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The present study was undertaken to assess whether the odds for incident radiographic osteoarthritis (OA) differ between men and women in regard to body mass index (BMI) and inflammatory magnetic resonance imaging (MRI) markers 1 and 2 years prior, and whether the presence of inflammation on MRI differs between normal-weight and overweight/obese individuals who develop radiographic OA up to 4 years prior. We studied 355 knees from the Osteoarthritis Initiative study that developed incident radiographic OA and 355 matched controls. MRIs were read for effusion-synovitis and Hoffa-synovitis for up to 4 consecutive annual time points. Subjects were classified as normal-weight (BMI

Background: Dental professionals have so many opportunities to use injection needles and sharp instruments during dental treatment that they face an increased risk of needlestick injuries. This retrospective study reports the utilization and clinical outcomes of occupational post-exposure prophylaxis (PEP) with anti-retroviral agents after being potentially exposed to HIV at dental departments of Hiroshima University Hospital. Objective: This study reports the utilization and clinical outcomes of occupational post-exposure prophylaxis (PEP) with anti-retroviral agents after being potentially exposed to HIV at dental departments of Hiroshima University Hospital. Methods: Data on the clinical status of HIV-infected source patients and information on HIV-exposed dental professionals from 2007 to 2018 were collected. Results: Five dentists with an average experience of 5.6 years (1-15 years) were exposed. The averaged CD4-positive cell number and HIV-RNA load were 1176 (768-1898) / l and less than 20 copies/ml, respectively, in all the patients. Two of the five HIV exposed dentists received PEP. Three months after the exposures, all of their results were negative in HIV antibody/antigen tests. Conclusion: These data might support the concept of “undetectable equals untransmittable”, although HIV exposure in this study was not through sexual transmission.

The prognostic value of metabolic tumor volume (MTV) in locally advanced laryngeal or hypopharyngeal cancer is established in the setting of chemoradiotherapy, while it remains unknown in the setting of upfront total laryngectomy.We retrospectively analyzed 88 patients receiving total laryngectomy and neck dissection, using Cox regression models.Variables related to metastatic lymph node were associated with overall survival, whereas those related to primary tumor were not. In multivariable models, MTV of metastatic lymph nodes (N-MTV) as a continuous variable (Akaike's information criterion (AIC), 277.5) was equivalent to pathological nodal status (AIC, 278.2; P = 0.40), and superior to pathological nodal classification as an ordinal variable (AIC, 281.4; P 0.05) in ability of predicting death. The risk of death was increased by 1.2-fold (95% confidence interval (CI), 1.0-1.4; P = 0.03) every 10-ml increment of N-MTV, while patients with pN+ disease were at a higher risk of death by 2.9-fold (95% CI, 1.0-12.2; P 0.05) compared with patients with pN0 disease. Using recursive partitioning analysis (RPA), we classified the patients as having a low, intermediate, or high risk of death on the basis of N-MTV and extranodal extension (ENE). This RPA classification system exhibited greater concordance with overall survival than the classification considering pathological nodal status and ENE (AIC, 275.8 versus 281.4; P = 0.02). In the setting of upfront total laryngectomy, N-MTV is a critical predictor of mortality. A staging system in which N-MTV is incorporated may better inform adjuvant treatment decisions.

BACKGROUND AND PURPOSE: The flow-diverter device has been established as a treatment procedure for large unruptured intracranial aneurysms. The purpose of this study was to compare the usefulness of Silent MR angiography and time-of-flight MRA to assess the parent artery and the embolization state of the aneurysm after a flow-diverter placement. MATERIALS AND METHODS: Seventy-eight large, unruptured internal carotid aneurysms in 78 patients were the subjects of this study. After 6 months of treatment, they underwent follow-up digital subtraction angiography, Silent MRA, and TOF-MRA, performed simultaneously. All images were independently reviewed by 2 neurosurgeons and 1 radiologist and rated on a 4-point scale from 1 (not visible) to 4 (excellent) to evaluate the parent artery. The aneurysmal embolization status was assessed with 2 ratings: complete or incomplete occlusion. RESULTS: The mean scores of Silent MRA and TOF-MRA regarding the parent artery were 3.18 ± 0.72 and 2.31 ± 0.86, respectively, showing a significantly better score with Silent MRA (P < .01). In the assessment of the embolization of aneurysms on Silent MRA and TOF-MRA compared with DSA, the percentages of agreement were 91.0% and 80.8%, respectively. CONCLUSIONS: Silent MRA is superior for visualizing blood flow images inside flow-diverter devices compared with TOF-MRA. Furthermore, Silent MRA enables the assessment of aneurysmal embolization status. Silent MRA is useful for assessing the status of large and giant unruptured internal carotid aneurysms after flow-diverter placement.

Summary Introduction The aim of this study was to determine whether loss of ACL integrity in an older cohort precedes the onset of radiographic OA (ROA). Methods Participants in this nested case–control study were selected from the Osteoarthritis Initiative (OAI) study who had risk factors for OA development but did not have ROA (Kellgren–Lawrence grading (KLG) of 0 or 1) in both knees at baseline. The MRIs were assessed for the presence of ACL tears. Case knees were defined by the development of ROA on knee radiographs between the 12 and 48 month visits. Their radiographs were assessed at P0 (time of onset of radiographic knee OA), 1 year prior to P0 (P-1) and at baseline. Controls were selected from amongst those who did not develop incident ROA and were matched to cases. Results 355 persons who developed ROA were matched to 355 controls. No relationship between loss of ACL integrity and incident ROA was found at any assessment time point. Odds ratios (OR) for baseline, 1 year prior to incident ROA (P1) and at point of occurrence of incident ROA (P0) were 2.00 (0.66–6.06), 2.5 (0.76–8.24) and 2.75 (0.85–8.88) respectively. A significant risk of incident ROA was found in participants who had a history of knee injury with an OR of 1.51 (1.05–2.16). Conclusion Loss of ACL integrity does not confer a significantly increased risk of incident ROA in an older adult cohort. In contrast, a history of knee injury was associated with an increased risk of incident ROA.

