n = 12). The distal femur and proximal tibia in the right leg of each animal were exposed to a therapeutic X-irradiation dose (17.5 Gy total in 3 or 5 fractions) with the contralateral left leg as control. In 12 of the animals, amifostine (100 mg/kg) was administered intraperitoneally 20 min before radiation exposure. Six weeks later, growth was calculated based upon measurement of the bone lengths. RESULTS: Fractionated radiation resulted in a mean percent overall limb growth loss of 21. 1 +/- 7.0%. The addition of amifostine brought the mean percent overall limb growth loss to 16.3% +/- 4.6%, which showed a strong trend toward significance compared to fractionation alone (p = 0. 061). The addition of radioprotection with amifostine to 5 fractions irradiation significantly reduced the femoral and overall percentage growth arrest and limb length discrepancy compared to 5 fractions alone. CONCLUSIONS: These results support further investigation of amifostine and other radioprotectants in combination with fractionation for use in growing children requiring radiotherapy to the extremity for malignant tumors.

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The dose-response radioprotectant effects of amifostine on rat growth plate have not been studied. The purpose is to examine the relative effects of varying doses of amifostine on functional damage to the Sprague-Dawley rat growth plate from a single fraction radiation exposure. Thirty-six weanling Sprague-Dawley rats underwent single dose 17.5 Gy radiation exposure to the right knee. The contralateral left limb served as the nonirradiated control. Six groups of six animals each received, 20 minutes before radiation exposure, intraperitoneally administered amifostine at the following doses: 0, 50, 100, 150, 200, and 250 mg/kg. Six weeks after treatment, the rats were euthanized and the lower limbs disarticulated, skeletonized, radiographed, and measured. Statistically significant dose-related differences were observed between amifostine dosage groups for mean right-side growth, growth-loss, and limb-length discrepancy. The mean right-side growth recovered by amifostine administration increased from 14% at 50 mg/kg to 57% at 250 mg/kg. Growth-loss and limb discrepency were significantly reduced in proportion to increasing amifostine doses. Despite these positive effects of amifostine, amifostine associated mortality was identifiable beginning at 200 mg/kg and increased rapidly thereafter. This report suggests a directly proportional relationship between amifostine dose and its protective effects on the growth plate. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 73-79 (2000).

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BACKGROUND: There are limited data regarding the effects of angiotensin II receptor blockade after myocardial infarction (MI). In addition, whether combined angiotensin converting enzyme (ACE) inhibitor and angiotensin II type I (AT(1)) receptor antagonist may be superior to either drug alone on ventricular remodeling remains unclear. The goal of this study was to determine if the cardiac effects of the combined administration of an ACE inhibitor and AT(1) receptor antagonist are greater than those produced by either of these agents administered individually after MI. METHODS AND RESULTS: After MI, rats were divided into 4 groups: 1) untreated animals, 2) lisinopril treatment (20 mg/kg/day), 3) losartan treatment (20 mg/kg/day), and 4) lisinopril plus losartan treatment. After 3 months, the cardiac parameters studied were: mortality, fibrosis (hydroxyproline), hypertrophy (ventricular weight/body weight ratio [VW/BW]), left ventricular enlargement (volume at end-diastolic pressure equaled zero/body weight ratio [V0/BW]), and ventricular function (isovolumetric developed pressure, dp/dt, -dp/dt). A lowest mortality rate in the animals treated with the combination of both ACE inhibitor and AT(1) receptor antagonist was observed. Although lisinopril and losartan significantly decreased VW/BW ratio, when administered concomitantly, VW/BW ratio was lower than when either agent was administered individually. There were no differences in right ventricle hydroxyproline concentration. Only combination therapy decreased V0/BW ratio. The treatment with lisinopril plus losartan resulted in increases in the development of pressure versus untreated group; without alteration in dp/dt and -dp/dt. CONCLUSIONS: The combination of the AT(1) receptor blockade and ACE inhibitor is more effective than individual treatment on ventricular remodeling and survival after MI in rats.

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OBJECTIVE: To evaluate the effects of losartan on ventricular remodeling and on survival after myocardial infarction in rats. METHODS: After surgical occlusion of left coronary artery, 84 surviving male Wistar rats were divided into two groups: LO treated with losartan (20mg/kg/day, n=33) and NT (n=51), without medication. After 3 months, we analyzed mortality; ventricular to body mass ratio (VM /BM); myocardial hydroxyproline concentration (HOP); isovolumetric pressure, +dp/dt, -dp/dt, and diastolic volume/left ventricle mass ratio (VO/LV). RESULTS: Mortality was: LO = 22 %, and NT = 47 % (p<0.05). Ventricular mass,(VM/BM, mg/g) was 4.14 +/- 0.76 and 3.54+/-0.48, in the NT and LO groups, respectively (p<0.05). HOP (median) was 4.92 upsilong/mg in the LO and 5.54 upsilong/g in the NT group (p>0.05). The V0/LV values (median) were 0.24 mL/g in group LO and 0.31 mL/g in group NT (p<0.05) compared to NT group. There were no differences between the groups for +dp/dt and -dp/dt parameters. CONCLUSION: 1. The use of losartan myocardial infarction causes an attenuation of ventricular remodeling, bringing about an increased survival, an attenuation of ventricular hypertrophy and dilation, and an improvement of the isovolumetric pressure; 2. the treatment does not modify the myocardial collagen concentration.

