A total of 210 isolates of Streptococcus pneumoniae (S. pneumoniae) were selected randomly to examine drug susceptibility which were obtained from out-and in-patients who visited Kurume University Hospital and other affiliated hospitals through May 1998 to September 1999. The prevalence of penicillin resistant S. pneumoniae in this study was 39.5% and was compatible with those of previous reports in Japan. From the clinical aspects, the resistant strains of S. pneumoniae have been shown not to be so highly virulent comparing with sensitive strains that only few severe or mortal cases had been reported. Carbapenems, glycopeptides, and fluoroquinolones were shown to be highly active against penicillin-resistant S. pneumoniae strains as evidenced by the low minimum inhibitory concentrations (MICs) though LVFX showed 4μg/ml or higher MICs against some strains. Regarding to the mechanisms of penicillin resistance, penicillin binding proteins coding gene (pbp1a, pbp2x and pbp2b) mutations that cause modifications in these proteins were also examined for all isolates. The multivariate analysis showed statistically significant correlation between higher MIC of penicillin and cephem and pbp1a mutation while no significant contribution of pbp2x and pbp2b to the resistance was demonstrated. Additionally, no significant correlation between pbp mutation and MIC of carbapenem was observed. Furthermore, there were two highly penicillin resistant S. pneumoniae strains with no pbp mutations. Thus the pbp mutations alone were not responsible for the elevation of MIC all β-lactams. Nevertheless the pbp mutations were detected in advance of actual MIC elevations by inducement experiment in vitro. It indicated that penicillin resistance might be detected earlier than conventional methods. In previous reports some other responsible genes for penicillin resistance were demonstrated. Therefore, it might be possible to presume exact values of MICs of β-lactams against resistant strains of S. pneumoniae by detecting still unknown genes other than pbps.

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Patients with non-small cell lung cancer who develop fever during anti-neoplastic chemotherapy are treated empirically, before the cause of fever has been determined. Little study has been made of episodes of infection during chemotherapy with respect to antineoplastic response, other adverse reactions, or survival time. In particular, the relationship between fever and long-term survival is not clear. The prognostic significance of febrile episodes was investigated in patients with non-small cell lung cancer receiving full-dose chemotherapy. Most were treated only with chemotherapy during the period of investigation, although some had concurrent or subsequent radiotherapy, and a few had surgery following chemotherapy. No significant difference was seen between febrile and afebrile patients regarding therapeutic modality. Patients with poor perfor mance status (PS) had a higher incidence of febrile episodes (P<.001). Multivariate analysis, however, showed febrile episodes to be a major prognostic factor independent of PS on clinical stage. PS and stage affected short-term survival, while febrile episodes were related to decreased long-term survival (203 vs. 366 days; with deaths in the first 3 months excluded, 241 vs. 377 days). Although existing evidence is inconclusive, our study suggests that prevention of infection during antineoplastic treatment by administration of granulocyte stimulating factors and early initiation of antimicrobials might improve long-term survival.

