Osteoporosis: current diagnosis and treatment.
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Biomedical subjects
Publications and source records attributed to J M Lane.
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Rat liver microsomal membranes contain a reduced-glutathione-dependent protein(s) that inhibits lipid peroxidation in the ascorbate/iron microsomal lipid peroxidation system. It appears to exert its protective effect by scavenging free radicals. The present work was carried out to assess the effect of this reduced-glutathione-dependent mechanism on carbon tetrachloride-induced microsomal injury and on carbon tetrachloride metabolism because they are known to involve free radicals. Rat liver microsomes were incubated at 37 degrees C with NADPH, EDTA and carbon tetrachloride. The addition of 1 mM-reduced glutathione (GSH) markedly inhibited lipid peroxidation and glucose 6-phosphatase inactivation and, to a lesser extent, inhibited cytochrome P-450 destruction. GSH also inhibited covalent binding of [14C]carbon tetrachloride-derived 14C to microsomal protein. These results indicate that a GSH-dependent mechanism functions to protect the microsomal membrane against free-radical injury in the carbon tetrachloride system as well as in the iron-based systems. Under anaerobic conditions, GSH had no effect on chloroform formation, carbon tetrachloride-induced destruction of cytochrome P-450 or covalent binding of [14C]carbon tetrachloride-derived 14C to microsomal protein. Thus, the GSH protective mechanism appears to be O2-dependent. This suggests that it may be specific for O2-based free radicals. This O2-dependent GSH protective mechanism may partly underlie the observed protection of hyperbaric O2 against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity.
Since October 1973, 185 patients 21 years of age or younger with primary osteogenic sarcoma of an extremity were treated with adjuvant chemotherapy. Twenty-five of the first fifty-two patients (48%) have remained free of disease for a median of 7 years. In the next chemotherapy protocol most patients had chemotherapy prior to amputation or resection, during which time the dose of high-dose methotrexate was escalated in many patients to that needed to shrink the primary tumor. For a median of 4 years 43 of 54 patients (80%) have remained free of disease. In the current protocol, the response of the primary tumor to chemotherapy with high-dose methotrexate was used to select postoperative adjuvant chemotherapy for the patient. With the latter approach 73 of 79 patients (92%) have remained continuously free of disease for a median of 2 years. This experience demonstrates the value of chemotherapy in increasing the cure rate in osteogenic sarcoma and that the response to preoperative chemotherapy can help select postoperative chemotherapy to produce an even higher potential cure rate for osteogenic sarcoma.
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Three patients with posterior paravertebral tumors are presented to illustrate the value of preoperative chemotherapy prior to surgical resection. All three had massive tumors adjacent to the spine, extending over several vertebral segments, with myelographic evidence of epidural involvement in one patient. Tissue diagnosis by incisional biopsy confirmed the diagnosis of extraosseous osteogenic sarcoma in one, extraosseous Ewing's sarcoma in the second, and embryonal rhabdomyosarcoma in the third. All patients were treated with chemotherapy preoperatively. Marked regression in tumor size was noted, and surgical excision of the tumor along with involved segments of spine was easily accomplished. Histological examination following surgery revealed completely necrotic tumor in two patients. Preoperative chemotherapy for fully malignant tumors offers the following advantages: 1) extremely bulky and otherwise unresectable tumors can be reduced in size to enable complete surgical resection; 2) systemic chemotherapy is instituted earlier in the course of disease to prevent more effectively the appearance of metastases; and 3) the information gained regarding the sensitivity of the tumor to a particular chemotherapy regimen allows postoperative adjuvant chemotherapy to be used on a more rational basis.
Intravenous fluorescein dye was applied as a test of skin viability in 11 en bloc resections for osteogenic sarcoma about the knee. Intravenous fluorescein dye is an easy, safe, efficient, and inexpensive method that helps to predict the viability of surgically created skin flaps. When patchy fluorescence is observed, primary debridement is recommended to prevent immediately postoperative skin necrosis. This test proved to be an accurate, significant indicator of nonviable skin, in both location and dimension. All flaps that were patchy by the fluorescein test consisted of nonviable skin. Conversely, flaps that took up the dye evenly went on to uneventful wound healing. The fluorescein test should be considered for further application in orthopedic surgical procedures when skin viability is uncertain, e.g., in cases of trauma and complicated reconstructions about the knee and elbow.
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Pentane, a volatile hydrocarbon, is cleared from inspired air by the rat. We have studied this clearance to learn whether or not it is a function of the liver. Rats were put individually into airtight chambers which contained CO2 absorbent and were connected to an O2 reservoir. Pentane was injected into each chamber and chamber atmosphere was assayed frequently for pentane over 6 h by gas chromatography. Semilog plots of pentane concentration had a rapid distribution phase and a log-linear terminal elimination phase. A chamber clearance value in milliliters at atmosphere cleared per minute per kilogram rat weight was calculated. Nephrectomy had no effect on pentane clearance. Liver injury by thioacetamide (5 mmol/kg) or by CCl4 (75 or 125 microliters/100 g) was associated with a marked decrease in pentane clearance, indicating a major role for the liver in pentane elimination. Treatment of rats with inducers or inhibitors of the hepatic microsomal cytochrome P450 system did not affect their ability to clear pentane. However, administration of ethanol or 4-methyl-pyrazole diminished pentane clearance, suggesting that alcohol dehydrogenase may be involved in pentane metabolism. These findings demonstrate that pentane clearance is a liver function.
