The effect of large dose ascorbic acid supplementation on hepatotoxicity and altered immunological parameters in alcoholics without apparent liver disease was investigated. Supplementation restored serum gamma glutamyl transpeptidase (GGT) activity, serum albumin and serum immunoglobulin levels, T and B cell numbers in the peripheral circulation and ascorbic acid amd dehydroascorbic acid levels both in plasma and leucocytes. This suggests an important role for ascorbic acid in combating free radical mediated damage and impaired immunological function in alcoholics.

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This study focused on developing a Health Risk Index for school children, including various indicators of lifestyle-related diseases that specify levels of degree of overweight corresponding to an increase in the Health Risk Index. Children from three elementary schools (297 nine-ten year olds) and three junior high schools (329 twelve-thirteen year olds) underwent rigorous physical examinations comprising calculation of levels of total cholesterol, HDL cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose, hemoglobin A_1c (HbA_1c), insulin and measurement of height, weight and blood pressure (SBP and DBP) . Four serum indicators, specifi-cally, atherosclerosis index (on cardiovascular disease), SBP (on hypertension), ALT (on liver dysfunction) and insulin (on diabetes) were associated with degree of overweight by multiple regression analyses. We formulated a Health Risk Index using these four variables to evaluate the future risk of lifestylerelated diseases. The Health Risk Index was significantly higher in children who were over 20% overweight than those under 0%. Extremely overweight children (degree of overweight 30%) displayed an approximately 8-12 times higher Health Risk Index than children of normal weight (degree of overweight : 0-10%) . The risk of future lifestyle-related diseases is possibly higher in children who are more than 20% overweight. Positive action for overweight children, such as controlling calorie intake in conjunction with daily exercise, is recommended to prevent obesity and related diseases.

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It has been reported that previous participation by subjects in Phase I studies may influence the incidence of adverse events; however, the relationship between them remains to be determined. Therefore, we compared the incidence of adverse events in first time drug trial subjects receiving active drug or placebo treatment at our institute with subjects who had been previously enrolled in a Phase I study. We retrospectively reviewed the adverse events reported in 26 single-dose studies (PK.) involving 939 healthy male volunteers (active drug 667, placebo 272) . The overall incidence of adverse events in subjects receiving an active drug was 16.0% (13.6% in the subjects who participated only once, 18.0% in those who participated more than once, P=0.194) whilst the frequency of adverse events in subjects receiving a placebo was 10.7% (14.4% in subjects who participated only once, 8.1% in those who participated more than once, P= 0.137) . The incidence of adverse events in the subjects who participated once and those who participated more than once was not significantly different with either active drug or placebo treatment. The number of times a subjects had participated in a drug study did not affect the incidence of adverse events in single-dose Phase I studies at our institute.

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Physiological responses to riding a scooter (scootering) are compared with walking, running and cycling at three different treadmill speeds (80, 110 and 140m min^-1) and slopes (0%, 4% and 8 %) . Five healthy male college students performed all exercises at different intensities in four trials a day, one or two days a week. Each experiment comprised of a 5-20 minute resting period, followed by 3 minutes of exercise and 10-50 minute recovery time. Apart from stationary cycling to measure maximal oxygen uptake, all exercises were performed on a treadmill. Heart rate (HR), oxygen uptake (VO₂), carbon dioxide production (VCO₂), pulmonary ventilation (VE), respiration rate (RR) and respiratory exchange ratio (RER) were measured every 15 seconds, and averaged using a computerized breath-by-breath expired gas monitor. From these measurements, the ventilation equivalent for CO₂ (VE/VCO₂) was calculated. No significant differences in the HR-VO₂ relation with exercise intensity were observed among the different types of exercise. The slopes of the regression lines for VE-VO₂ and RER-VO₂ in scootering were steeper than those in other exercises (p<0.05) . A significant correlation was noted between stroke frequency and RR in scootering (R=0.727, p <0.001) . Measurement of the changes in VE/VCO₂ during scootering at 73, 80 and 90% VO₂max revealed a notably (p<0.05) larger ‘short period of depression’ (undershooting) with a peak around 30 seconds after exercise, which was rarely observed with the other exercises examined. These results suggest that the cardiorespiratory responses to scootering differ from those to walking, running and cycling, due to the unique locomotion pattern of this vehicle.