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To investigate the usefulness of bronchoscopy for the diagnosis of Mycobacterium avium complex (MAC) pulmonary disease, we retrospectively reviewed the clinical charts, and radiographic and bacteriologic findings of all patients who were admitted to our hospital between 1994 and 2000, and who fulfilled the 1997 American Thoracic Society (ATS) criteria for MAC pulmonary infection. A total of 132 patients were diagnosed as affected by MAC pulmonary disease during that period. Of these, bronchoscopic examination was performed in those patients who showed negative sputum smear for mycobacteria on three consecutive days (n=43) or who could not expectorate sputum (n=2). Of 42 patients, sputum culture was positive for MAC in 34 patients (81.0%). Bronchial washing sample was smear-positive for MAC in 17 of 39 patients (43.6%), and culture-positive for MAC in 33 of the 39 patients (84.6%). Transbronchial lung biopsy (TBLB) specimens revealed specific findings (epithelioid cell granuloma and/or acid-fast bacilli) in 14 of 38 patients (36.9%). Bronchial washing of all patients who showed specific histology in TBLB grew MAC in culture. Based on the bronchoscopic examination, we could diagnose MAC pulmonary disease in 36 patients. In addition, smear and polymerase chain reaction (PCR) results of bronchial washing made possible an early diagnosis of MAC pulmonary disease in 15 patients. We examined the relation of CT findings to bronchial washing results. Isolation of MAC in bronchial washing is significantly related to small nodular opacity around the ectatic bronchi on the CT scan (p=0.016). In our retrospective study, in sputum smear-negative patients with MAC pulmonary disease, MAC isolation by culture of bronchial washing was no more frequent than that with sputum culture. However, bronchial washing is useful to differentiate infection from casual isolation of MAC. In addition, we could make early diagnosis of MAC pulmonary disease based on smear and PCR results of bronchial washing. To make a diagnosis of MAC, bronchial washing is superior to TBLB, and should be done in the bronchus which drains the area revealing small nodular opacity around ectatic bronchi.

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Of the 139 patients who underwent excision for invasive cancer in the pancreatic duct at Kurume University Hospital between January 1965 and December 1998, the subjects were 38 patients in whom blood vessels around the cancer were simultaneously excised. The surgical methods were pancreatoduodenectomy (PD) in 31 patients, distal pancreatectomy (DP) in 5, and total pancreatectomy (TP) in 2. The excised blood vessels were the portal vein alone in 32 patients, the artery alone in 1, and both portal vein and artery in 5. Excision of the portal vein was performed by circumcision in 25 patients and by segmentectomy in 12. The range of circumcision was 1.0-7.0 cm (mean, 3.5±1.4cm), and the blocking time of the portal vein was 8-36min (mean, 19.5±8.8 min). Of the 25 patients who underwent circumcision, reconstruction was performed by end-to-end anastomosis in 23 and by transplantation of the autologous vein between the ends in 2. Of the 12 patients who underwent segmentectomy, direct suture was performed in 10, and transplantation of an autologous vein patch was performed in 2. Postoperative complications occurred in 14 of the 32 patients. In 5 of the 6 patients who underwent excision of the artery, reconstruction was performed by end-to-end anastomosis in 3 and by transplantation of the autologous vein between the ends in 2. Postoperative complications did not occur in the patient who had undergone excision of the artery alone, but 4 of the 5 patients who had undergone simultaneous excision of the portal vein and artery had postoperative complications, of whom 2 died during the period of hospitalization. Three patients with pv₀, pv₁ or pv₂ survived for more than 3 years. Because some of the patients who had undergone excision of the portal vein alone survived for a long time and this method is relatively safe, this surgery can be generally applied, but simultaneous excision of the portal vein and artery should be carefully applied because the incidences of postoperative complications and death during the period of hospitalization are high. With the development of surgical techniques and postoperative control, simultaneous excision of pancreatic cancer and the surrounding blood vessels has become safe, but this method should only be applied to patients who have the potential to recover completely.

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The aim of this study is to evaluate the efficacy of targeted screening on the basis of the results from the universal screening of Japanese children. A total of 698 children consisting of 348 in the 3rd grade of elementary school (third graders) and 350 in the 3rd grade of junior high school (ninth graders) were enrolled in one local school district, during the period 1985 to 1998. When body mass index was used as the sole indicator, the sensitivity in detecting hypercholesterolemia was 14.3% in the case of third graders, and 14.7% in that of ninth graders. Family history was investigated through a questionnaire inquiring about the history of 6 atherosclerosisrelated diseases in 6 relatives. The sensitivity on the basis of family history was calculated as 0% to 54.5%. According to the atherosclerotic index calculated from the measured levels of total and HDL cholesterol, sensitivity of abnormal levels of atherosclerotic index in children was almost the same as those of hypercholesterolemia. Using targeted screening, it was possible to detect only around half or less of the subjects with hypercholesterolemia. With respect to the sensitivity of the screening, universal screening is recommended for detecting hypercholesterolemia in Japanese children.