In a study of eighteen patients with pelvic Ewing's sarcoma who were treated with a multidisciplinary approach, chemotherapy was effective in controlling systemic spread of the tumor. Surgery coupled with improved methods of chemotherapy provided results that were statistically superior to those obtained with radiation and chemotherapy alone in control of the local pelvic lesion. A twofold increase in the survival rate was seen at a median follow-up of thirty-six months in the patients who had the resection. Our results suggest that pelvic Ewing's sarcoma is best treated by initial chemotherapy, followed by local wide marginal resection of the pelvic lesion coupled with perimeter radiation therapy and concluded with additional chemotherapy. Survival rates of patients with pelvic Ewing's sarcoma may then approach the excellent survival rates of patients with lesions in more favorable anatomical locations.
The presence of hydroxyapatite has been determined based on ultrastructure, X-ray diffraction, electron diffraction, and chemical analysis, and confirmed by microprobe analysis in multiple deposits surgically excised from four unrelated patients with tumoral calcinosis. The chemical composition of each of the mineralized deposits resembled bone, rather than dermis, in mineral, uronic acid, total lipid, and complexed acidic phospholipid composition. No collagen abnormalities were detected. However, all of these deposits differed from normal bone mineral, being heavily mineralized and containing larger, more perfect hydroxyapatite crystals. Ultrastructurally, the crystals were both extracellular and within mononuclear cells in close proximity to dilated rough endoplasmic reticulum.
The global eradication of measles is desirable because the disease occurs almost universally, affects large numbers of children, can cause serious complications, and is responsible for about 900 000 deaths a year in developing countries. The feasibility of a measles eradication programme is suggested by the success of smallpox eradication, the availability of a heat-stable, cheap, and effective vaccine, and the fact that interruption of measles transmission has been achieved in some places. Eradication of measles globally would also result in the saving of the large sums of money being spent on measles treatment, vaccination, and surveillance.
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Since June 1978, 57 patients with primary osteogenic sarcoma of an extremity were treated with high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR), Adriamycin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) given for 4-16 weeks prior to definitive surgery. Histologic examination of the resected primary tumor determined the effect of preoperative chemotherapy with many primary tumors showing greater than 90% tumor necrosis attributable to preoperative chemotherapy. All patients having this favorable effect of chemotherapy on the primary tumor were continued on the same chemotherapy regimen postoperatively (regimen B). However, in those patients not having a good effect of preoperative chemotherapy on the primary tumor, HDMTX with CFR was subsequently deleted from their postoperative chemotherapy and they were placed on a regimen containing cisplatinum at the dose of 120mg/M2 with mannitol diuresis combined with Adriamycin in addition to BCD (regimen A). In the current study, 35 of the 57 patients did not demonstrate a good effect of chemotherapy on the primary tumor and were assigned to regimen A postoperatively. Of these 35 patients, 32 (91%) have remained continuously free of recurrent or metastatic disease from 6-34 months following the start of therapy. Among the 22 remaining patients having a good histologic response and treated with regimen B postoperatively, there has been only one relapse in a patient who had a local recurrence in the area of an inadequately resected primary tumor three months after the cessation of chemotherapy. Thus, 53 of 57 patients (93%) are continuously with no evidence of recurrent or metastatic disease from 6-35 months (median, 20 months) from the start of treatment. This study demonstrates the value of thorough histologic examination in predicting survival in responding patients and in helping identify patients whose disease-free survival rate can be substantially increased if they are given alternative postoperative adjuvant chemotherapy after failing to have a good response to preoperative chemotherapy. This individualized chemotherapeutic strategy has yielded the highest disease-free survival rate reported to date for osteogenic sarcoma.
Fracture healing in both non-immobilized and immobilized rat fracture callus, though different radiographically and histologically; is characterized by similar biochemical changes in the ground substance. Although the callus formed in the immobilized model is appreciably smaller than that formed when the fracture is not immobilized, the chemical composition of the organic matrix of the existing callus undergoes similar modifications regardless of fixation and histological response. Previous studies of endochondral fracture repair have demonstrated an elevation in fracture callus hexosamine content during the early stages of healing of the non-immobilized fracture. This corresponded histologically to a predominance of cartilaginous tissue in the callus matrix. In the present study, the biochemistry, histology, and roentgenographic features of stabilized and non-stabilized rat fractures are compared. Similar elevations in hexosamine are noted at two weeks in both models. These elevations are attributed to changes in proteoglycan rather than glycoprotein concentration of the tissue.
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A method is presented to obtain an autologous iliac bone graft which is technically simple, provides adequate bone quantity, and affords minimal morbidity to the graft source.
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