Long-term results of conventional varus half-wedge proximal femoral osteotomy for the treatment of osteonecrosis of the femoral head.

We have previously described the mid- to long-term results of conventional simple varus intertrochanteric osteotomy for osteonecrosis of the femoral head, showing that 19 of the 26 hips had good or excellent results. We extended the follow-up to a mean of 18.1 years (10.5 to 26) including a total of 34 hips in 28 patients, with a mean age at surgery of 33 years (19 to 53). There were 18 men and ten women and 25 hips (74%) had a satisfactory result with a Harris hip score ≥ 80. In all, six hips needed total hip replacement (THR) or hemiarthroplasty. The collapse of the femoral head or narrowing of the joint space was found to have progressed in nine hips (26%). Leg shortening after osteotomy was a mean of 19 mm (8 to 36). With conversion to THR or hemiarthroplasty as the endpoint, the ten-year survival rate was 88.2% (95% confidence interval (CI) 82.7 to 93.7) and the 20-year survival rate was 79.7% (95% CI 72.1 to 87.3); four hips were converted at ten years and other two hips were converted at 20 years. Shortening of the leg after osteotomy remains a concern; however, the conventional varus half-wedge osteotomy provides favourable long-term results in hips with less than two-thirds of the medial part of the femoral head affected by necrotic bone and with normal bone superolaterally.

The Chiari pelvic osteotomy for patients with dysplastic hips and poor joint congruency: long-term follow-up.

We report the mid- to long-term (mean 20.3 years, 10 to 32.5) results of the Chiari pelvic osteotomy in patients with pre- to advanced stage osteoarthritis in dysplastic hips. We followed 163 Japanese patients (173 hips) with a mean age at surgery of 20 years (9 to 54). Overall, 124 hips (72%) had satisfactory results, with Harris hip scores ≥ 80. Satisfactory results were seen in 105 of 134 hips with pre- or early osteoarthritis (78%) and 19 of 39 hips with advanced osteoarthritis (49%). A total of 15 hips (9%) underwent a total hip replacement (THR) with a mean interval between osteotomy and THR of 16.4 years. With conversion to THR as the endpoint, the 30-year survival rate was 85.9% (95% confidence interval 82.3 to 89.5). It was 91.8% for patients with pre- or early osteoarthritis and 43.6% for those with advanced osteoarthritis (p < 0.001). We now perform the Chiari osteotomy for patients with dysplastic hips showing poor joint congruency and who prefer a joint-conserving procedure to THR.

Health-related quality of life in patients with systemic lupus erythematosus after medium to long-term follow-up of hip arthroplasty.

Health-related quality of life (HRQOL) of systemic lupus erythematosus (SLE) patients with hip arthroplasty after medium to long-term follow-up has not been reported. We conducted a retrospective study for SLE patients with osteonecrosis of the femoral head (ONF). Forty-seven consecutive arthroplasties were performed in 36 patients. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Medical Outcome Survey Short Form 36 (SF-36) and Harris hip score were evaluated. Two patients died before the four-year follow-up and two patients were lost to follow-up. The remaining 43 hips in 32 patients with an average age at surgery of 35 years and an average follow-up of 12.0 years (range 4.0-25.0) were assessed. Bipolar hemiarthroplasty was performed for 18 hips in 12 patients, and total hip arthroplasty (THA) was performed for 25 hips in 20 patients. The mean WOMAC scores for pain and function at the recent followup were 90.8 +/- 8.5points and 79.0 +/- 18.3 points. Patients with THA had significantly high scores in SF-36 physical functioning (P < 0.05) and bodily pain (P < 0.03) compared to those with bipolar hemiarthroplasty. Although improvement could not reach the level of general population, the hip arthroplasty contributed to support HRQOL of SLE patients.

Three-dimensional computer-aided design based design sensitivity analysis and shape optimization of the stem using adaptive p-method.