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To elucidate the origin of transient heart murmur during the late neonatal period, we examined 50 neonates with this type of heart murmur and compared them with 50 controls. We serially examined the morphology of and blood flow in the main pulmonary artery (MPA), the right pulmonary artery (RPA), and the left pulmonary arteries (LIDA) using two-dimensional and Doppler echocardiography. The heart murmurs were first noticed at 6 to 60 days after birth (mean 33±14). At that time, the diameters of both the RPA and the LPA in the heart murmur group were significantly smaller than those in the control group, and the velocities of blood flow in the right and left pulmonary arteries in the heart murmur group were significantly greater than those in the control group. When the heart murmur disappeared, the diameters and the flow velocities of both the RPA and the LPA were not different compared with the control group. Two cases in the heart murmur group continued to have a heart murmur and were diagnosed as having intrinsic congenital peripheral pulmonary artery stenosis. In conclusion, our findings suggest that a transient heart murmur in the late neonatal period is caused by transient branch pulmonary arteries stenosis during the transitional circulation from fetus to neonates.

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We demonstrated transmission of human cytomegalovirus (HCMV) from the human lung fibroblast MRC-5 to peripheral blood leukocytes (PBLs). mRNA of the HCMV immediately early (IE) antigen was detected in PBLs cultured with IL-2 or IL-2+ IL-4 that made direct contact with HCMV-infected MRC-5, whereas it was not detected in PBLs prevented from making cell-to cell contact. However, mRNA of HCMV IE was not detected in PBLs cultured with IL-2 and IFN gamma that made direct contact with HCMV-infected MRC-5. Transmission of the pp65 antigen was increased in culture medium containing IL-4. At a higher viral infection titer, cell-free HCMV infected adherent PBLs cells. The subset, which did not adhere, did not infect cell-free viruses even at a very high multiplicity of infection. Moreover, the adhered subset of PBLs infected with HCMV was able to transmit HCMV to non-infected fibroblasts. Our results suggest that cell-to-cell contact (when PBLs make direct contact with HCMV-infected cells) is important in the mechanism of HCMV transmission and that the adherent cells of PBLs are one of the most important vehicles for HCMV infection. Moreover, we suggest that type 2 cytokines such as IL-4 enhance the transmission of HCMV to PBLs.

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Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors. This study aimed at clarifying the clinical significance of the changes in the serum VEGF (S-VEGF) concentrations in patients with lung cancer during anticancer chemotherapy. Subjects comprised 29 patients with lung cancer (13 adenocarcinomas, 7 squamous cell carcinomas, and 9 small cell carcinomas) who were treated with cisplatin-based chemotherapy. S-VEGF was measured by ELISA. We compared the S-VEGF concentrations between the responders and nonresponders to anticancer chemotherapy. S-VEGF concentrations before treatment of the chemotherapy (pretreatment S-VEGF concentrations) were correlated with the number of WBC, neutrophil count, monocyte count and platelet count but not the lymphocyte count. The mean pretreatment S-VEGF concentrations in responders and those in nonresponders were not significantly different, 509.7 pg/ml in the former and 382.8 pg/ml in the latter, respectively. The SVEGF concentrations in the responders decreased to a mean of 356.0 pg/ml and 304.1 pg/ml during and at the end of therapy, respectively while those in the nonresponders increased to a mean of 474.2 pg/ml and 598.4 pg/ml during and at the end of therapy. The S-VEGF concentration changes in the responders were significantly different from those in the nonresponders (p=.006). The S-VEGF concentration may relate to tumor burden, however it may not be a good marker for tumor burden, because it can be influenced by various factors such as neutrophil which increases during infection. A decrease in S-VEGF concentrations may improve neoangiogenesis and the immune response, and may correlate with improvements in the quality of life and survival of patients.