The patient was a 45-year-old man with underlying alcoholic liver cirrhosis. Two years prior, he was repeatedly hospitalized for liver failure symptoms and requested a living-donor liver transplantation (LDLT) because of end-stage cirrhosis. A pretransplantation blood test revealed a high 1,3-beta-d-glucan (BDG) value of 102.0 pg/mL (reference value

Aims To investigate the relationship between the progression of anaemia and renal pathological findings in patients with diabetic nephropathy. Methods A total of 223 patients with diabetes underwent renal biopsy from 1985 to 2010 and were confirmed to have pure diabetic nephropathy according to the recent classification, of whom 113 (baseline haemoglobin ≥ 11 g/dl) were enrolled in the study. Linear regression analysis was used to estimate the changes in haemoglobin levels during the follow-up period. Results In a multivariate model adjusted for clinical and histopathological variables, higher interstitial fibrosis and tubular atrophy scores were more strongly associated with a decrease in haemoglobin levels than were lower scores. Compared with an interstitial fibrosis and tubular atrophy score of 0, the standardized coefficients for interstitial fibrosis and tubular atrophy scores of 1, 2 and 3 were 0.20 (95% CI −0.31 to 0.93), 0.34 (95% CI −0.22 to 1.34) and 0.47 (95% CI 0.07 to 1.96), respectively, whereas a higher glomerular class, a higher vascular lesion score and the presence of exudative lesions were not strongly correlated with the decrease in haemoglobin. Conclusions Tubulointerstitial lesions that are more advanced are significantly associated with the progression of anaemia in patients with diabetic nephropathy after adjustment for numerous covariates. This finding suggests that tubulointerstitial lesions may be a useful prognostic indicator for anaemia in patients with diabetic nephropathy, and that decreased erythropoietin production attributable to the progression of tubulointerstitial lesions is a major cause of anaemia in these patients.

Objective To assess structural progression in knees with no/mild radiographic osteoarthritis (OA) (i.e., Kellgren/Lawrence [K/L] grades 0-2) that will undergo knee replacement during a 5-year period; to assess differences in structural damage on magnetic resonance imaging (MRI) in knees with no/mild radiographic OA versus those with severe radiographic OA (i.e., K/L grades 3 and 4) at baseline; and to assess differences in pain levels between those groups. Methods All participants who underwent knee replacement from baseline to 60 months were drawn from the Osteoarthritis Initiative. MRIs were assessed for bone marrow lesions (BMLs), Hoffa synovitis, and effusion synovitis (i.e., hyperintensity signal changes in the fat pad and abnormal amount of capsular distension due to intraarticular joint fluid and/or synovial thickening) at baseline and at the time point before knee replacement (T0). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score (KOOS) pain were used for pain characterization. WOMAC activities of daily living and KOOS quality of life were applied to characterize functional status of the included participants. Logistic regression was used to assess the association of no/mild radiographic OA with these MRI features and pain. Results Based on inclusion criteria, 181 knees were selected. Participants were predominantly female (57.8%) with a mean age of 64.4 years. A total of 51 knees (28.2%) had no/mild radiographic OA at baseline. Of these, 51.0% progressed to severe radiographic OA. No/mild radiographic OA knees showed higher odds of BMLs in the patellofemoral joint at baseline (odds ratio [OR] 7.92 [95% confidence interval (95% CI) 3.45-18.16]) and T0 (OR 9.44 [95% CI 4.00-22.28]) compared to severe radiographic OA knees. In addition, no/mild radiographic OA knees were associated with change from no pain to pain from baseline to T0 (adjusted OR 5.48 [95% CI 1.25-24.00]). Conclusion More than half of the knees with no/mild radiographic OA before knee replacement progressed to severe radiographic OA during 4 years of follow-up. BMLs in the patellofemoral joint were more often seen among knees that had no/mild radiographic OA. Worsening pain status may contribute to knee replacement in knees with no/mild radiographic OA.

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients. Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

The efficacy of the local application of recombinant human fibroblast growth factor-2 (FGF-2) in periodontal regeneration has been investigated. In this study, a randomized, double-blind, placebo-controlled clinical trial was conducted in 253 adult patients with periodontitis. Modified Widman periodontal surgery was performed, during which 200 µL of the investigational formulation containing 0% (vehicle alone), 0.2%, 0.3%, or 0.4% FGF-2 was administered to 2- or 3-walled vertical bone defects. Each dose of FGF-2 showed significant superiority over vehicle alone (p < 0.01) for the percentage of bone fill at 36 wks after administration, and the percentage peaked in the 0.3% FGF-2 group. No significant differences among groups were observed in clinical attachment regained, scoring approximately 2 mm. No clinical safety problems, including an abnormal increase in alveolar bone or ankylosis, were identified. These results strongly suggest that topical application of FGF-2 can be efficacious in the regeneration of human periodontal tissue that has been destroyed by periodontitis.

SUMMARY Ultrasonic hearing is widespread among moths, but very few moth species have been reported to produce ultrasounds for sexual communication. In those that do, the signals are intense and thus well matched for long distance communication. By contrast, males of the Asian corn borer moth (Crambidae) were recently shown to whisper extremely low-intensity ultrasonic courtship songs close to females. Since low sound levels will prevent eavesdropping by predators, parasites and conspecific rivals, we predicted low intensity ultrasound communication to be widespread among moths. Here we tested 13 species of moths including members of the Noctuidae, Arctiidae, Geometridae and Crambidae. Males of nine species, 70%, produced broadband ultrasound close to females. Peak frequencies ranged from 38 to above 100 kHz. All sounds were of low intensity, 43-76 dB SPL at 1 cm [64±10 dB peSPL (mean ± s.d.), N=9 species]. These quiet and/or hyper-frequency ultrasounds are audible to nearby mates, but inaudible to unintended receivers. Although largely unknown because it is so inconspicuous, acoustic communication using low intensity ultrasound appears to be widespread among hearing moths. Thus, acoustic communication may be the norm rather than the exception.

