The biology,pathology and immunology of a virus induced rat osteosarcoma

Summary The immunogenicity of a virus-induced rat osteosarcoma was studied utilizing the lymphocyte microcytoxicity test. Lymphocytes from progressor animals (in which the tumour progressed and metastasized) demonstrated an ability to kill osteosarcoma cells in vitro, while serum from these animals abrogated or blocked the cell-mediated cytotoxicity.Lymphocytes from regressor animals (in which tumours failed to develop or regressed spontaneously) also showed cytolytic activity against osteosarcoma cells in vitro, but their serum failed to block the lymphocyte-mediated cytolysis. Both progressor and regressor animals demonstrated the presence of humoral cytotoxic antibodies to tumour antigens on the basis of the ability of their serum to kill tumour cells in vitro. In an attempt to alter the fatal course of the disease in progressor animals, immunoprophylaxis and immunotherapy of the osteosarcoma in F1 hybrid rats war carried out by injecting them with parentalor, third party, allogeneic lymphoid cells. Injection of parental spleen lymphocytes into F1 hybrids produced a transient graft versus host reaction (GVHR), and prolonged the survival of the animals when lymphocytes were injected three days before, seven days after and on the day of tumour induction. Injection of allogeneic, third party lymphoid cells produced no detectable GVHR and prolonged the survival of F1 hybrids with osteosarcoma only when injected on the day of tumour induction. The prolonged survival of the groups treated with parental lymphoid cells was a result of stimulation of the host's immunological mechanisms during a transient GVHR, whereas the prolongation of survival in the group given allogeneic cells was most likely the result of a direct action of the donor lymphocytes on tumour cells, and not connected to a GVHR.SICOT Fellowship Award Paper, presented at the XIV-th World Congress of SICOT, Kyoto, Japan, October 15–20, 1978     

Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats.

PURPOSE: Exemestane (EXE) and letrozole (LET) are third-generation aromatase inhibitors currently prescribed for postmenopausal hormone-dependent breast cancer. The impact on end organs of estrogen depletion in menopausal women is of significant clinical importance. We studied the effects of EXE, its principal metabolite, 17-hydroexemestane (17-H-EXE), and LET on bone and lipid metabolism in ovariectomized (OVX) rats. EXPERIMENTAL DESIGN: OVX rats were treated by weekly intramuscular injection for 16 weeks with 20, 50, and 100 mg/kg EXE, 20 mg/kg 17-H-EXE, and daily oral gavage of 1 mg/kg LET. At the end of the treatment period, bone mineral density (BMD), the bone resorption marker serum pyridinoline, the bone formation marker serum osteocalcin, bone mechanical properties, histomorphometry, and serum lipid concentrations were determined. RESULTS: Lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume were significantly higher in OVX animals given EXE and 17-H-EXE than in OVX controls. EXE and 17-H-EXE significantly reduced an ovariectomy-induced increase in serum pyridinoline and serum osteocalcin. EXE and 17-H-EXE given to OVX rats caused significant reductions of serum cholesterol and low-density lipoprotein cholesterol. In contrast, OVX rats treated with LET had BMD, bone biomarkers, mechanical failure properties, and lipid levels similar to those of OVX controls. CONCLUSIONS: EXE and 17-H-EXE significantly prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol and low-density lipoprotein levels in OVX rats. These protective effects on end-organ function are not seen with the nonsteroidal inhibitor LET.     

Chordoma arising in a mature cystic teratoma of the ovary: a case report

Mature cystic teratoma of the ovary (MCTO) is the most common type of ovarian teratoma and also the most frequent tumor originating from germ cells. It is usually diagnosed in early adulthood and, by definition, is composed of well-differentiated tissues, which originate from all three germ cell layers. Unusual types of tissues can be found in MCTO, such as kidney, adrenal, and prostatic tissues. Malignant transformation is reported in less than 2% of teratomas. Squamous cell carcinoma is the most common malignancy arising in these otherwise benign tumors. We present the first case of MCTO containing a chordoma. The chordoma differentiation was supported by immunohistochemical staining and interphase fluorescence in situ hybridization (IP-FISH) technique showing 19% of the nuclei of the MCTO displaying polysomy for the chromosome X, while 28% of the chordoma nuclei showed chromosome 7 mosaicism. These results are concordant with previous studies, showing chromosomal anomalies in chromosomes X and 7 in MCTO and chordomas, respectively.     