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To better understand immune mechanisms involved in onset of cytomegalovirus pneumonia, we initially examined the replication of a low virulence strain of mouse cytomegalovirus (MCMV) in nude and BALB/c mice infected by intranasal inoculation. MCMV was detected by plaque assay in the salivary glands of nude mice from days 3 to 16, and in those of BALB/c mice from days 7 to 11. Nude mice became infected with MCMV earlier than BALB/c mice. Moreover, MCMV-DNA was detected in the salivary glands until day 16 after MCMV inoculation in nude and BALB/c mice. However, we did not find evidence of interstitial pneumonia at day 16 in either BALB/c or nude mice. These results suggest that this system represents a latent infection model in BALB/c mice and a persistent infection model in nude mice. We treated latently infected BALB/c mice with methylprednisolone or IL-4 every other day. The mice treated with IL-4 developed interstitial pneumonia, whereas those treated with m-PSL did not. In the present study, we constructed a model of MCMV latent infection that could be used to induce development of interstitial pneumonia. IL-4 appears to be a key cytokine for onset of interstitial pneumonia in mice with latent MCMV infection.

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It was previously reported that SART3 is a tumor-rejection antigen recognized by HLA-A24-restricted cytotoxic T lymphocytes (CTLs). This study investigated expression of the SART3 antigen in oral cancer as a candidate of tumor antigens for use in specific immunotherapy. The SART3 antigen was detected in all of the oral cancer cell lines tested, 24 of 31 (77%) oral cancer tissue samples, 0 of 3 oral benign tumors and 0 of 3 normal oral tissues. Oral cancer cell lines had the ability to stimulate IFN-γ production by the HLA-A24-restricted and SART3-specific CTLs that were established from the peripheral blood mononuclear cells (PBMCs) of an esophageal cancer patient. Therefore, the SART3 antigen could be an appropriate vaccine candidate for a large number of oral cancer patients.

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Fetal echocardiography has been used for the noninvasive evaluation of human fetal cardiac anatomy, function, and hemodynamics. The purpose of the present study was to use Doppler echocardiographic methods to measure diastolic flow velocity patterns across the tricuspid and mitral valves in human fetuses during gestation. Fifty normal fetuses, 35 fetuses with intrauterine growth retardation (IUGR), and 30 fetuses of diabetic mothers (DM) were studied. Peak flow velocities during early diastole (peak E wave) and peak flow velocities during atrial contraction (peak A wave) were measured, and the peak EtA ratio was calculated. The peak E/A ratio of the left ventricle in fetuses increased gradually with increasing gestational age (r=0.57, p<0.05), and the peak EtA ratio of the right ventricle in fetuses increased linearly with increasing gestational age (r=0.48, p<0.05). In early gestational age, the peak EtA ratios of both the left and right ventricle in fetuses with IUGR and of DM were not significantly different from those in the controls. However, in late gestational age, the peak EtA ratios of both the left and right ventricle in fetuses with IUGR and of DM were significantly smaller than those in the controls. This gradual decrease in the peak EtA ratio during gestation may represent the maturational or developmental alteration of diastolic cardiac properties in utero. Fetuses with IUGR and of DM may have abnormal diastolic cardiac function in later gestation.

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We monitored the effectiveness of lymphoma therapy by measuring the serum levels of soluble CD44std (sCD44std) and soluble CD44v6 (sCD44v6). Furthermore, we measured the level of soluble interleukin 2 receptor (sIL-2R). A total of 24 patients with non-Hodgkin's lymphoma were enrolled. sCD44std, sCD44v6, and sIL-2R on serum were measured using ELISA system. In all patients, only the sIL-2R level decreased significantly following therapy. However, an analysis of CR and PR showed that the degree of decrease in the sCD44std level was significantly greater than that in the sIL-2R level. Furthermore, among the CS IV cases, only the CD44std level decreased significantly after therapy. These findings suggest that the level of serum sCD44std reflects clinical pathology more closely than the level of serum sIL-2R in CS IV patients and those who respond well to therapy. Moreover, when T-cell and B-cell lymphomas were analyzed separately, the levels of sCD44std and sIL-2R decreased significantly after therapy in patients with Bcell lymphomas, and the degree of decrease in the sCD44std level was very significant with a pvalue of 0.0003. This suggests that when sCD44std is used as an index of treatment, it more closely reflects the treatment of B-cell lymphomas. Level of serum sCD44std should prove to be a useful marker for assessing the effectiveness of lymphoma therapy.

