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Background Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691

It is not known whether perioperative chemotherapy, compared with adjuvant chemotherapy alone, improves disease-free survival (DFS) in patients with upfront resectable colorectal liver metastases (CLM). The aim of this study was to estimate the impact of neoadjuvant 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) on DFS in patients with upfront resectable CLM.Consecutive patients who presented with up to five resectable CLM at two Japanese and two French centres in 2008-2015 were included in the study. Both French institutions favoured perioperative FOLFOX, whereas the two Japanese groups systematically preferred upfront surgery plus adjuvant chemotherapy. Inverse probability of treatment weighting (IPTW) and Cox regression multivariable models were used to adjust for confounding. The primary outcome was DFS.Some 300 patients were included: 151 received perioperative chemotherapy and 149 had upfront surgery plus adjuvant chemotherapy. The weighted 3-year DFS rate was 33·5 per cent after perioperative chemotherapy compared with 27·1 per cent after upfront surgery plus adjuvant chemotherapy (hazard ratio (HR) 0·85, 95 per cent c.i. 0·62 to 1·16;Compared with adjuvant chemotherapy, perioperative FOLFOX does not improve DFS in patients with resectable CLM, provided adjuvant chemotherapy is given successfully.Se desconoce si la quimioterapia perioperatoria en comparación con la quimioterapia adyuvante sola mejora la supervivencia libre de enfermedad (Se incluyeron pacientes consecutivos que presentaban hasta cinco CLM resecables en dos centros japoneses y dos centros franceses entre 2008 a 2015. Ambas instituciones francesas favorecían FOLFOX perioperatorio, mientras que los dos grupos japoneses utilizaban sistemáticamente la cirugía de entrada y quimioterapia adyuvante. Se utilizaron la probabilidad inversa del tratamiento ponderado (Se incluyeron 300 pacientes (grupo de quimioterapia perioperatoriaEn comparación con la quimioterapia adyuvante, el FOLFOX perioperatorio no mejora la DFS en CLM resecables siempre y cuando la quimioterapia adyuvante se administre de forma efectiva.

To determine responses to tocilizumab between patients with rheumatoid arthritis (RA) who switched to anti-TNF agents and those who are biologics-naïve.This retrospective study investigated 107 patients with RA who were treated with tocilizumab. At baseline, 61 of them had already been treated with anti-TNF agents (switched group; 46 for inefficacy and 15 for adverse events), and 46 were biologics-naïve (naïve group). Treatment responses to tocilizumab at week 12 and 24 were compared between the switched and naïve groups using the disease activity score 28 (DAS28).Forty-two (91.3%) and 50 (82.0%) patients in the naïve and switched groups, respectively, completed 24 weeks of tocilizumab treatment. The DAS28-ESR and DAS28-CRP values (means±SD) at weeks 12 and 24 compared to baseline decreased significantly for the naïve and switched groups. The DAS28-ESR and DAS28-CRP values at weeks 12 and 24 were significantly decreased in the naïve group, compared to the switched group. Disease activity was improved in the naïve patients compared to the switched patients.Tocilizumab was safe, tolerable, and clinically effective for patients with inadequate responses to anti-TNF therapy and for those who were biologics-naïve, and it was more effective among the latter.

serum against SBC-3/DOX cells to a similar extent compared with parental SBC-3 cells. Pretreatment of human effector cells with various cytokines induced further enhancement of the KM966-dependent ADCC against SBC-3/DOX cells. Intravenous injection of SBC-3 or SBC-3/DOX cells into natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice developed metastases in multiple organs (liver, kidneys and lymph nodes). Interestingly, SBC-3/DOX cells produced metastases more rapidly than SBC-3 cells, suggesting more aggressive phenotype of SBC-3/DOX cells than their parental cells in vivo. Systemic treatment with KM966, given on days 2 and 7, drastically inhibited the formation of multiple-organ metastases produced by both SBC-3 and SBC-3/DOX cells, indicating that KM966 can eradicate metastasis by SCLC cells irrespective of MDR phenotype. These findings suggest that the mouse-human chimeric KM966 targets the GM2 antigen, and might be useful for the immunological circumvention of multiple-organ metastases of refractory SCLC.