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Absorbable fixation materials would seem especially useful for treating transphyseal fractures in growing children, but their degradation products may affect physeal growth. The histologic response of an open physis to placement of transphyseal, polydioxanone (PDS), bioabsorbable pins was studied in skeletally immature New Zealand White rabbits. A 1.3-mm PDS pin was inserted across the right femoral physis, and a 1.3-mm empty drill hole across the left femoral physis served as a control. The animals were sacrificed at 3, 6, 9, and 12 weeks postsurgery. Biplanar radiographs, bone length measurements, and histology sections of the physis and adjacent bone were made. Three independent observers graded the histologic response of the physis to the drilling and implant. There was no evidence of inflammation, foreign body reaction, or distortion of the growth plate during the entire growth period. This suggests bioabsorbable pins do not cause any appreciable inflammatory response or adverse effect on physeal function during active longitudinal growth of the bone.

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PURPOSE: The use of protective equipment has been absent or inconsistent in scholastic women's lacrosse leading to increasing concern for eye and head injury. There is a paucity of field data, however, on which to base strategic decisions on how best to prevent head injuries in young athletes. METHODS: This study examined the effects of protective eyewear on injury rates in scholastic women's lacrosse in a cohort of approximately 700 varsity and junior varsity players in central New York studied prospectively for 2 yr during a transition from sparse to almost complete eyewear use. RESULTS: The overall head/face injury rate was 0.71 injuries per 1000 exposures (games and practices) and was 16.5% lower in goggle wearers. In games alone, where more aggressive play and stick use prevails, the rate associated with protective eyewear use was markedly lower (51%). Considering specific regions, the rates for peri-orbit and forehead injuries among goggle users were substantially lower than for nonusers (6% and 13%, respectively). Cheek and scalp injury rates tended to be higher among goggle wearers, but not statistically significantly so. Significant compensatory increases with goggle wear at other sites were not observed. Only a few injuries appeared to be mediated by the goggles themselves and potentially could have been more serious if the goggles had not been present. No direct eye (orbit) injuries were reported throughout the study period. CONCLUSION: On balance, then, the use of eyewear in women's lacrosse appears to be beneficial when users are compared with nonusers.

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The radioprotectant compound amifostine (S-2[3-aminopropylamino]-ethylphosphorothioic acid), administered prior to radiotherapy, has been demonstrated to provide differential protection of normal cells from the damaging effects of ionizing radiation. The aim of this pilot was to determine if amifostine could preserve the integrity of, or minimize the damage to, the physis during exposure to radiation in an animal model. Thirty weanling Sprague-Dawley rats were randomized into five groups of six animals each. Groups 1 and 2 received a single exposure to radiation consisting of 12.5 and 17.5 Gy, respectively. Groups 3 and 4 received similar exposures of 12.5 and 17.5 Gy, respectively, but with prior administration of amifostine at 100 mg/kg. Group 5 (control) received neither radiation nor amifostine. At 6 weeks, femoral and tibial lengths were measured in treated and untreated hindlimbs and compared with the baseline lengths to calculate growth. Concordant with previous reports in the literature, the radiation doses of 12.5 and 17.5 Gy reduced net femoral growth in length by a mean of 23% (range = 12-33%, SD = 7.41) and 59% (range = 54-64%, SD = 4.45), respectively, in the irradiated limb. Amifostine reduced anticipated growth loss normally resulting from a single 12.5-Gy radiation dose by 48.9% in the femur, 13.1% in the tibia, and 27.6% overall in the total limb (p < or = 0.05). Similarly, anticipated growth loss from a single 17.5-Gy radiation dose was reduced by 30.8% in the femur, 20.3% in the tibia, and 25.7% overall in the total limb (p < or = 0.05). Amifostine administered prior to clinically relevant radiation exposures significantly reduced the amount of anticipated growth arrest in our animal model.

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OBJECTIVE - Angiotensin-converting enzyme inhibitors (ACEIs) have gained importance in preventing or attenuating the process of ventricular remodeling after myocardial infarction. The significance of infarct size in regard to the response to ACEIs, however, is controversial. This study aimed to analyze the effects of lisinopril on mortality rate, cardiac function, degree of cardiac hypertrophy and fibrosis in rats with different infarct sizes. METHODS - Lisinopril (20 mg/kg/day) dissolved in drinking water was administered to rats immediately after coronary artery occlusion. After being sacrificed, the infarcted animals were divided into two groups: one group of animals with small infarcts (< 40% of the left ventricle) and another group of animals with large infarcts (> 40% of the left ventricle). RESULTS - The mortality rate was 31.7% in treated rats and 47% in the untreated rats. There was no statistical difference between the groups with small and large infarcts in regard to myocardial concentration of hydroxyproline. In small infarcts, the treatment attenuated the heart dysfunction characterized by lower levels of blood pressure and lower values of the first derivative of pressure and of the negative derivative of pressure. The degree of hypertrophy was also attenuated in small infarcts. In regard to large infarcts, no differences between the groups were observed. CONCLUSION - Treatment with the ACEIs had no effect on mortality rate and on the amount of fibrosis. The protective effect of lisinopril on heart function and on the degree of hypertrophy could only be detected in small infarcts