The number of stem designs for total hip arthroplasty is increasing, and occasionally design changes have yielded unexpected clinical results. At present, we are not able to clearly identify which parameter of the stem is most important, and the optimum value of many parameters. The goals of this study were to identify which parameter is most important, to understand the effect of design change, and to find the optimum stem shape. For this purpose, we used adaptive p-method together with three-dimensional computer-aided design software program for the design sensitivity analysis (DSA) and shape optimization of the stem. The results suggested that increasing the lateral and medial width of the distal cross-section together with decreasing the medial-lateral width and the medial radius of the distal cross-section from the default value would lead to a decrease in the largest maximum principal stress of the distal cement. The medial width of middle cross-section, however, was not so simple. The result of DSA suggested that decreasing this parameter from the default value decreased the stress in the distal cement, but the optimum shape was obtained by increasing this parameter. The method used in this study will assist our engineers and surgeons in the process of modifying and optimizing the stem design.

Alterations of phospholipase C isozymes in rat cerebral cortex through hyperoxia.

The effect of hyperoxia on the level of three phospholipase C (PLC) isozymes (beta1, gamma1, delta1) was assessed in the rat cerebral cortex. When the rats were exposed to 100% oxygen for 60 h, there was a significant reduction in the catalytic activity of low molecular weight phosphotyrosine phosphatase, which was susceptible to activity loss under oxidative stress. The result suggests that oxidative stress is induced in the rat cerebral cortex through hyperoxia. The protein levels of PLC-beta1 and -delta1 were significantly increased in the cerebral cortex where oxidative stress had been induced, although that of PLC-gamma1 was not altered. There was no significant difference in the total PLC activity of the cerebral cortex between hyperoxia and control rats. Using gel filtration chromatography, it was revealed that the PLC-beta1 activity in the cerebral cortex of the hyperoxia rats was higher than that in the control rats, but the PLC-delta1 activity in the former did not differ from that in the latter, despite an increase in the PLC-delta1 protein level. These findings suggest that the PLC-beta1 and -delta1 protein levels of brain tissues are increased by oxidative stress, and that the increased PLC-delta1 molecule is less active.

The sphericity of the bearing surface in total hip arthroplasty.

This study evaluated the sphericity of bearing surfaces in total hip arthroplasty. The out-of-roundness of metal femoral heads, the inner surface of polyethylene liners, and commercially available ball bearings was measured. The hip prostheses were obtained directly from the manufacturers. The sphericity of the bearing surfaces was significantly inferior to that of the ball bearings. The sphericity of the femoral head on the sagittal plane was inferior to that on the transverse plane. Several significant differences were found among different manufacturers. The sphericity of the femoral head on the sagittal plane and that of polyethylene significantly improved in 1999 and 2000 compared with those in 1995. Further improvement is desirable, however, because good sphericity is expected to prolong the functional performance of the prosthesis after total hip arthroplasty.

Differential expression of rat brain caspase family proteins during development and aging.

It is well recognized that caspases are essential effector molecules for carrying out apoptosis in eukaryotic cells. The expression of rat brain caspase family proteins (caspase-2, -3, -6, -7, -8, -9, 10) in development and aging was assessed using immunochemical detection. All of these caspases were expressed in the rat brain. Immunoblot analysis of brain extracts from embryonic day 19 (E19) to postnatal 96-week-old rats indicated that cytosolic caspase-3, -7, -8, and -10 were highly expressed at E19, and decreased after birth. In contrast, cytosolic caspase-2, -6, and -9 were constitutively expressed from the early stages to 96 weeks of age. These results show that the expression of rat brain caspase family proteins is differentially regulated during the development and aging.

Differential subcellular localization of caspase family proteins in the adult rat brain.

The distribution of the caspase family (caspase-2, -3, -6, -7, -8, -9, -10) was assessed using immunochemical detection of subcellular fractions of 8-week-old rat brain tissues. The present study demonstrated that the relative protein level of caspase-2, -3, -6, -8 and -10 was highest in the soluble cytosolic fraction, while that for caspase-9 was highest in the nucleus. We also found that caspase-3 and -6 were present at high levels and caspase-2, -8 and -9 at moderate levels in the nerve endings fraction as well as in the soluble cytosolic fraction. These results suggest that rat brain caspases are differentially expressed in the subcellular fractions of the rat brain, and that caspases not only contribute to the regulation of neuronal death, but also to synaptic plasticity.

[Non-small cell lung cancer with liver metastasis responsive to gemcitabine--a case report].