A 37-year-old man was admitted to our hospital complaining of dry cough and dyspnea. His chest radiographs showed severe bullous changes in the upper lobes and scattered small nodules in the lower. During the course of further examination, a spontaneous left pneumothorax developed in the lung, and video-assisted thoracic surgery was performed to remove a bulla. Multiple noncaseous granulomas were seen and sarcoidosis was diagnosed. Here we report a case of pathologically investigated bullous sarcoidosis, which is rarely seen to generate bullae due to granulomatous lesions. Therefore, it is important to consider sarcoidosis in making a differential diagnosis when a diffuse lung disease with cystic change is encountered.

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine with various biological activities, including augmentation of cytotoxic activity of monocytes and natural killer (NK) cells. The present study was undertaken to determine whether transfection of the MCP-1 gene into lung cancer cells affected their tumorigenicity and metastatic potential by the NK cell-mediated mechanism. The human MCP-1 gene inserted into an expression vector (BCMGSNeo) was transfected into human lung adenocarcinoma (PC-14) cells. There was no difference in in vitro proliferation between MCP-1 gene-transfected PC-14 cells and the parent cells or mock-transfected cells. The tumorigenicity and in vivo tumor growth of MCP-1 gene-transfected PC-14 cells were similar to those of the parent cells or mock-transfected cells when tumor cells were injected into the s.c. space of NK cell-intact severe combined immunodeficient (SCID) mice. Although parent cells and mock-transfected cells inoculated i.v. formed lung metastatic colonies and pleural effusion, MCP-1 gene transfectants reduced the systemic spread in NK cell-intact SCID mice. Interestingly, these modulations in a systemic spread by MCP-1 gene transfection were not observed in NK cell-depleted SCID mice. Decreased survival of MCP-1 gene transfectants in the lung was observed in NK cell-intact SCID mice but not in NK cell-depleted SCID mice. Recombinant MCP-1 or the supernatant of MCP-1 gene transfectants enhanced the cytotoxicity of human CD56+ NK cells and spleen cells of SCID mice against PC-14 cells. These findings suggest that locally produced MCP-1 suppresses tumor progression by a NK cell-mediated mechanism, depending on organ microenvironment.

Lysophosphatidic acids (LPAs) are known to be normal constituents of mammalian serum, and they mimic some biological effects of the serum. We previously reported that lysophospholipase D (LPLD) was involved in the accumulation of LPAs in incubated rat plasma and serum. In this study we detected, by gas-liquid chromatography, various molecular species of LPA in follicular fluids collected from women programmed for in vitro fertilization. When the follicular fluid was incubated at 37 degrees C for 48 h, persistent increases in the amounts of LPAs were observed concomitant with decreases in the amounts of the corresponding lysophosphatidylcholines (LPCs), although the concentrations of saturated LPCs increased in the first 6 h of incubation. These results suggest that human follicular fluid has LPLD activity, and this was confirmed by experiments with follicular fluids mixed with an exogenous radioactive LPC. The LPLD showed preference for unsaturated over saturated LPCs, similar to plasma LPLD, indicating that it originated from the circulation.

A 61-year-old man with chronic renal failure caused by polycystic kidney disease requiring hemodialysis three times weekly developed small cell carcinoma of the lung. The patient received combination chemotherapy with nedaplatin (50 mg) and etoposide (50 mg). Blood levels were monitored, showing that nedaplatin was more dialyzable than cisplatin. The patient achieved a complete response. These results suggest that nedaplatin-etoposide combination chemotherapy may be safer than cisplatin-containing regimen for patients with chronic renal failure hemodialysis and that a satisfactory response can be expected.