Aims: The histogenesis and biological behaviour of peripheral intrahepatic cholangiocarcinoma (peripheral CC) remain unclarified. The aim of this study was to examine the growth pattern of peripheral CC (24 cases) in comparison with hepatocellular carcinoma (HCC, 27 cases) and metastatic colorectal adenocarcinoma (MCA, 24 cases). Methods and results: Tumour/surrounding liver borders were classified as: (i) fibrous encapsulation, (ii) compressive growth, and (iii) infiltrating replacement. Nineteen of 24 peripheral CCs showed (iii), whereas 23 of 27 HCCs showed (i) and 17 of 24 MCAs showed (ii). In (iii), carcinoma cells infiltrated the surrounding liver without compression, and hepatic supporting vascular structures such as portal tracts were secondarily incorporated into the tumour. In (i) and (ii), the surrounding liver was compressed and no or few portal tracts were incorporated within the tumour. Fifteen of 24 peripheral CCs were composed of carcinoma cells resembling reactive bile ductules and these cells were positive for neural cell adhesion molecule (NCAM), a marker of proliferating bile ductules. The remaining nine peripheral CCs were composed of ordinary adenocarcinoma and negative for NCAM. Conclusions: A subgroup of peripheral CCs with an infiltrating replacement growth pattern resembles reactive bile ductules and expresses NCAM. ‘Bile ductular carcinoma’ may be a better term for this subgroup.

Objective: To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods. Materials and methods: Disks containing 5 μg of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis. Results: Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV–SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV–SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV–SC group. Conclusion: Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.

Historically, total pharyngolaryngectomy with total esophagectomy has been the standard radical surgical treatment for synchronous cancer of the thoracoabdominal esophagus and pharyngolaryngeal region, and for cancer of the cervical esophagus that has invaded as far as the thoracic esophagus. Although definitive chemoradiotherapy that enables preservation of the larynx has often been the first choice of treatment for cancers involving the cervical esophagus, total pharyngolaryngectomy with total esophagectomy is required as a salvage therapy for cases involving failure of complete remission or locoregional recurrence after chemoradiotherapy. However, salvage esophageal surgery after definitive high-dose chemoradiotherapy is generally associated with high morbidity and mortality. The aim of this study was to examine the short-term outcome of salvage total pharyngolaryngectomy with total esophagectomy. From 2001 to 2014, nine patients underwent salvage total pharyngolaryngectomy with total esophagectomy at the Department of Gastroenterological Surgery, Nagoya University. The mortality and morbidity rates were high at 22% and 89%, respectively. Four patients (44%) developed tracheal necrosis, which in two patients eventually led to lethal hemorrhage. Salvage total pharyngolaryngectomy with total esophagectomy is an uncommon and highly demanding surgical procedure that should be carefully planned and conducted in selected centers of excellence. Measures must be taken to preserve the tracheal blood supply, thus avoiding fatal complications.

Despite improvements in surgical techniques, perioperative management, and multidisciplinary therapy, treatment outcomes of patients with esophageal squamous cell carcinoma (ESCC) remain poor. Therefore, development of novel molecular biomarkers, which either predict patient survival or become therapeutic targets, is urgently required. In the present study, to facilitate early detection of ESCC and predict its clinical course, we investigated the relationship of the serum level of melanoma-associated antigen (MAGE)-D4 to patients' clinicopathological characteristics. Using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays, we determined the levels of MAGE-D4 mRNA and protein in cell lysates and conditioned medium of cultures, respectively, of nine ESCC cell lines. Further, we determined MAGE-D4 levels in serum samples collected from 44 patients with ESCC who underwent radical esophagectomy without neoadjuvant therapy as well as from 40 healthy volunteers. Samples of conditioned medium and cell lysates contained comparable levels of MAGE-D4 that correlated closely with the levels of MAGE-D4 mRNA. Preoperative MAGE-D4 levels in the sera of 44 patients with ESCC, which varied from 0 to 2,354 pg/mL (314 ± 505 pg/mL, mean ± standard deviation), were significantly higher compared with those of healthy volunteers. By setting the cutoff at the highest value for healthy volunteers (50 pg/mL), the MAGE-D4-positive group of patients was more likely to have shorter disease-specific and disease-free survival compared with those of the MAGE-D4-negative group, although the differences were not statistically significant. Our results indicate that the elevation of preoperative serum MAGE-D4 levels in some patients with ESCC was possibly caused by excess production of MAGE-D4 by tumor cells followed by its release into the circulation. Clinical implications of serum MAGE-D4 levels should be validated in a large population of patients with ESCC.

To create and test a multistation telemedicine support system, three remote locations were connected: the homes of two patients with chronic respiratory failure, the hospital of the attending physician, and the hospital of the pulmonary specialist. Real-time connections were set up between the three locations. Medical history and biologic variables were noninvasively recorded, including blood pressure, arterial oxygen saturation, three-lead electrocardiogram, and end-tidal carbon dioxide. Both physicians shared in these data real-time. If necessary, the respiratory specialist could provide medical advice to the attending physician based on the patient's condition. The trial program resulted in the same information being exchanged remotely using the multi-station telemedicine system that would be exchanged in a direct, face-to-face encounter. This result, together with the improvement in quality of life and the establishment of appropriate treatment and cooperation between the respiratory specialist and attending physician, suggests our system can be considered useful and promising for further use.