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We investigated the TEM-type extended spectrum beta-lactamases (ESBLs) in cefotaxime-resistant S. marcescens strains by means of a 24-month retrospective study between October 1996 and September 1998 at Showa University Hospital. Among the 579 S. marcescens strains isolated during this period, 51 were resistant to cefotaxime. We tested the expression of ESBLs in the cefotaxime-resistant strains using the disk susceptibility test with cefotaxime and cefotaxime / clavulanic acid. We then amplified the betalactamase gene in each strain by the polymerase chain reaction (PCR) .
The inhibition diameters observed with cefotaxime and cefotaxime plus clavulanic acid were similar in all of the resistant strains, suggesting that the cefotaxime-resistant S. marcescens strains do not express ESBLs. Sequence analysis of the PCR-amplified beta-lactamase gene from clinical isolates of the cefotaxime-resistant strains identified it as TEM-lb. We detected the TEM-type beta-lactamase genes, TEM-1a and TEM-1b, in four cefotaximesensitive strains. In the TEM-1a-like gene of a cefotaxime-sensitive strain, we found one base substitution at nucleotide position 753 (C to A) causing an amino acid substitution from alanine 184 to valine. No ESBL TEM enzymes were found among these strains, but we isolated a novel TEM-type enzyme.
The cefotaxime-resistant S. marcescens isolates, like many gram-negative enterobacteria, had the TEM-1b gene of beta-lactamase. Resistance to cefotaxime seemed to have been acquired through other ESBLs, cephalosporinases or carbapenemases, and not through TEM-type ESBLs.

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Prognostic factors were determined retrospectively in surgical patients with pathologically staged T3 lung cancer invading adjacent organs. Of 304 patients who underwent pulmonary resection for primary non-small cell lung cancer, 39 (13% ) had contiguous spread to a rib (n=16), the parietal pleura (n=13), the pericardium (n=7), or the diaphragm (n=3) and underwent en bloc resection. A complete resection was achieved in 33 cases (85%) . Five-year survival rates of patients who received complete versus incomplete resection were 33% and 20%, respectively (p<0.05) . Five-year survivals of patients whose cancer was detected by mass screening (n=8) and by tumor-related symptoms (n=25) were 73% and 33%, respectively, and the 3-year survival rate of patients whose cancer was detected incidentally during a work-up for another disease (n = 6) was 15% (p< 0.05) . The 5-year survival rate for patients with T3N0 lesions (n=22) was 47%, and the 3-year survival rate for those with T3N 1, 2 lesions (n=17) was 0% (p<0.01) . Five-year survival figures for squamous cell carcinoma (n=17) and adenocarcinoma (n=16) patients were 60% and 15%, respectively (p<0.05) . No patient with either adenosquamous cell carcinoma (n=2) or large cell carcinoma (n= 4) survived for longer than 3 years. Five-year survival rates following rib resection, parietal pleurectomy, or pericardial resection were 15%, 25%, and 75%, respectively. The 3-year survival rate after diaphrag-matic resection was 50%. The survival rate differences were significant (p< 0.05) between treatment by pericardial resection and rib resection or parietal pleurectomy, but not between the patients with rib resection and pleurectomy (p>0.05) . No patient who underwent first or second rib resection survived for longer than 3 years (n=6), while the 5-year survival rate after third or lower rib resection (n=10) was 22% (p<0.05) . Multivariate analyses revealed that the lymph node status (p<0.01) and site of invasion (p<0.05) to be significant prognostic factors for this patient group. In conclusion, lymph node status, histological type, invaded structures, and level of rib resection affected the survival rates for surgically treated patients with T3 primary lung cancer invading adjacent structures. Of these, lymph node status and level of rib resection significantly affected patient prognosis.

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Using a guinea pig model, we examined the mechanism of cell loss in experimental pancreatitis by immunohistochemistry and electron microscopy. Acinar cells in pancreatitis foci were completely deleted by one week, and proliferation of pancreatic ductuli appeared at three days, increased by two weeks, and then decreased by six months. Approximately 30% of acinar cells in the pancreatitis foci were positive with TUNEL immunohistochemistry at three days. By one week, numbers of positive cells had decreased. TUNEL-positive ductular cells appeared at three days, increased by two weeks, and then gradually decreased by three months. At three days, most acinar cells showed necrotic change by electron microscopy, with some cells undergoing apoptosis. Proliferated ductular cells did not show necrotic change, but were undergoing apoptosis continuously from one week to six months, therefore apoptosis does participate in the course of ductular deletion. As apoptosis is a mechanism of silent cell death carrying no inflammatory aggregates, it should be favorable for pancreatic ductuli to be deleted by apoptosis in the healing state of pancreatitis. It is concluded that apoptosis, rather than acinar cell loss, plays a major role in subsequent loss of proliferated pancreatic ductuli in experimental pancreatitis.