The TH2-type cytokines have been reported to contribute to the asthmatic response. STAT6 has an essential role in IL-4 signalling and in production of TH2 cytokines from T cells and is involved in IgE and IgG1 responses after nematode infections, indicating that STAT6 has an important role in allergic diseases.In this study we investigated the effects of STAT6 deficiency on allergen-induced airways inflammation in mice.Both ovalbumin (OVA)-sensitized STAT6 deficient (STAT6-/-) mice and wild-type C57BL/6 mice were challenged with aerosolized OVA. Changes in inflammatory cell infiltration and cytokine levels in lung tissue as well as serum immunoglobulin levels were analysed in OVA-challenged STAT6-/- and wild-type mice.The eosinophilia and lung damage normally resulting from aeroallergen challenge were not seen in STAT6-/- mice. Expression of TH2 cytokines (IL-4 and IL-5) in the lung tissue as well as IgE and IgG1 responses after OVA challenge were profoundly reduced in STAT6-/- mice, whereas expression of IFNgamma was the same in STAT6-/- mice and wild-type mice after OVA challenge. Immunocytochemical analysis of T cells showed the infiltration of CD4+ T cells but not CD8+ T cells increased into the lung of wild-type mice after OVA challenge. However, the OVA-exposed STAT6-/- mice demonstrated the infiltration of both CD4+ T cells and CD8+ T cells with a significant increase in percentage and total number of CD8+ T cells compared with OVA-exposed wild-type mice.These results indicate that factors which signal through STAT6 are important regulators of eosinophilia of allergic airway inflammation, regulating TH2-type cytokine production both in CD4+ T cells and CD8+ T cells.

Dendritic cells (DC) play critical roles in the initiation and modulation of immune responses and may determine the balance between tolerance and immunity. Viral interleukin-10 (vIL-10), encoded by the Epstein-Barr virus, is highly homologous to the "immunosuppressive" cytokine, mammalian IL-10. It impairs antigen-presenting cell function but lacks certain immunostimulatory properties of mammalian IL-10. We accomplished the following: (1) evaluated the effects of vIL-10 protein on DC phenotype and function, (2) transduced mouse bone marrow-derived DC to express vIL-10, and (3) assessed the impact of transgene expression on DC allostimulatory activity.DC progenitors propagated from bone marrow of B10 (H2b) mice in granulocyte-macrophage colony-stimulating factor plus IL-4 were repeatedly transduced by centrifugation, using retroviral supernatant obtained from the BOSC 23 ecotropic packaging cell line. To evaluate transduction efficiency, DC were transduced with the retroviral vector MFG-enhanced green fluorescence protein as a marker gene. Transgene and key cell surface molecule expression were examined by flow cytometry. The level of vIL-10 gene product in the culture supernatant was quantitated by ELISA. DC function was assessed by evaluation of the ability of DC to induce allogeneic (C3H;H2k) T-cell proliferation and cytotoxic T lymphocytes in primary mixed leukocyte reactions. Secondary mixed leukocyte reactions were used to test for T-cell hyporesponsiveness.The early addition of vIL-10 protein to cultures inhibited DC maturation and function. vIL-10 gene transfer was achieved with an approximate transduction efficiency of 35 to 40%. Transduced DC expressed vIL-10 at a level of 40 ng/10(6) cells/48 hr. In comparison with controls, vIL-10-transduced cells showed decreased surface expression of major histocompatibility complex class II and costimulatory molecules, reduced ability to stimulate T-cell proliferation and cytotoxic T lymphocyte generation, and potential to induce alloantigen-specific hyporesponsiveness.DC can be effectively transduced to express vIL-10 and limit their ability to stimulate in vitro. These genetically engineered antigen-presenting cells may have therapeutic potential to inhibit undesired immune responses to allo- or autoantigens.