Neither postoperative radiotherapy nor chemotherapy alone provided a survival benefit after curative esophagectomy for esophageal squamous carcinoma.Of 103 consecutive patients who underwent potentially curative esophagectomy for esophageal squamous carcinoma, 45 patients with advanced cancers without preoperative adjuvant treatments were prospectively randomized to two groups; postoperative chemotherapy alone (Group A, n=23) and postoperative radio/chemotherapy (Group B, n=22). In Group A, cisplatin (CDDP) (50 mg/m(2)) was given by intravenous infusion on days 1 and 15, and 5-fluorouracil (5-FU) (300 mg/m(2)) was given daily by continuous intravenous infusion for 5 weeks. In Group B, in addition to the same chemotherapeutic regimen of Group A, 50 Gy of radiotherapy was given to the mediastinum over 5 weeks. The immunohistochemical staining of tumoral p53 and microvessel density was undertaken to correlate to the radio/chemosensitivity.There were no significant differences in the clinicopathologic characteristics between the two groups. The median dose of 5-FU and CDDP administered were not significantly different between the two groups. The mean (SD) dose of radiotherapy in Group B was 42+10 Gy. The 1-, 3- and 5-year survival rates in Group A were 100, 63 and 38% and those in Group B were 80, 58 and 50%, respectively (P=0.97). In each group, four patients succumbed to locoregional recurrences. Tumoral p53 was immunohistochemically negative in 43% in Group A and 77% in Group B (P=0.03), indicating that many patients in Group B might be potentially sensitive to radiochemotherapy. The 3- and 5-year survival rates (75 and 64%) of patients with p53 negative expression (n=18) were significantly (P=0.03) better than those with p53 positive expression (n=27, 44 and 26%). The long-term survival was better for patients with p53 negative tumours than those with p53 positive tumours in Group B (P=0.06 by long-rank test, P0.05 by Generalized-Wilcoxon test). However, the long-term survival was not different between the patients who had p53 negative and positive tumours in Group A (P=0.19). These data suggest that there were no survival advantage for patients receiving radiotherapy in Group B, instead p53 negative tumours appeared to have a favorable prognosis.Postoperative radiotherapy administered concurrently with chemotherapy does not provide a survival benefit compared with chemotherapy alone. Tumoral p53 expression has a predictive value for survival in patients treated with postoperative radio/chemotherapy.

Background: We assessed the radiographic characteristics of early colorectal carcinomas with submucosal invasion (CCSI) with the use of double-contrast images. Methods: From 1989 to 1997, 193 patients with 196 CCSI lesions underwent double-contrast barium enema examinations. Three gastrointestinal radiologists retrospectively reviewed the radiographic characteristics of the lesions and classified them as protruding and depressed types by consensus. Further, subclassifying the protruding into lobular and smooth types was accomplished on the basis of surface structure. Each type was compared with pathologic findings of resected specimens. Results: The incidence of the protruding type was 98.0%, and that of the depressed type was only 2.0%. The proportion of smooth lesions was 49.0% for the protruding type; these had a mean diameter of 17.9 mm, which was significantly smaller than the 23.1 mm mean observed for lobular lesions (p < 0.01). Of the smooth lesions, 44.7% demonstrated massive invasion, whereas 91.8% of lobular lesions exhibited only slight or moderate invasion into the submucosa (p < 0.01). The extent of invasion of the smooth lesions was greater than that for their lobular counterparts in terms of venous and lymph node involvement. Conclusion: Almost all CCSIs could be identified radiologically as protruding lesions; these had a smooth rather than a lobulated surface and demonstrated greater malignancy, despite the smaller size. It is clinically important to discriminate these from other polypoid lesions in establishing patient treatment. Double-contrast imaging is useful for evaluation of the surface characteristics of CCSIs in barium enema studies.

A 33-year-old man who developed progressive multifocal leukoencephalopathy (PML) with HIV infection is reported. The patient exhibited rapid decline in neurological status after initiation of antiretroviral therapy (ART), which was attributed to the PML-immune re-constitution inflammatory syndrome. Following the administration of mefloquine in combination with ART, the patient's neurological status improved substantially. This case suggests that further investigation of the use of mefloquine might be warranted for treatment of PML in HIV-infected patients.

When the signs and symptoms of temporomandibular joint disorders (TMD) are present, it is possible that occlusal conditions and mandibular movements are changed. Accordingly, the presence of occlusal interferences may be misjudged. It is therefore reasonable to consider that occlusal conditions should be examined just after the relief of symptoms. The comparison of occlusal conditions in 52 temparomandibular joint (TMJ) pain patients and 27 muscle pain patients with that in 60 asymptomatic controls was made. Occlusal examination in the patients was administered just after the relief of pain by bite plane therapy alone. The only occlusal factor which was associated with pain symptoms was no canine contact on the working side on laterotrusion. It is suggested therefore that further studies as regards this type of interference should be performed.

We provided psychological preparation to children who were hospitalized for endoscopy. We performed a multifaceted evaluation of the effects of the preparation to identify appropriate methods for individual children. The subjects were 20 children, ages 4 to 15 years (average 9.9 years), who were divided into 3 groups according to the preparation methods. From our study, we suggest that it is important to discuss the preparation methods for medical procedures using methods appropriate to the level of cognitive development of each individual child.

Background. The number of metastatic lymph nodes is applied to the staging system of gastric cancer and colorectal cancer. However, it has not been evaluated in oesophageal cancer. Patients and Methods. Of 258 patients with primary squamous cell carcinoma of the thoracic oesophagus between February 1981 and December 1999, 160 underwent three-field oesophagectomy with a curative intent. Clinicopathologic characteristics of those 160 patients were retrospectively investigated according to the number of metastatic lymph nodes. Results. Seventy-eight patients had no lymph node metastases and 82 (51.3%) had lymph node metastases; 51 (31.9%) had between 1 and 4 positive lymph nodes, and 31 (19.4%) had ≥5. The number of metastatic lymph nodes was significantly correlated with tumour size, macroscopic classification, histological differentiation, pT, pN, and vessel invasions. Multivariate analysis showed that lymph vessel invasion (relative risk 12.6), histological differentiation (relative risk 4.2), and tumour size (relative risk 3.8) were independent factors correlated with number of metastatic lymph nodes. The number of metastatic lymph nodes was also well correlated with the Japanese nodal level and TNM stage, respectively (p

NDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondrial complex I involved in the respiratory chain. The human NDUFA1 has been cloned, completely sequenced and mapped to Xq24. In the present study, we searched for sequence variations in NDUFA1 as causative defects in complex I deficiency using genomic DNA of 152 patients with various clinical phenotypes. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Germany and 98 patients (72 male and 26 female) with biochemically proven complex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter region of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 patients tested, no mutation was found that could be related to any of the disease phenotypes included. However, three single-nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt -71 and SNP T/C at nt -189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I-deficient patients. There was no significant difference between the control population, the LHON patients, or the severely affected patients with complex I deficiency, excluding an association of the polymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and complex phenotypes with complex I deficiency.