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Low-intensity pulsed ultrasound recently has been shown to accelerate long bone fracture healing, but its effect on bone growth and development is unknown. The longitudinal growth and bone density of the femur and tibia in young rats was measured after application of an ultrasound transducer emitting 1.5-MHz pulsed ultrasound (30 mW/cm2, SATA) for 20 min/day. After 28 days, no length difference was detected (< or = 2%) compared to the sham-treated leg or to unexposed controls. Also, no significant difference in bone mineral density (BMD) of the femur or tibia was found (< or = 6%). In a repeated experiment in which a periosteal trauma stimulus was created in the femoral diaphysis, the ultrasound also had no effect on growth or BMD. This results suggests that physeal bone growth is far less sensitive to this level of ultrasound application than is fracture repair. This may be related to the cascade of cellular events and regulatory factors that are present after a fracture.

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This case report describes a technique to close an intermediate aortopulmonary window with the use of the buttoned device in an adult.

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PURPOSE: To analyse the effect of early (< 24h) administration of lisinopril on ventricular remodeling and mortality after myocardial infarction (MI) in rats. METHODS: Wistar rats weighing 200-250 g were submitted to ligation of the left coronary artery (LCA) and divided into three groups: SHAM (S, n = 9); infarcted and lisinopril (20mg/kg/day) treated rats (L, n = 38); infarcted and non-treated animals (NT, n = 24). Three months later, the cardiac function was studied in isolated heart preparation according to the Langendorff technique. Starling curves were constructed using fluid injection in the left ventricular balloon, which permitted to alter the diastolic pressure range from 0 to 30mmHg by means of pressure increments of 5mmHg. Body weight (BW), right ventricular weight (RVW), and RVW/BW were also determined. RESULTS: Three months after the surgery, the comparative mortality rate among groups was: S = 0; L = 34.4% and NT = 54.4% (p > 0.05, for L vs NT). In infarctions < 40% of the left ventricle (LV), the RVW/BW relation was S = L < NT (p < 0.05); the left ventricular systolic pressure was S > L > NT (p < 0.05). In infarctions > 40% of LV, the RVW/BW relation was S < L = NT (p < 0.05). For the Starling curves, the results were S > L > NT (p < 0.05). CONCLUSION: In our model lisinopril did not interfere with post-infarction mortality of rats, although decreasing the mortality risk in 49%, in the treated group. The drug also altered the remodeling process, preventing hypertrophy and systolic disfunction after MI, mainly in infarctions < 40% of LV.

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The natural remodeling and adaptation of skeletal tissues in response to mechanical loading is a classic example of physical regulation in biology. It is largely because it involves forces that do not seem to fit into the familiar schemes of biochemical controls that bone adaptation mechanisms have intrigued us for at least a century. The effect of electromagnetic fields on organisms is another example of this, and the two have become linked in an attempt to explain bone remodeling ("Yasuda's hypothesis"). This paper re-examines the roles of endogenous and exogenous electromagnetic fields in the response of bone to mechanical forces. A series of experiments is reviewed in which mechanical and electrical stimuli were applied to implants in the medullary canal of rabbit long bones. The results suggest that endogenously generated electrical currents are not required to initiate mechanically stimulated bone formation, but that direct mechanical effects on bone cells is the more likely scenario. Based on this and other evidence from the literature, it is suggested that when exogenous electromagnetic stimuli are applied, bone cells respond by modulating the activity of more primary activators such as hormones, growth factors, cytokines, and mechanical forces.

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The factors leading to overgrowth following fixation of long-bone fractures in children have never been clearly understood. The amount of trauma and the type of fixation may play a role. A rabbit model was used to investigate the influence of a femoral osteotomy and plate fixation on subsequent growth. Unilateral midshaft femoral osteotomy was performed in 6-week-old rabbits, and the bone was fixed internally with a plate and screws. End-to-end reduction was performed either at full length or with a segment removed. Bone length measurements at the end of growth revealed no significant difference in growth between the control femur and the femur that had undergone osteotomy and plate fixation. Shortened plated femora also showed no tendency to grow longer or faster than full-length fixed femora or controls. Interestingly, in the ipsilateral tibia a small but statistically significant length increase, equivalent to about 2% increase in additional growth, was observed, whereas technetium-99 methylene diphosphonate uptake was reduced in the tibial physes. In the context of the rabbit experimental model chosen, these results suggest that significant femoral over-growth does not occur following femoral osteotomy and plate fixation.

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