Apoptosis has been suggested as a means to facilitate the resolution of eosinophilic inflammation in bronchial asthma. However, the natural course of apoptosis has not been elucidated in vivo, and there is no direct evidence for eosinophilic apoptosis within lung tissue.The purpose of this study is to clarify whether the apoptosis occurs within the lung tissue, and to define the time-course of change in apoptosis ratio during the resolution of pulmonary eosinophilic inflammation.Ovalbumin (OVA)-sensitized Balb/c mice were challenged with aerosolized OVA. We studied apoptotic cells in the lung of OVA-sensitized mice at 1, 3, 7 and 14 days after OVA challenge by in situ detection of DNA fragmentation with deoxynucleotidyl transferase deoxyuridyl triphosphatase nick endlabelling (TUNEL) technique. Apoptotic cells also were identified by electron microscopic analysis in the lung 7 days after OVA challenge.The TUNEL-method revealed that eosinophils localized in the subepithelium of bronchi undergo apoptosis following OVA challenge. Electron microscopy confirmed the presence of apoptotic cells, apoptotic bodies, and macrophages ingesting apoptotic bodies within the lung tissue. The number of apoptotic cells increased concomitantly with the increase in eosinophilic infiltration for 3 days post-challenge. However, both the apoptotic cell counts and the apoptotic ratio continued to increase even after the eosinophil count peaked, indicating rather late induction of apoptosis in the lung. In addition, TUNEL-positive cells were localized in the lung for 14 days post-challenge, indicating prolonged induction of apoptosis after the OVA challenge.Our findings constitute direct evidence of eosinophilic apoptosis in situ, and display the kinetics of apoptosis in the lung of the allergic inflammation.

Sho-saiko-to, one of the most widely used Chinese herbal preparations, has long been used for the treatment of chronic liver diseases. We have investigated its effect in retarding the process of liver fibrosis and accelerating liver regeneration, especially its effect on Ito cells that are thought to be deeply involved with liver fibrosis. Sho-saiko-to extract and its active constituents were orally administered to rats with dimethylnitrosamine-induced liver-injury. After treatment with sho-saiko-to extract hepatic function improved, histopathological results confirmed repair of liver tissue, and retinoid levels increased. On the other hand, when active constituents of sho-saiko-to extract were administered alone, liver retinoid levels remained low, implying that interaction among active constituents of the extract was suppressing Ito cell activation. When sho-saiko-to extract was administered to 70% hepatectomized normal and liver-injured rats, liver weight, the number of S-phase-cells and retinoid levels increased with time. However, these changes were different for normal and liver-injured rats, suggesting that the site of action of sho-saiko-to extract in regenerating liver is different for normal and liver-injured rats. These results show that sho-saiko-to extract was useful for suppressing the activation of Ito cells.

The activities of cell-associated IL-1 (IL-1 alpha) and extracellular IL-1 (IL-1 beta) in alveolar macrophages (AM) from rats with bleomycin-induced pulmonary fibrolosis were measured to determine their role in fibroblast growth. AM were obtained on Days 1, 3, 6, 9 and 12 after a intratracheal injection of bleomycin, and the IL-1 activity and fibroblast growth-stimulating activity in fixed AM and AM supernatants were measured. Higher cell-associated IL-1 activity was detected in AM from bleomycin-treated rats than in those of control on Day 1 through 9. But extracellular IL-1 activity in the supernatant of AM from bleomycin-treated rats significantly higher only on Day 1. Expression of IL-1 alpha mRNA in AM from bleomycin-treated rats was significantly higher than that in AM of control, but there was no significant difference in the mRNA levels of IL-1 beta in AM of these two groups. Fixed AM from bleomycin-treated rats caused growth-inhibition of fibroblasts in a density-dependent manner. The inhibitory activity was decreased by pretreatment of fixed AM with anti IL-1 alpha antibody, but not anti IL-1 beta antibody. These results suggest that cell-associated IL-1 (IL-1 alpha) is produced continuously in AM from rats with bleomycin-induced pulmonary fibrosis and may be important in regulation of this disorder by inhibiting fibroblast growth.

Thirty-four (17 paired) extracted second primary molars were obtained from 17 individuals (9 boys and 8 girls) aged from 9 yr 2 months to 12 yr 7 months. A tooth on one side was extracted as a control, and an acidulated phosphate fluoride (APF) gel was then applied to the paired contralateral second primary molar. Three months later, the experimental tooth was extracted. Nine sites were assayed by a microsampling technique from small areas of the approximal enamel surface. The fluoride and phosphorus concentrations were determined by a fluoride electrode and by colorimetric procedure, respectively. Fluoride concentrations were higher in the teeth treated with the APF gel than in the control teeth. The highest fluoride uptake was observed in the central area of the approximal surfaces. Deeper areas (10 microns) had a marked uptake of fluoride as compared with surface areas (3 microns). It was concluded that the APF gel application increased the fluoride levels of approximal tooth surfaces, particularly the mid-central site, of second primary molars, even at 3 months after application.