A 56-year-old male patient underwent a right upper lobectomy and lymph node dissection for non-small cell lung cancer in March 1994. Multiple lung metastases in the right lung were found 45 months after the operation, and chemotherapy with docetaxel was administered. A liver metastasis was detected 11 months later, and it was refractory to docetaxel. Therefore, the patient was treated with cisplatin, mitomycin C and vinorelbine, which resulted in no change to the liver metastasis. He was next treated with gemcitabine, which resulted in a partial response of the liver metastasis. The adverse effects of gemcitabine were Grade 3 thrombocytopenia and Grade 2 neutropenia. The response duration for gemcitabine therapy was three months.

[A case of docetaxel-resistant breast cancer responsive to paclitaxel therapy].

A 73-year-old woman underwent docetaxel therapy for lung metastasis from breast cancer after having received CAF therapy. Because of the progressive disease due to secondary resistance to docetaxel, the patient was given three courses of paclitaxel therapy (60 mg/m2, day 1, 8, 15 and 22, repeated every 6 weeks). The paclitaxel therapy brought about no adverse effects and a 51%-reduction in the size of the metastatic lung tumor (PR). Although the duration of the response to the paclitaxel therapy was limited to about one month due to progression of a brain metastasis, paclitaxel therapy may be effective against docetaxel-resistant breast cancer.

Acquisition of multidrug resistance in recurrent breast cancer demonstrated by the histoculture drug response assay.

Recurrent breast cancer has a very poor response rate to chemotherapy. To understand the degree of acquisition of multidrug resistance in recurrent disease, 24 recurrent breast tumors and 127 primary tumors were evaluated and compared for chemosensitivity in the histoculture drug response assay (HDRA). The evaluation rate was 98.8%. The HDRA utilizes 3-dimensional culture of human tumors on collagen-gel rafts. Doxorubicin (DXR), 5-fluorouracil (5-FU) and mitomycin C (MMC) were tested as standard agents and cisplatin (CDDP) as a candidate agent on surgical specimen of breast cancer in the HDRA. In vitro drug exposure in the HDRA was for 7 days. At the end of the assay, tumor response was assessed by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The mean inhibition rates of primary tumors vs. recurrent tumors were 57.9% and 38.6% for DXR (p<0.0005); 59.9% and 42.8% for MMC (p<0.01); 49.0% and 33.4% for 5-FU (p<0.01); and 34.5% and 16.0% for CDDP (p<0.005), respectively. The recurrent cases were pretreated clinically with CAF (cyclophosphamide, DXR and 5-FU), CEF (cyclophosphamide, epirubicin and 5-FU) or CMF (cyclophosphamide, methotrexate and 5-FU). In the CAF and CEF group, the HDRA sensitivity to CDDP was significantly lower in recurrent disease (p<0.005) than that of primary breast cancer suggesting that one agent can induce resistance to another. This is further suggested by the fact that 64.7% of the recurrent cases were resistant to all 4 agents tested as opposed to 27% of the primary cases and that only 5.9% of the recurrent cases were sensitive to three or more agents as opposed to 18% of the primary cases. The correlation of the HDRA results to clinical outcome in the study was 80.0% with 15 cases evaluated consisting of 5 true positives, 3 false positives, 7 true negatives and no false negatives. Thus, the HDRA gives useful clinical information, in particular for the specific individualized treatment design necessary to overcome the multidrug resistance problem of recurrent breast cancer.

Resistant mechanisms of anthracyclines--pirarubicin might partly break through the P-glycoprotein-mediated drug-resistance of human breast cancer tissues.