Objectives : To clarify the virological state of human immunodeficiency virus (HIV)-1-infected patients, we compared the plasma HIV-1 RNA copy number (plasma viral load (VL)), viral DNA and mRNA burdens in peripheral blood mononuclear cells (PBMCs), and the other clinical predictors. Methods : One hundred and thirty-one samples of PBMCs and plasma from 26 patients infected with HIV-1 were obtained during 20 consecutive months for the measurement of VL, viral DNA and mRNA burdens, and CD4 positive (CD4+) cells count. The quantitative polymerase chain reaction (PCR) method with detection by solid phase DNA was utilized for the assay of VL, viral DNA and mRNA burdens. Results : Eighty-six VL, 101 viral mRNA and 129 viral DNA out of 131 samples were detected. There was a significant positive correlation between VL and the viral mRNA burden ( r = 0.600, P ≤ 0.001), and between VL and the viral DNA burden ( r = 0.368, P ≤ 0.001). Focused on individuals, the viral mRNA burdens varied in a manner relatively dependent on VL when both values were detectable. However, viral DNA burdens varied relatively independently of VL and the viral mRNA burdens. In six patients the viral mRNA burden was detectable and changed even if the VL was undetectable throughout the observation period. Conclusions : Both viral DNA and viral mRNA burdens still showed detectable changes even when the VLs became undetectable in most patients. The measurement of viral mRNA or DNA burdens may be clinically available to identify viral replication when VL is undetectable.

The objective of our study was to clarify the radiologic spectrum of disease entities belonging to the SAPHO syndrome (SAPHO being an acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis). A retrospective analysis of radiologic data was undertaken to determine the relationship of the osteoarthritic changes seen in palmoplantar pustulosis (PPP, n = 179), acne (n = 3), psoriasis vulgaris (PsV, n = 355), generalized pustular psoriasis (GPP, n = 25), and chronic recurrent multifocal osteomyelitis (CRMO, n = 4). Osseous changes of PPP, acne, and CRMO overlap each other; 7 PPP, 2 acne, and 3 CRMO patients manifested stenocostoclavicular hyperostosis as well as hyperostosis of the spine, pelvis, and/or femur. These findings were not seen in either PsV or GPP patients. Thirteen PsV and 4 GPP patients had peripheral arthritis and/or symmetrical sacroiliitis, which were not observed in the PPP, acne, and CRMO patients. The PPP, acne, and CRMO patients may be grouped as belonging to the single disease entity, namely SAPHO syndrome. Our findings do not support the inclusion of PsV and GPP in the spectrum of this syndrome.

The prognostic influence of 6 biomarkers correlated to histologic subtypes of non-small cell lung cancer (NSCLC) on loco-regional control, overall survival, disease-free survival (DFS), and distant disease control (DDC) rates, all measured at 5 years, were examined.Cell blocks from the primary tumors of 137 patients with pathologically staged N1 NSCLC at MDACC were analyzed by 6-biomarker status correlated to histological subtypes and their outcomes.The ranges of biomarker values were as follows: apoptotic index, 0.2-2.8%; mitotic index, 0-1.8%; the proportion of cells in S+G2M, 3-36%; p53 status, 0-100%; Ki-67, 0-9.3%; DNA index, 1.0-2.74. Subtypes of 137 cases from the postoperative pathology specimen showed that 74 patients had squamous carcinoma and 63 patients had adenocarcinoma. Mean and median lengths of follow-up were 4.21 years and 2.43 years, respectively. Patients with squamous cell carcinoma (SCC) had a better 5-year survival (p = 0.006), DFS (p = 0.002), and distant metastasis control (p = 0.002) than patients with adenocarcinoma (AC). Among patients with AC, the DNA index was a significant predictor of 5-year DFS (p = 0.02), DDC rate (p = 0.04), and local-regional control (p0.05). Higher apoptosis (p = 0.03) and mitosis indices (p = 0.03) were also univariate predictors of increased distant disease among patients with AC. Multivariate analysis of patients with AC revealed that the DNA index and Ki-67 were the only significant independent predictors of distant metastasis (p0.04 and p0.02, respectively) and DFS (p0.04 for both). Among patients with SCC, univariate analysis showed that S+G2M proportion (p0.05) and Ki-67 levels (p0.02) were significant predictors for local-regional control; for SC, multivariate analysis showed that only mitosis was a significant predictor in this case for overall survival (p0.04).Spontaneous apoptotic index and Ki-67 were significantly higher in SC than in AC. Patients with SC had less distant metastasis better DFS and overall survival than those with AC. Multivariate analysis revealed that DNA index and Ki-67 status were significant predictors for DDC and DFS in patients with AC, but only mitotic index was a significant predictor of overall survival for patients with SCC.

In the previous study, we have demonstrated that nicotine hardly induces catecholamine release from adrenal medulla of 21-day-old rats. The present study examined the responsiveness of the adrenal chromaffin cells to acetylcholine in vitro and neostigmine and oxotremorine in vivo in 21-day-old and 8-week-old rats. As assessed by electron microscopy, the number of the chromaffin granules was markedly decreased and the content of adrenaline in adrenals was diminished significantly by oxotremorine treatment in 8-week-old rats, whereas these changes did not occur in 21-day-old rats. Morphological changes of the adrenal chromaffin cells, with respect to exocytosis, were not observed in neostigmine-treated 21-day-old rats and acetylcholine-treated adrenal slices prepared from 21-day-old rats. Catecholamine release was hardly evoked by acetylcholine in these slices as judged by measuring the catecholamine content in the medium. These results indicate that the sensitivity of the chromaffin cells to these secretagogues in 21-day-old rats is very low when compared to that in young adult rats.