Assessing depressive symptoms in persons who die of suicide in mainland China

BACKGROUND: The potential insensitivity to depression of translated diagnostic instruments makes it difficult to assess the relationship of depressive symptoms to suicide in non-Western cultures. METHODS: Addition of culturally sensitive probes and other modifications were made to the depression section of the Chinese version of the SCID; the standard SCID probes and the expanded-probes are separately used to assess each symptom of depression, the resultant diagnoses and the overall severity of depression. This modified SCID was included in the psychological autopsy interviews with family members and, separately, close associates of 887 suicides and 721 non-suicidal decedents from 23 regions of mainland China. RESULTS: Compared to the standard interview, the expanded-probe method increased reported prevalence of major depressive episode among suicide decedents from 26.4% (234/887) to 40.2% (357/887) and for other deaths from 1.0% (7/721) to 2.1% (15/701). The additional 131 cases identified using the expanded-probe method had substantial social impairment and a greatly elevated risk of suicide compared to those with no depressive symptoms (OR=37.0, 95% CI=17.6-77.6). Inter-observer reliability for major depressive episode between the two independent interviews was greater for the expanded probe method (ICC=0.77 vs. 0.67, P<0.001). For both interview methods there was a strong dose-response relationship between suicide risk and the number and severity of depressive symptoms. LIMITATIONS: This study uses proxy informants to obtain information about the psychological status of deceased subjects; the value of this expanded-probe method for the diagnosis of depression in non-Western cultures needs to be confirmed with living subjects. CONCLUSIONS: Adding culture-appropriate probes about depressive symptoms to standardized diagnostic instruments identifies many Chinese subjects with unrecognized depression. Dimensional measures of depressive symptoms are more powerful predictors of suicide risk than categorical diagnoses.     

A cartilage derived novel compound DDP (2,6-dimethyldifuro-8-pyrone): isolation, purification, and identification

OBJECTIVE: Fluorescent biomolecules within cartilage matrix can be used as specific markers of cartilage metabolism. While establishing the protocol to evaluate mature collagen crosslinks in articular cartilage (AC) associated with maturation, aging, and osteoarthritis, chromatographic analysis of the crosslinks also revealed an apparently novel fluorescent peak. Preliminary investigation of this compound (now abbreviated DDP) in various tissues from rabbits, calves, chickens, and humans showed that this compound is AC-specific. We aimed to isolate, purify, and identify this fluorescent compound. METHODS: Fully encapsulated, bovine metacarpophalangeal joints (n = 350, age < 2 years) were used as the source for AC. DDP was isolated and purified by reverse phase high pressure liquid chromatography, and its elution was monitored using a fluorescence detector at excitation lambda = 306 nm, and emission lambda = 395 nm. The liquid phase of DDP was characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. DDP solution (5.7 microg/microl) was crystallized in 100% deuterated methanol and the DDP crystal was characterized by single crystal x-ray diffraction. RESULTS: From bulk preparations, 12 pg (58 nmol) per gram dried AC of the novel compound was isolated and purified. Analytical techniques to identify this AC-specific compound, 2,6-dimethyldifuro-8-pyrone, corroborate and confirm its molecular structure and atomic connectivity in both liquid and solid phase. DDP is a symmetrical aromatic compound with molecular weight 204, molecular forrmula C11H8O4, and a molar extinction coefficient 4,700 M(-1) at maximal UV absorption (lambda = 306 nm). CONCLUSION: 2,6-dimethyldifuro-8-pyrone (DDP) is a novel cartilage-specific compound that could have potential application as a unique biochemical marker in joint diseases involving articular cartilage degradation.     

Histopathology of failed osteoarticular shell allografts

Fresh cadaveric osteochondral fragment allografts were used to replace damaged articular surfaces of knee joints. Of the original 100 patients, 22 experienced graft failure necessitating graft removal. From these patients, a total of 44 osteochondral allografts were extirpated between 12 and 84 months after insertion. These were examined radiologically, histologically, and ultrastructurally. The bone and bone marrow were necrotic and had undergone variable replacement by host bone, which appeared to be independent of the duration of the graft. The articular cartilage showed degenerative changes ranging from fibrillation to erosion. Viable donor cartilage was present as late as seven years, proving that fresh graft cartilage can survive transplantation. Host bone interfaced with the cartilage, but in 14 grafts there was focal invasion of the cartilage. In some grafts, pannus formation with resorption of cartilage was evident. There was no histologic evidence of transplant rejection. This study is encouraging because hyaline cartilage has been shown to survive for as long as seven years and because bone can be replaced in a homogeneous fashion if the correct biomechanical conditions are met.     

Increased cytokine secretion in patients with failed implants compared with patients with primary implants

All total joint replacements generate wear debris; yet, some implant prostheses fail while others survive despite the presence of ultrahigh molecular weight polyethylene particulate. It was hypothesized that patients with failed hip implants who have osteolysis will secrete higher inflammatory cytokines than patients receiving total joint replacements. Our study evaluated the peripheral blood monocyte response to varying polyethylene particle volume ratios through cytokine quantification in two patient populations: patients having revision surgery for failed total hip replacements (failed implant group) and patients having primary total hip surgery for osteoarthritis of the hip (primary implant group). We observed elevation of all three proinflammatory cytokines tested (interleukin-6, interleukin-1, and tumor necrosis factor-alpha) in response to polyethylene particulate challenge when compared with the controls in both patient groups. The population with failed implants also had a higher absolute cytokine response to polyethylene exposure compared with the control patients having primary implants. These findings suggest that patients with failed implants have a greater inflammatory cytokine response to polyethylene than seen in patients with primary implants.