Juliano and Ling initially reported the expression of a 170 kDa glycoprotein in the membrane of Chinese hamster ovarian cells in 1976, and named this glycoprotein P-glycoprotein (P-gp) based on its predicted role of causing "permeability" of the cell membrane. After much research on anthracycline-resistance, this P-gp was finally characterized as a multidrug-resistant protein coded by the mdr1 gene. Multidrug resistance associated protein (MRP) was initially cloned from H69AR, a human small cell-lung carcinoma cell line which is resistant to doxorubicin (DXR) but does not express P-gp. MRP also excretes substrates through the cell membrane using energy from ATP catabolism. The substrate of MRP is conjugated with glutathione before active efflux from cell membrane. Recently, membrane transporter proteins were re-categorized as members of "ATP-Binding Cassette transporter"(ABC-transporter) superfamily, as shown at http://www.med.rug.nl/mdl/humanabc.htm and http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html. A total of ABC transporters have been defined, and MDR1 and multidrug resistance associated protein 1 (MRP1) were reclassified as ABCB1 and ABCC1, respectively. Their associated superfamilies include 11 and 13 other protein, in addition to ABCB and ABCC, respectively. Lung resistance-related protein (LRP) is not a member of the superfamily of ABC transporter proteins, because it shows nuclear membrane expression and transports substrate between nucleus and cytoplasm. LRP was initially cloned from a non-small cell lung carcinoma cell line, SW1573/2R120 which is resistant to DXR, vincristine, etoposide and gramicidin D and does not express P-gp. The mechanisms of resistance remains unclear, and why some resistant cell lines express P-gp and others express MRP and/or LRP is likewise unclear.

Bisphosphonate therapy for bone metastases from breast cancer: clinical results and a new therapeutic approach.

BACKGROUND: We evaluated the usefulness of bisphosphonate (BIS) monotherapy, the safety of rapid infusion of BIS and the efficacy of BIS-sequential therapy for bone metastases from breast cancer. PATIENTS AND METHODS: Twenty-nine patients with bone metastasis or invasion were treated with BIS monotherapy. Each BIS (pamidronate 30 mg, alendronate 10 mg, or incadronate 10 mg) was infused over 30 minutes every two weeks a median of 12 times. RESULTS: With BIS therapy, five patients (17%) showed partial response of the bone lesions, and eighteen patients (64%) had pain relief. Of the nine patients treated with BIS-sequential therapy, one (11%) showed a partial response of the bone metastases, three (33%) had pain relief, and one (11%) showed a decrease in the serum tumor marker level. CONCLUSION: BIS therapy is effective against bone metastases from breast cancer, and rapid infusion of BIS is both safe and convenient for patients. BIS-sequential therapy can be a unique therapeutic option in some cases.

[Histoculture drug response assay on non-small cell lung cancer].

We examined the chemosensitivity of non-small cell lung cancer (NSCLC) tissues to CDDP, 5-FU, ADM, MMC, ETP and SN38 using histoculture drug response assay (HDRA). One-hundred and thirty surgical specimens from NSCLC patients who were not given preoperative chemotherapy were used. The inhibition indexes of CDDP, 5-FU, MMC, ADM, ETP and SN38 were 39.1 +/- 18.2%, 48.0 +/- 19.7%, 63.3 +/- 17.7%, 47.6 +/- 22.0%, 36.9 +/- 21.1%, and 37.9 +/- 25.2%, respectively. Inhibition indexes were above the cutoff level, i.e., 'judged sensitive,' in 40 cases (31.3%) for CDDP, 34 cases (27.4%) for 5-FU, 54 cases (44.3%) for MMC, 36 cases (33.0%) for ADM, 29 cases (29.8%) for ETP, and 34 cases (37.4%) for SN38, respectively. In almost one-third of patients, the inhibition indexes of all drugs were under cutoff levels. Correlations between in vitro chemosensitivity data and patient responses to chemotherapy were obtained from 16 evaluable patients, and a 44.4% true positive rate and a 100% true negative rate were observed. Our results with HDRA for NSCLC showed a high incidence of intrinsic multidrug resistance. HDRA may help doctors to avoid non-effective chemotherapy for NSCLC patients.

Activation of NADPH oxidase in Alzheimer's disease brains.

The present study is the first to show that superoxide (O(-)(2)) forming NADPH oxidase is activated in Alzheimer's disease (AD) brains by demonstrating the marked translocation of the cytosolic factors p47-phox and p67-phox to the membrane. In conjunction with a recent in vitro study showing that amyloid beta activates O(-)(2) forming NADPH oxidase in microglia, where these phox proteins are localized in this study, the present results suggest that, in AD, NADPH oxidase is activated in microglia, resulting in the formation of reactive oxygen species which can be toxic to neighboring neurons in AD.