To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. MAGE-D4 messenger RNA (mRNA) expression was analyzed in nine EC cell lines using quantitative reverse transcription polymerase chain reaction. In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative reverse transcription polymerase chain reaction. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P 0.001). Patients with the highest MAGE-D4 mRNA expression in EC tissues (top quartile, n = 17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (≥65 years), lymphatic involvement, and high MAGE-D4 mRNA expression as significant prognostic factors; high MAGE-D4 mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039) and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4 mRNA profiling. Our results suggest that MAGE-D4 overexpression influences tumor progression, and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC.

1. Binding and inhibition of antimicrobial fluoroquinolones towards liver CYP1A2 purified from 3-methylcholanthrene-treated rats were investigated using proton nuclear magnetic resonance (nmr) and phenacetin metabolism. 2. The proton nmr longitudinal relaxation rate study indicated that the paramagnetic effects of the haem iron of CYP1A2 were observed in protons of enoxacin with a 1,8-naphthyridine skeleton and its 4'-nitrogen atom on the 7-piperazine ring probably participated in specific binding to the haem iron. These data suggest a facile accessibility and strong binding of enoxacin to the active site of the enzyme. On the contrary, the binding region of norfloxacin with a quinoline skeleton could not be specified, and an 8-fluorinated derivative (AT-3970) had much lower paramagnetic effects and no specific binding region. 3. In a reconstituted CYP1A2 system, enoxacin exhibited the most potent inhibition of phenacetin O-deethylation. The metabolism was less inhibited by norfloxacin, and AT-3970 had a weak inhibitory activity. 4. The binding ability of the fluoroquinolones to the CYP1A2 active site is likely to determine their inhibitory activity against phenacetin metabolism.

We investigated the optimal conditions for the application of the MTT assay to determine the viability of cell in primary cultures of rat hepatocytes. The optimal conditions were found to be: inoculation at cell density of 1.31 x 10(5) cells/cm2; concentration of 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 0.12 mM; and MTT incorporation time, 2 h or more. We also found that insulin and glucocorticoid, which are usually added to the medium to maintain cell function, had no effect on the viability of the primary cultures of rat hepatocytes.

Objective: To examine the effects of stool dilution on the results of the faecal Helicobacter pylori antigen test. Methods: Stool samples from nine children with H. pylori infection were diluted with normal saline at dilutions of 1, 5, 10, 50, 100 and 500 times, and optical density (OD) was measured. Results: The faecal H. pylori antigen test yielded positive results for all samples at dilutions of 1:10 and less, although the sample from the case whose original stool showed the lowest OD value changed from positive to negative at a dilution of 1:50. Conclusion: Our results suggest that stools at dilutions of less than 1:10 usually do not yield false-negative results in the faecal H. pylori antigen test, even in patients with low faecal antigen levels.

Nineteen patients with definite and suspected temporomandibular joint (TMJ) osteoarthritis participated in this study. All patients were treated by dental care including bite plane therapy. By comparing the pre-treatment clinical symptoms and TMJ tomograms with those post-treatment, efficacy of the dental treatment applied for these patients has been assessed. Since TMJ pain and limitation of mouth opening were considerably improved in almost all patients post-treatment, this suggests that the clinical prognosis of TMJ osteoarthritis can be favourable. On the other hand, radiographic changes post-treatment were variable. The longitudinal changes found in the TMJ tomograms were classified into four types. The frequency of Type 2 and Type 3, which indicate the occurrence of TMJ remodelling during the observation period, was fairy high (20 TMJs and 14 patients).

The identification of rat faecal metabolites of a new antihistaminic agent, ebastine, 4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, is presented. After oral administration of (14C)ebastine (20 mg kg-1) to rats, 84% of the radioactive dose was excreted in the 24 h faeces. Unchanged drug and five metabolites were isolated from the faeces by thin-layer chromatography and solid-phase extraction, and their structures were identified by liquid secondary ion mass spectrometry using the B/E linked scanning technique. The main metabolic pathways were oxidation of a terminal methyl group to give the hydroxymethyl and carboxyl derivatives, and hydroxylation of a phenyl ring in the diphenylmethoxy moiety. In addition to the oxidative mechanism, metabolism of ebastine involved sulphate conjugation. It is noteworthy that M-4, having both phenolic and alcoholic hydroxyl groups, was sulphated selectively in the latter position.

Flat and depressed cancers of the colon have now been recognized in several centers throughout the world. We report here a case of a 0.8-mm depressed adenoma with high-grade dysplasia in a 70-year-old man. We believe this to be the smallest adenoma ever reported, and unusually (for a small lesion) it was positive for the K-ras mutation.

A 54-year-old man was admitted to our hospital because of chest discomfort. Cardiac catheterization revealed partial anomalous pulmonary venous connection with an intact atrial septum. The right upper pulmonary vein (RUPV) drained into the upper segment of the superior vena cava (SVC). Using the Williams procedure, an atrial septal defect (ASD) was created and a fresh autologous pericardial patch was used to fashion a new pulmonary vein return route from SVC to the ASD. Although the patient was stable after the procedure, he was admitted again 6 months later because of obstruction of RUPV. At reoperation, it was found that the previous pulmonary vein route was obstructed and that the pericardial baffle had adhered to the atrial septum above the ASD. The shrunken and thickened pericardial baffle was removed and the orifice of the ASD was extensively enlarged, after which an expanded polytetrafluoroethylene (ePTFE) patch was used as a new baffle. After the reoperation, the patient's condition improved.

