Intestinal damage induced by zinc deficiency is associated with enhanced CuZn superoxide dismutase activity in rats: effect of dexamethasone or thyroxine treatment.

Zinc has a wide spectrum of biological activities and its deficiency has been related to various tissue dysfunctions and alterations of normal cell metabolism. Zinc also plays an important role in the antioxidant cellular defenses being a structural element of the non-mitochondrial form of the enzyme superoxide dismutase (CuZnSOD). We have already reported that Zn deficiency induces severe alterations in the rat intestine, that are reverted by treatment with dexamethasone (Dex) or thyroxine (T4). Here we report a paradoxical increase of CuZnSOD activity in rat intestine after 20 and 40 days of zinc deficiency. The increase of CuZnSOD activity is not due to an upregulation of gene expression because both Northern and Western blot analysis indicate that CuZnSOD mRNA and protein levels are not affected by zinc deficiency. A significant increase of lipid peroxidation was also observed in duodenum and jejunum associated with zinc deficiency. Treatment with either Dex or T4 to zinc-deficient rats protects against intestinal oxidative damage and results in SOD activity similar to control rats. Because glutathione peroxidase and catalase activities decreased in zinc deficiency, we speculate that the increase in SOD activity may be associated with an accumulation of hydrogen peroxide that may activate inflammatory molecules, further worsening tissue damage.

Treatment of rats with dexamethasone or thyroxine reverses zinc deficiency-induced intestinal damage.

Structural and functional damage to the intestine and the potential beneficial effects of dexamethasone (Dex) and thyroxine (T4) were examined in zinc-deficient rats. Rats were assigned to zinc deficient (ZD), control (C) or pair-fed (PF ) groups and fed for 40 d a zinc deficient (1 mg/kg) diet (ZD rats) or a similar diet supplemented with 50 mg Zn/kg (C and PF rats). Some rats of the ZD group were treated for the last 10 d with low (250 mg/kg) or high (5 mg/kg) doses of Dex or with T4 (100 mg/kg). Serum corticosterone of T4-treated ZD rats did not differ from untreated ZD rats. Serum T4 of T4-treated ZD rats did not differ from C rats. ZD rats developed ulcerations, inflammation and edema in the small intestine, particularly in the jejunum. PF rats did not show mucosal changes relative to C rats. ZD rats showed significantly lower crypt cell production rate (CCPR) and labeling index (LI) in the three intestinal regions, and lower cell migration rate and higher turnover time in the duodenum relative to C rats. Sucrase and maltase activities of ZD rats were significantly lower than C rats in the three mucosal regions. Treatment with the low dose of Dex resulted in fewer ulcerations compared with ZD rats. In rats administered the high dose of Dex or T4, all morphological alterations disappeared; the CCPR, LI, cell migration rate, cell turnover time and disaccharidase activities did not differ from C rats. In conclusion, Dex and T4 exert beneficial effects on zinc deficiency-induced intestinal alterations in rats.

[A prospective study on nephrotoxicity induced by continuous infusion of high-dose ifosfamide (15/m2)]. / Studio prospettico della tossicità renale da alte dosi di ifosfamide (15/m2) in infusione continua endovenosa.

BACKGROUND: A good response rate to high-dose ifosfamide (HDIFO) has been reported in metastatic osteosarcoma and soft tissue tumors. As standard dose of IFO (< 12 g/m2) can give several renal complications and patients previously treated with nephrotoxic drugs are at high risk of nephrotoxicity, a prospective study to evaluate the pattern of nephrotoxicity induced by HDIFO was carried out. METHODS: Twelve patients (11 metastatic osteosarcoma, 1 synovial sarcoma; mean age 17, R 14-34) were treated with 4 courses of HDIFO/ MESNA (15 g/m2, IV 5 day continuous infusion with bicarbonate and K supplements). All but two were previously treated with cisplatin and methotrexate. Several parameters of renal function were measured before treatment, after each HDIFO course and two months after chemotherapy completion. RESULTS: Significant changes in the urinary excretion of beta 1-microglobulin, beta 2-microglobulin, Alanine Aminopeptidase, N-Acetil-beta, D-glucosaminidase and a significant reduction in phosphate tubular absorbtion according to the cumulative dose of IFO infused, were observed. Phosphaturia and hypophosphatemia occurred in all the patients studied. In 5 patients, CrCl fell below 70 ml/min with normal serum creatinine level after 45 g/m2 IFO. Plasma bicarbonate concentration less than 20 mmol/l was observed in 5 of 48 HDIFO courses. Glycosuria was detected in 4 patients. Two months after chemotherapy completion, mild glycosuria and slightly reduced CrCl persisted in two patients, whereas the other parameters of renal function studied were similar to the baseline values. An acute, usually reversible subclinical nephrotoxicity involving glomerule and renal tubule was demonstrated in all the patients treated with HDIFO. A persisting subclinical renal impairment was shown with mild glycosuria (2/12 patients) and slightly reduced CrCl (2/12 patients).