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We investigated the relationship between pathological data and chromosome copy number in 27 colorectal carcinomas. The copy number of pericentromeric sequences on chromosomes (ch) 7, 17 and 20 was estimated by fluorescence in situ hybridization (FISH) within interphase nuclei from frozen sections of touch preparations. Polysomy for ch7 was found in 74.1% (20/27) of cases, and in 89.5% (17/19) of Dukes' C cases (P<0.05) . Polysomy of ch7 correlated with the ly factor and lymph node metastasis (P<0.05) . Nine of 11 (81.1%) of cases with liver metastasis showed trisomy of ch20, compared with 5 of 16 cases (31.2%) without liver metastasis. Polysomy of ch 17 was found in 70.4% (19/27) of cases, however no correlation was found between polysomy of ch 17 and pathological factors. Trisomy of ch20 was significantly correlated with liver metastasis (P<0.05) . Accordingly, ch20 copy numbers were examined in 11 cases of metastatic liver tumors and they similarly showed trisomy of ch20 in 9 cases (81.8%), indicating that trisomy of ch20 correlates with liver metastasis. This study suggests that the analysis of ch7 and ch20 copy numbers in primary tumors of colorectal carcinoma may be predictive for lymph node metastasis and liver metastasis, respectively.

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The present study examines the level of secondary hyperlipidemia in a useful model of doxorubicin (DOR) -induced nephrotic rats, and the hypolipidemic effects of fenofibrate (FF) and bezafbrate (BF) on this model. A single intravenous administration of DOR at 5 mg / kg showed mild nephrotic symptoms, and a slight increase in serum lipid levels. DOR at the dose levels of 7.5 and 10 mg / kg caused severe nephrotic syndrome and hyperlipidemia. However, rats with DOR at 10 mg / kg showed distinct differences in the degree of nephrotic and hyperlipidemic levels, and the abnormal behavioral profiles observed, such as piloerection, emaciation and hyperirritability. Therefore, rats administered 7.5 mg/kg of DOR seemed to be a useful model for evaluating the efficacy of hypolipidemic drugs. FF and BF inhibited increases in TC, TG, LDL, VLDL, and chylomicron induced by the administration of DOR at 7.5 mg/kg. The low dose of FF and BF especially inhibited secondary hyperlipidemia caused by the nephrotic syndrome without the exacerbation of nephrotic symptoms. These results suggest that FF and BF may also inhibit secondary hyperlipidemia induced by other diseases such as diabetes, cholestasis and hypothyroidism.

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To investigate the malignant potential of T1 sized type-D and type-F pulmonary adenocarcinoma (PA), the proliferative and invasive growth potentials of the tumor cells were examined. Ten surgically resected cases of type-D PA and eight cases of type-F PA, each classified as T1 and less than 3 cm in the largest dimension, were selected for this study. None of these cases had received pre-operative chemotherapy or radiotherapy. Using the Ki-67 labeling index (LI) for tumor cells, which indicates the proliferating growth potential, tumors averaged 42.80±19.66% in type-D PA, and 28.38±6.58% in type-F PA. This labeling index showed specific relationships with tumor dimension and lymph node involvement in both type-D and type-F PA. The cathepsin D-positive rate, indicative of invasive growth potential, was 70.0% in type-D PA, and 50.0% in type-F PA. The cathepsin D-positive rate showed specific relationships with tumor dimension and level of lymph node involvement in type-D PA, but only with dimension in type-F PA. We conclude that the malignant potential of type-D PA depends on the Ki-67 LI and the cathepsin D expression in the tumor cells, however for type-F PA the malignant potential depends on the Ki-67 LI. These findings should be useful in determining prognosis in routine pathologic examinations.

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Anal fissures rarely occur in patients with ulcerative colitis. Here we report a 26-year-old man diagnosed with ulcerative colitis involving intractable anal fissures. The patient underwent restorative proctocolectomy for ulcerative colitis and sliding skin graft (SSG) for intractable anal fissures. Anal function was monitored by a manometric study. Generally, patients subjected to pouch surgery should retain fairly well-preserved anal sphincter muscle structure and function. A manometric study confirmed that SSG was an effective procedure for the preservation of the sphincter in patients receiving restorative proctocolectomy for ulcerative colitis and intractable fissures.

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