The larval integument of the silkworm, Bombyx mori, is opaque because urate granules accumulate in the epidermis. Although the biosynthetic pathway of uric acid is well studied, little is known about how uric acid accumulates as urate granules in epidermal cells. In the distinct oily (od) mutant silkworm, the larval integument is translucent because of the inability to construct urate granules. Recently, we have found that the od mutant has a genomic deletion in the B. mori homologue of the human biogenesis of lysosome-related organelles complex1, subunit 2 (BLOS2) gene (BmBLOS2). Here, we performed a molecular and functional characterization of BmBLOS2. Northern blot analysis showed that BmBLOS2 was ubiquitously expressed in various tissues. We analysed the structure of a newly isolated mutant (od(B) ) allelic to od and found a premature stop codon in the coding sequence of BmBLOS2 in this new mutation. Moreover, the translucent phenotype was rescued by the germ-line transformation of the wild-type BmBLOS2 allele into the od mutant. Our results suggest that BmBLOS2 is responsible for the od mutant phenotype and plays a crucial role in biogenesis of urate granules in the larval epidermis of the silkworm. The relationships amongst Hermansky-Pudlak syndrome (HPS) genes in mammals, granule group genes in Drosophila and translucent mutant genes in B. mori are discussed.

The contribution of frontal tomography to the diagnosis of temporomandibular joint (TMJ) osteoarthritis has been investigated. Ninety-one patients with clinically defined TMJ disorders were examined by simultaneous lateral and frontal TMJ tomograms taken in the intercuspal position. Abnormal findings were observed on frontal tomograms in 31 joints and suspicious findings in 22 joints. On the other hand, there were 41 joints with abnormal findings and 22 joints with suspicious findings on the lateral tomograms. Suspicious or abnormal findings were found on frontal tomograms alone in 14 joints (7.7%) of 14 patients (15.4%). It is concluded that simultaneous lateral and frontal tomography produces a more accurate radiographic diagnosis of TMJ osteoarthritis.

The potential toxicity and carcinogenicity of thiabendazole (TBZ) was investigated in F344 rats. TBZ was given in pelleted diets at different dietary levels (0, 0.05, 0.1, 0.2 or 0.4%) to groups of 30 rats of each sex for 104 wk. Throughout the study, a marked decrease in body-weight gain was observed in males and females fed 0.4% TBZ. Transitional cell hyperplasia of the renal pelvis and/or papilla was observed in dosed groups of each sex with significant positive trends. Low incidence of transitional cell papilloma or carcinoma of the urinary system was recorded in the dosed groups. Preputial gland adenoma occurred in males treated with 0.4% TBZ, and the incidence was significantly higher than in controls. There was no clear-cut evidence of the carcinogenic activity of TBZ in the urinary system of male and female rats.

Summary To evaluate the immunological development of preterm infants, especially in early infancy, we examined the serum cytokine levels and the expression of Th2 and Th1 chemokine receptors, CCR4 and CCR5, on days 0, 14 and 28 in 16 low birth weight infants (1720·38 ± 502·80 g) born at less than 37 (33·63 ± 3·29) weeks of gestation. Using an enzyme-linked immunosorbent assay (ELISA), serum interleukin (IL)-4 levels exhibited an increase on day 14, but decreased to the initial level on day 28 (P

Off-pump coronary artery bypass grafting (off-pump CABG: OPCAB) has become a standard procedure, but the indication for the patients with severe acute coronary syndrome (ACS) has not been established. The purpose of this study is to evaluate the role of OPCAB for patients with acute myocardial infarction (AMI) and impending myocardial infarction (IMI). Clinical indication of OPCAB for acute coronary syndrome between November 1997 and December 2002, 14 patients diagnosed ACS out of 220 CABG cases underwent surgery. Twelve male and 2 female with a mean age of 66.3 +/- 7.5 were NYHA grade IV condition before surgery. Three of nine AMI cases and 4 of 5 IMI cases underwent OPCAB. Thirteen cases needed intra-aortic balloon pumping (IABP) support pre-operation, in 1 AMI and 2 IMI cases IABP had to be weaned during operation. The mean graft number was 2.6. Except one AMI case with severe cardiac damage, 13 cases were discharged in NYHA grade I-II condition.In early onset cases with still rising CK-MB, operative risk and result is difficult to evaluate pre-operatively. Equal results could be seen in IMI cases with no previous myocardial damage. We suggest, that in cases without severe myocardial damage, OPCAB could be one alternative treatment.

This study aimed to investigate the relationship between the facial side of pain or clicking symptoms and the side of occlusal interference, and to examine the features of pain and clicking patients in terms of frequencies of occlusal interferences in relation to the symptomatic side. Occlusal conditions in 31 pain patients and 40 clicking patients were investigated just after the relief of pain or clicking solely by means of bite plane therapy. The symptomatic side did not associate with the side of fewer occlusal contacts in intercuspal position, no canine contact on the working side, occlusal contact on the non-working side, or unilateral contact in retruded contact position. The results of this study suggest that pain or clicking does not necessarily tend to appear on the side of these occlusal interferences. Additionally, characteristic inclination for pain and clicking patients in terms of frequencies of occlusal interferences in relation to the symptomatic side was not identified.

Background: Most Japanese pediatric neurologists attempt other treatments before using adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS), and even then, they use only a low-dose synthetic ACTH to avoid serious adverse effects. In this multi-institutional study, the authors analyzed the initial effects, adverse effects, and long-term outcome in patients treated with low-dose synthetic ACTH in Japan. Methods: The medical records of 138 patients with WS, who were treated with low-dose synthetic ACTH therapy for the first time at the authors’ institutions between 1989 and 1998, were analyzed. Results: At the end of ACTH therapy, excellent effect on seizures was noted in 106 of 138 (76%) patients, good effect in 23 (17%), and poor effect in 9 (7%). Initial effects on EEG were excellent in 53 of 138 (38%) patients, good in 76 (55%), and poor in 9 (7%). As for seizure prognosis at the time of follow-up, 51 of 99 (52%) patients were seizure-free, whereas 48 (48%) patients had seizures. Mental outcome was normal in 6 of 98 (6%) patients, mild mental retardation in 16 (16%), moderate mental retardation in 26 (27%), and severe mental retardation in 50 (51%). The initial effects of ACTH on seizures and long-term outcome were not dose dependent (daily dosage 0.005 to 0.032 mg/kg, 0.2 to 1.28 IU/kg; total dosage 0.1 to 0.87 mg/kg, 4 to 34.8 IU/kg). The severity of adverse effects correlated with total dosage of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily dosage and total dosage of ACTH. Conclusion: Low-dose synthetic ACTH therapy is as effective for the treatment of WS as the higher doses used in previous studies. The dosage of synthetic ACTH used in the treatment of WS can be decreased as much as possible to avoid serious adverse effects.