Increase in phospholipase C-delta1 protein levels in aluminum-treated rat brains.

The effect of administration of aluminum to rats on the level of three phospholipase C (PLC) isozymes (beta1, gamma1, and delta1) was assessed in a variety of brain tissues. After exposure to aluminum, a statistically significant increase in malondialdehyde, an index of lipid peroxidation, was observed. In addition, there was a significant reduction in the catalytic activity of low molecular weight phosphotyrosine phosphatase, which loses its activity during oxidative stress. This suggests that oxidative stress is induced in brain tissues exposed to aluminum. The protein level of PLC-delta1, but not that of PLC-beta1 or -gamma1, was significantly increased in brains where oxidative stress had been induced. The total PLC activity in aluminum-treated rat brains was significantly higher than that in control brains. These results suggest that PLC-delta1 protein levels in brain tissues are increased by the induction of oxidative stress, giving an explanation for its up-regulation in Alzheimer's disease.

[Efficacy of docetaxel for recurrent breast cancer: evaluation based on chemosensitivity test and clinical response].

We investigated the chemosensitivity of anticancer agents against primary (230 patients, 268 tumors) and recurrent breast cancer (40 patients, 51 tumors) using histoculture drug response assays (HDRA) of surgical specimens. Of the 40 recurrent breast cancer patients, 26 were pretreated with anthracycline. The efficacy of the agents was assessed according to an inhibition index of optical density detected by an ELISA reader. The inhibition rate of docetaxel against recurrent tumors was similar that against primary ones, although the rates of adriamycin, 5 fluorouracil, mitomycin and cisplatin against recurrent tumors were significantly lower than those against primary ones. The clinical response of docetaxel was also evaluated in ten patients with recurrent breast cancer. Of the ten patients with recurrent breast cancer, eight were pretreated with anthracycline, and seven showed a partial response. These results indicate that docetaxel is effective against recurrent breast cancer, even anthracycline-resistant breast cancer.

Chemosensitivity of breast cancer lymph node metastasis compared to the primary tumor from individual patients tested in the histoculture drug response assay.

Lymph node metastasis is often the first indication of the aggressiveness of breast cancer. Effective chemotherapy in breast cancer depends on targeting the metastatic component of the disease. In order to optimize chemotherapy in the metastatic target of breast cancer, the histoculture drug response assay (HDRA) was performed on surgical specimens of primary tumor and axillary lymph node metastasis from 30 breast cancer patients. The surgical specimens were cut into approximately 10 mg pieces, and placed onto the collagen gel sponges in the medium containing previously-determined cutoff concentrations of doxorubicin (DXR), 5-fluorouracil (5-FU), cisplatin (DDP), and mitomycin C (MMC). After incubation for 7 days, the chemosensitivity of the tumor fragments was evaluated with the 3-(4,5-dimethythiazol2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) endpoint. The lymph node metastases were more resistant than the primary tumor for DXR, 5-FU, and MMC (p < 0.05) but not for CDDP. The data suggest that both primary tumor and metastases from individual patients should be tested in the HDRA to enhance clinical efficacy of chemotherapy.

Abundance of low molecular weight phosphotyrosine protein phosphatase in the nerve-ending fraction in the brain.

The distribution of low molecular weight phosphotyrosine protein phosphatase (LMW-PTP) in subcellular fractions of rat brain tissue was investigated by immunoblotting analysis using anti-LMW-PTP antibody. The enzyme was detected in the 105000 g precipitate in addition to the supernatant of brain homogenate, even after the precipitate was extensively washed, and was abundant in the particulate fraction of nerve endings. Nerve ending LMW-PTP was effectively solubilized by 1% Triton X-100 or 1% deoxycholate, though the enzyme was solubilized by thorough sonication. Two forms of LMW-PTP, designated as LMW-PTP-I and -II, were separated from the nerve ending-rich fraction by chromatofocusing. Nerve endings PTP-I and -II were different in molecular weight, isoelectric point and susceptibility to activators and inhibitors. The properties of nerve endings LMW-PTP-I and -II were similar to those of cytosolic LMW-PTP-I and -II. The abundance of LMW-PTP in nerve endings as well as in the cytosol suggests that this enzyme plays an important role in synaptic function.