The role of corrected QT interval in the cardiologic follow-up of young patients treated with Adriamycin.

UNLABELLED: The behavior over time of the corrected QT interval (QTc) in patients treated with Adriamycin (ADM) was evaluated in order to detect any possible correlations between the modifications of the QTc duration and the cardiac function of patients treated with different cumulative doses of ADM (360, 390, 480 mg/m2). PATIENTS AND METHODS: Electrocardiograms (ECGs) performed 2 months (178 patients), 1 year (65) and 3 years (43) after the completion of chemotherapy, were examined. RESULTS: after 2 months a prolonged QTc interval (> or = 0.45 sec) was found in 50% of patients, after 1 year in 26% and after 3 years in 14%. The patients treated with the highest dose of the drug (480 mg/m2) showed the highest incidence of prolonged QTc intervals. No patients treated with 360 mg/m2 ADM showed prolonged QTc intervals after 3 years. No correlations between prolonged QTc and functional echocardiographic alterations were noticed. The QTc interval prolongation, easily observable after treatment with ADM, seems to be related to the quantity of the drug administered and is generally a reversible phenomenon. Nevertheless a prolonged QTc can persist after 3 years. The persistence of prolonged QTc intervals is not associated with a higher incidence of functional cardiac deficits which are echocardiographically detectable.

Proximal deep vein thrombosis: the use of the echoDoppler for diagnosis and therapeutic indications.

Our objective was to assess the impact of echo-Doppler technique on the diagnosis of Deep Vein Thrombosis (DVT) in major orthopedic surgery (80% of DVT diagnosed are asymptomatic). We therefore analyzed 200 consecutive pts submitted to elective surgery for total hip replacement. The postoperative echo-Doppler study indicated DVT in 13 pts: these pts underwent a postoperative lower limb phlebography. Echo-Doppler and phlebography had concordant results in 11 of 13 echo assessed proximal DVT. These observations suggest that Duplex scanning is a good method to diagnose and to guide therapy for proximal DVT in orthopaedic clinic.

High-dose methotrexate treatment and liver function in patients with osteosarcoma.

OBJECTIVES: To study the effects of short-term high-dose methotrexate therapy on liver function in patients with osteosarcoma. DESIGN: Open prospective study. SETTING: Department of Internal Medicine and Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy. SUBJECTS: Fourteen patients with osteosarcoma, with no evidence of previous or actual liver disease at the time of diagnosis. INTERVENTIONS: All patients received a cumulative dose of 30-57 gm-2 of methotrexate within 6 months as neo-adjuvant chemotherapy (pre- and post-surgery). Each course of chemotherapy included methotrexate at a dose of 8-12 gm-2 and, in addition, adriamycin and cisplatinum. MAIN OUTCOME MEASURES: Galactose elimination capacity and antipyrine clearance were measured at baseline, after the first course of chemotherapy, at the end of the pre-operative period and at the end of chemotherapy. In each case they were carried out after transaminase levels had returned to normal. RESULTS: Galactose elimination capacity decreased from 2.45 (+/- 0.48) mM min-1 to 2.04 (+/- 0.60) mM min-1 after the five planned courses of chemotherapy (P = 0.013, Wilcoxon signed-rank test), without any change in routine liver function tests. No differences in antipyrine clearance and half-life were demonstrated (n = 8). CONCLUSIONS: The data are consistent with a decreased reserve capacity of the liver after short-term, high-dose methotrexate. Long-term survivors deserve monitoring of liver function for safer methotrexate use, in the light of progressive dosage increments to improve prognosis in neoplastic diseases.

Electromagnetic fields in the treatment of postmenopausal osteoporosis: an experimental study conducted by densitometric, dry ash weight and metabolic analysis of bone tissue.

The authors conducted an experimental study on 32 female rats which had been castrated at 10 months of age in order to verify the ability of pulsating electromagnetic fields to prevent osteoporosis induced by surgical menopause. Two different values of intensity of PEMFs were used: 30 G and 70 G. After 4 months of treatment the following testing was done: monophotonic bone densitometry of the lumbar spine, quantitative measurement of the dry ash weight of the femurs, and hematochemical tests to evaluate bone metabolism. The experimental study showed that the PEMFs supplied at 30 Gauss were capable of slowing down the loss of bone mass, while the PEMFs supplied at 70 Gauss obstructed bone decay, providing values for Bone Mineral Density and dry ash weight which were very similar to those observed in the non-castrated control group. Hematochemical tests did not reveal significant variations between the two groups.

[The oral strontium load test in the assessment of intestinal calcium absorption]. / Il test da carico orale di stronzio nella valutazione dell'assorbimento intestinale del calcio.