Twenty patients with West syndrome were initially treated with high-dose vitamin B6 (40 to 50 mg/kg/day) and valproate (40 to 50 mg/kg/day). Three became seizure free. For the remaining 17 patients, low-dose synthetic ACTH (0.01 mg [0.4 IU]/kg/day) was added to the regimen. One month after the end of ACTH therapy, 13 patients were seizure free. Thus 16 patients in total(80%) were free of seizures(group A). The treatment was ineffective for the remaining 4 patients (20%; group B). During the following for a mean period of 64 months (range, 48 to 83 months), 9 in group A had a relapse of epileptic seizures. However, only 4 in this group had epileptic seizures at the end of the study (5-7 years of age), all of which were partial and infrequent. In group B, two had frequent intractable seizures, and one was seizure free at the end of the study. One died at the age of 1 year. In group A, 2 patients showed normal or subnormal mental development. Mild, moderate and severe mental retardation were seen in 3, 4 and 7 patients respectively. In group B, all patients showed severe mental retardation. In this study, the rate of evolution into intractable epilepsy was low, but long-term mental development was poor. Seizure control by itself seemed to be insufficient to improve long developmental prognosis of West syndrome.

To prevent treatment withdrawal due to flutamide-induced liver dysfunction, we performed maximum androgen blockade (MAB) therapy by combining a luteinizing hormone-releasing hormone agonist or orchiectomy with low-dose flutamide (125 mg x 2/day) in patients with prostate cancer. In this study, the efficacy, adverse effects such as hepatotoxicity, and compliance were compared retrospectively between 35 patients who received low-dose flutamide therapy (1995-1999) and 27 patients who received flutamide at its ordinary dose (125 mg x 3/day). No significant difference was observed in the response rate (or = PR) as determined from the prostate-specific antigen parameter (p = 0.6211) or the incidence of hepatotoxicity based on the aspartate aminotransferase and alanine aminotransferase levels. However, flutamide withdrawal due to liver dysfunction was less frequent in the low-dose group (2.9%) than in the ordinary dose group (18.5%) (p = 0.0386). MAB therapy using low-dose flutamide is expected to prevent the reduction in the compliance due to side effects and to improve the long-term prognosis in patients with prostate cancer, who are mostly elderly individuals.

Small intestinal microsomes of cynomolgus monkeys were found to catalyze hydroxylation and dealkylation of an H(1)-antihistamine prodrug, ebastine. To identify the main enzyme responsible for ebastine hydroxylation, which has been hitherto unknown, we purified two cytochrome P450 isoforms, named P450 MI-2 and P450 MI-3, from the intestinal microsomes on the basis of the hydroxylation activity. P450 MI-2 and P450 MI-3 showed the respective apparent molecular weights of 56,000 and 53,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The internal amino acid sequence of P450 MI-2 had high similarity with those of human CYP4F2, CYP4F3, and CYP4F8. The first 27 amino acid residues of P450 MI-3 were highly homologous with those of monkey CYP3A8 and human CYP3A4/5/7. Furthermore, P450 MI-2 and P450 MI-3 were recognized by anti-CYP4F and anti-CYP3A antibodies, respectively, in immunoblot analysis and catalyzed leukotriene B(4) omega-hydroxylation and testosterone 6beta-hydroxylation, which are known to be mediated by CYP4F and CYP3A, respectively. Although both enzymes had ebastine hydroxylation activity, the V(max) value of P450 MI-2 was much higher than that of P450 MI-3 (37.0 versus 0.406 nmol/min/nmol of P450), and the former K(M) (5.1 microM) was smaller than the latter K(M) (10 microM). Anti-CYP4F antibody inhibited the hydroxylation in small intestinal microsomes strongly (70%), but anti-CYP3A antibody did not. These results indicate that P450 MI-2 belongs to the CYP4F subfamily and is mainly responsible for hydroxylation of ebastine in monkey small intestinal microsomes. This suggests that the small intestinal CYP4F enzyme, P450 MI-2, can play an important role in the metabolism of drugs given orally.

Recently OPCAB has become more and more common in CABG, although one problem of OPCAB like the quality of anastomosis has not been solved yet. We discussed the usefulness of intra-operative angiography during OPCAB.During March 1997-July 2000, 55 patients underwent OPCAB (including 35 MIDCAB cases) in our institute. Graft flow and anastomosis were examined by intra-operative or immediate post-operative angiography.Immediate postoperative angiography was performed in 22 MIDCAB cases. In 15 cases an excellent graft flow without stenosis could be confirmed, in 7 cases the native LAD was so small, which caused a poor flow of the LITA and three cases needed additional PTCA because of anastomosis stenosis. Intra-operative angiography was done in 9 MIDCAB and 17 OPCAB. As a result, re-anastomosis was performed in one case of MIDCAB because of severe anastomosis stenosis, one case of OPCAB had confirmed poor flow because of a small LAD, but in 24 cases an excellent graft flow could be seen on time. In 2 cases OPCAB was combined with PTCA to achieve complete revascularization.Intra-operative angiography is a useful strategy to confirm the surgical results quickly in OPCAB (included MIDCAB). Using such a strategy, combination of OPCAB and PTCA as a new approach for complete revascularization can be performed safe and smooth.