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Although intermaxillary fixation (IMF) is performed to treat the patients with maxillary fracture, this procedure is very stressful to the patients. IMF has been reported to increase noradrenaline (NA) release in the brain and elevate plasma corticosterone contents in the rat. These changes were significantly attenuated by diazepam, an anxiolytic of the benzodiazepine family. These results suggest that IMF could greatly affect the pituitary-adrenal system as a stress. In the present study, in order to examine the influence of IMF on the human body function, we measured levels of 17-hydrocorticosteroids (17-OHCS) and 17-ketosteroid (17-KS), which are metabolites of the adreno-cortical hormone cortisol, in the urine of inpatients undergoing IMF. The subjects were requested to fill out a questionnaire on irritableness caused by IMF. In these patients, urinary 17-OHCS levels were significantly increased after IMF and well correlated to the results of the questionnaire. The finding suggested that urinary 17-OHCS levels reflect stress related to IMF, and that such stress mainly causes an irritated feeling. Natural killer cell activity (NK activity), which is considered to be related to stress, was measured in these patients. The relationship between 17-OHCS levels and NK activity was examined in reference to the results of the questionnaire. Questionnaire showed that most patients noted insomnia and an irritated feeling during IMF. To examine the influence of anxiolytic agents on stress related to IMF, an anxiolytic agent, ethyl loflazepate, was administered during IMF, and urinary 17-OHCS levels were measured. There was no correlation between 17-OHCS levels and NK activity in the patients. Furthermore, no correlation was observed between visual analogue scale (VSA) and NK activity. Increases in 17-OHCS levels in the group treated with ethyl loflazepate, an anxiolytic of the benzodiazepine family, were significantly lower than in the untreated group. This suggests that ethyl loflazepate reduced stress responses to IMF. It has been reported that NK activity is reduced inpatients with depression or chronic fatigue syndrome. However, NK activity may not be affected by mechanical stress such as IMF. The finding that an anxiolytic agent, ethyl loflazepate, inhibited stress responses to IMF further suggests that anxiolytic drugs are very useful for treatment of irritated feeling of the patients undergoing IMF.

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Reovirus isolates from human, striped-field mouse (Apodemus agrarius) and Korean field mouse (A. peninsulae) in Korea showed extensive variability in the patterns of electrophoretic migration of the double-stranded RNA (dsRNA) genome segments. Hemagglutination inhibition (HI) test was performed for serotype determination of 12 reovirus isolates. To clarify genetic diversity and molecular phylogeny of Korean reoviruses, L1, S3 and S4 genomic segments of reoviruses were amplified by RT-PCR and directly sequenced. Among 12 reovirus strains, 9 strains were type 3 and 3 strains were type 2. The L1 was highly conserved showing 91.5-100%, 94.7-100% similar ities among Korean isolates, and 77.5-97.9%, 92.6-96.8% similarities compared to other reference strains of each genotypes at nucleotide and amino acid levels, respectively. In S3 and S4 segments, 84.4-99.3%, 72.3-99% nucleotide sequence similarities and 92-99.3%, 89.1-98.4% amino acid sequence similarities among Korean isolates were observed, and 70.8-93.9%, 72.3-98.7% nucleotide sequence similarities and 81.8-100%, 88.3-97.7% amino acid sequence similarities compared with other reference strains of each genotype were observed, respectively. Phylogenetic analyses based on the S3 and S4 nucleotide sequences indicate that genotypes of reovirus are more related with geographic differences rather than host species or date of isolation.

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