A close correlation between calcium and strontium intestinal absorption has been described. In this study, a test using Stable Strontium has been assessed in women without abnormal calcium or bone metabolism, with no history of drugs which might affect calcium or bone metabolism. Decreasing values of Strontium intestinal absorption, according to the length of the postmenopausal period, have been observed. Besides, the Stable Strontium Test has been given in postmenopausal women with osteoporotic femur fractures. In comparison with age matched healthy women, this latter group showed a significantly lower Strontium intestinal absorption. Analogous behaviour has been reported for Calcium intestinal absorption.

[Prevention of post-ovariectomy osteoporosis in the rat. Comparative study of synthetic salmon calcitonin and eel calcitonin aminosuberic analogue]. / Prevenzione della osteoporosi post-ovariectomia nel ratto. Studio comparativo fra calcitonina sintetíca di salmone e derivato aminosuberico della calcitonina di anguilla.

The authors evaluate the efficacy of salmon calcitonin and aminosuberic analogue of eel calcitonin in the prevention of post-oophorectomy osteoporosis in rats. Both drugs, administered at the same dosage, are equally effective in preventing oophorectomy bone loss in rats. Besides, plasma biochemical evaluations demonstrate that calcitonins reduce bone turnover in treated rats, compared with control oophorectomized ones.

Evaluation of an experimental model of osteoporosis induced in the female rat through ovariectomy.

The present paper intends to check the possibility of improving convenience of the osteoporosis model from ovariectomy in the rat by anticipating the operation to the 40th week rather than the 52nd week of age, thought by some authors to be the optimum model. To this end two parameters have been examined: 1. the bone mass variation determined with the vertebral photon densitometer and weighing of the femur ashes; 2. the chemico-crystallographic characteristics of the bone determined through chemical analysis and X-ray diffractometry. The results obtained induce us to believe that ovariectomy carried out on rats of 40 or 52 weeks of age determine bone mass losses that are statistically comparable. The variations in the dry bone weight/ash bone weight ratio are superposable and the structural chemical characteristics, due to the increase in bone turnover are testified by the increase in osteocalcin. Moreover, it was observed that the most reliable evaluation of bone mass loss can be obtained with the vertebral photon densitometry. Thus, it is thought that the model which foresees ovariectomy of rats 40 weeks after birth compared with those operated 52 weeks after birth, represents a good model of osteoporosis from estrogen deficiency which, due to the evident practical advantages deriving from the use of younger animals it associates a decrease in the use of laboratory animals with statistically reliable results.

[Effect of high and low doses of methotrexate (MTX) on bone mass in subjects treated for osteosarcoma of the limbs]. / Effetti del methotrexate (MTX) ad alte e a basse dosi sulla massa ossea in soggetti trattati per osteosarcoma delle estremità.

Twenty-three patients with highly malignant localized osteosarcoma receiving neoadjuvant chemotherapy with MTX randomly administered at high (7500 mg/m2) and low (750 mg/m2) doses underwent serial densitometric controls at the start of treatment and after 18 and 36 months. Increasing BMC levels at both examination points were observed in all subjects examined over time, but, contrary to findings in the control group, this increase was not statistically significant using the paired T test. Significantly lower BMC levels in relation to the control group were only found in the group treated with high doses of MTX at MDP but not PM. Reduced density at MDP alone, a site in which trabecular bone is prevalent, shows that MTX predominantly acts at the level of the latter in line with its greater sensitivity to the action of osteopenic agents.

[Ultrasound in the diagnosis of fragilitas ossium]. / Gli ultrasuoni nella diagnosi della fragilità ossea.

Recently, a proposal has been made to evaluate bone fragility in osteoporotic women by measuring ultrasound transmission velocity at the patella. Theoretically, sound transmission velocity depends on both bone mass and other factors which are not mass-dependent--e.g. bone architecture. Ultrasound transmission technique was thus tested for the capability of evaluating bone fragility factors, which are not mass-dependent, in the screening of osteoporotic women. To this purpose, the sound velocity at the patella of 31 healthy women was compared with that of 62 osteoporotic women with spontaneous vertebral fractures having similar bone mineral content. In 31 cases bone mineral content was similar to that of healthy women at the middle radius, and in 31 at the distal radius. Sound transmission velocity was significantly lower in osteoporotic than in healthy women. Fifty-two per cent of healthy women was correctly selected by US, relative to the risk threshold, versus 13% with bone mineral densitometry. This finding suggests that US is capable of distinguishing normal from osteoporotic women having similar bone mineral content, which means that non-mass-dependent factors may affect US velocity in the bone. Since the measurement were taken in various sites, different for US and bone densitometry, our results need confirmation in further studies where measurements are taken in the same sites.

The importance of urinary hydroxyproline and serumal osteocalcin in the evaluation of post-menopausal osteoporosis.

Forty-nine women aged 49 to 65 who had been in menopause for more than fifteen years were selected on the basis of densitometric data and clinical symptomatology. Twenty-four of these suffered from severe backaches and had a bone mineral content (B.M.C.) level inferior by at least three standard deviations to the average level according to the standards of our laboratory; these women were diagnosed with severe osteoporosis. The remaining twenty-five subjects were asymptomatic with a B.M.C. between one and two SD from the average; these were diagnosed with moderate asymptomatic osteopenia. A control group was formed by ten apparently healthy women of childbearing age. The women with severe osteoporosis showed a significantly lower level of serumal osteocalcin (Student t Test: P less than 0.05) than the control group, while no significant difference was observed between the latter and the women with moderate asymptomatic osteopenia. The level of hydroxyproline was significantly higher (Student t Test: P less than 0.01) in both groups of menopausal women than in the control group. This data shows that the increase in the level of urinary hydroxyproline characterizes menopause independent of the severity of bone loss. On the other hand, low levels of osteocalcin mainly appear in menopausal women who show severe skeletal demineralization. As a result, we feel that the urinary hydroxyproline/osteocalcin ratio is shown to be useful in both evaluating the risk of post-menopausal osteoporosis and monitoring it.

Evaluation of the relative rates of bone mineral content loss in postmenopause due to both estrogen deficiency and ageing.

To evaluate the relative rates of bone mineral content loss in postmenopause due to both estrogen deficiency and ageing, three groups of women were studied by computerized bone densitometry at the radius mid-point and at the distal point, modified according to the Abwrey technique. All women were in apparent good health and never had estrogen therapy. In the first group there were 64 women aged between 30 and 50 who were ovariectomized between 25 and 35 years of age. The second group was made up of 309 women between 50 and 55 years. In the third group there were 136 women aged 30-50 with normal ovaric function. The ordinary functions of linear polynomial regression were used to describe the variations in density with age. The percentage of postmenopausal bone loss was determined by calculating the BMC value at the start of the menopause and again twenty years later, according to the linear regression equation of postmenopausal period of each group of women in the study. The women who had natural menopause showed an average bone loss per year of 1.63% at the mid radius and 1.0% at the distal point. The ovariectomized women had an average loss of 0.85% at the mid point and 0.66% at the distal point. No significant decrease of bone mass was found before menopause. From a comparison between the two groups of women with analogous periods of menopause, it comes out that, during the first 20 years of natural menopause, estrogen deficiency is responsible for 52.5%-66.4% of the bone mineral loss, the remaining amount being attributable to other causes, connected with ageing. Estrogen deficiency is therefore, the principal factor causing bone mineral loss in natural menopause.

Contribution to the diagnostic study of pulmonary embolism occurring as a complication of operations for the insertion of hip prostheses.

The authors report the clinical, electrocardiographic and radiological aspects of pulmonary embolism as a post-operative complication which occurred in 46 patients after total hip replacement. They discuss the relative value of their findings in relation to arriving at a correct diagnosis, which they believe should be possible without recourse to more complicated procedures such as the use of contrast media radiography.

Thromboembolism in total hip replacement.

The efficacy of low dosage heparin in the prevention of pulmonary embolism has been assessed in a group of 177 "high risk" patients undergoing hip replacement operations compared with a control group of 236 "high risk" patients not so treated. The diagnosis of pulmonary embolism was made on the basis of the commonly accepted clinical signs and symptoms, confirmed by electrocardiography, chest radiography, serum enzymes, and blood gas analysis. Pulmonary embolism occurred in 9.74% of the patients in the control group and in 1.69% of those treated with heparin. These figures indicate that heparin is effective in preventing pulmonary embolism.

Full-lung tomograms and bone scanning in the initial work-up of patients with osteogenic sarcoma. A review of 126 cases.

The value of full-lung tomograms and of bone scanning in the initial work-up of patients with osteogenic sarcoma is evaluated in 126 consecutive cases observed at the Bone Tumor Center of the Istituto Ortopedico Rizzoli from July 1976 to December 1980. Full-lung tomograms and bone scanning showed unsuspected metastases in 3 patients and 2 patients respectively. False abnormal results were observed in 4 cases by tomography and in 3 cases by bone scan. The authors conclude that in osteosarcoma, the yields of full-lung tomography and of bone scanning are small in detecting unsuspected lung and bone metastases at the time of presentation. It therefore appears improbable that the improvements recently observed in this tumor with adjuvant chemotherapy are the result of unintentional case selection bias due to these examinations not having been performed in the historical group.

Thrombo-embolism as a complication of prosthetic replacement operations of the hip: prophylaxis with heparin at low doses.

A trial conducted in 183 high-risk patients who had had joint prosthesis operations showed that prophylaxis with Heparin reduces the frequency of pulmonary embolic complications and thrombophlebitis.