The present study was designed to analyze the state of 203 patients with rheumatoid arthritis (RA) in our clinic using a personal computer. The duration of the disease was significantly correlated with the progression of radiographical stages of RA, indicating that no drugs were able to prevent the progression of joint destruction. Nevertheless, bucillamine, a newly developed anti-rheumatic drug, was found to be effective in some patients who did not respond to D-penicillamine, but not vice versa. Although seropositive RA patients had more severe disease than seronegative RA patients, serum rheumatoid factor levels were not significantly correlated with Lansbury indices in seropositive RA patients. Overall, either the liver function or the renal function was not significantly affected in any category of the patients. Taken together, it is suggested that analysis of the data of the RA patients with personal computer systems provide useful information on the management of the RA patients.

Continuous changes of respiratory impedance by the oscillation method using Asthograph and 81mKr ventilation image during saline and sulpyrine solution (100 mg/ml, 250 mg/ml) provocation were simultaneously measured in 15 adult asthmatics and 7 normal individuals. Estimation of airway obstruction by respiratory impedance using Asthograph was difficult during sulpyrine inhalation, since respiratory impedance increased gradually. In addition to the measurement of respiratory impedance, images of 81mKr ventilation were also obtained to estimate the regional ventilatory distribution. Estimation of the airway obstruction was easily obtained. Another advantage of 81mKr ventilation image is that it can estimate the regional ventilatory distribution. The site of airway obstruction provoked by sulpyrine was observed predominantly in the lower lung field. The results of our present study were as follows. 1) In 3 patient, increase of respiratory impedance and defect of 81mKr ventilation image were observed. Two cases in this group were clinically diagnosed as having aspirin-induced asthma. 2) In 7 patients, a defect of 81mKr ventilation image was observed, but no increase of respiratory impedance was observed. Five cases in this group could not be clinically diagnosed as having aspirin-induced asthma. 3) In 5 patients, neither defect of 81mKr ventilation image nor increase of respiratory impedance could be detected. These results suggest that 81mKr ventilation image on sulpyrine inhalation challenge test is a useful method for evaluating regional ventilatory distribution, but should be further investigated for application to aspirin-induced asthma.

A 78-year-old man was admitted to hospital because of episodes of high grade fever and multiple nodular shadows on chest roentgenogram. He had a past history of percutaneous drainage and partial resection of the left lobe of the liver for liver abscess of unknown origin in 1987. The high grade fever was secondary to sepsis due to Citrobacter freundii. The sepsis improved with antibiotic therapy, but the abnormal shadows on chest roentgenogram did not improved. Immunoserological tests indicated a probable diagnosis of alveolar hydatid disease of the lung, which is very rare in the Kansai district of Japan. Open lung biopsy was performed and the diagnosis of alveolar hydatid disease of the lung was confirmed.

The effects of recombinant human interleukin-4 (IL-4) on the production of interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF alpha) by human alveolar macrophages (AM) and autologous peripheral blood monocytes (PBM) in response to lipopolysaccharide (LPS) were examined. AM and PBM were obtained by bronchoalveolar lavage and centrifugal elutriation, respectively, from healthy donors. The production of IL-1 (alpha and beta) and TNF alpha by human AM and PBM were quantitated by enzyme immunoassays (EIA). When activated with LPS, AM secreted much more TNF alpha, but less IL-1 beta than PBM. The production of IL-1 (alpha and beta) by activated AM and autologous PBM was suppressed dose-dependently by IL-4. The inhibitory effect of IL-4 was greatest when it was added to AM or PBM simultaneously with LPS or within 3 h after LPS. The suppressive effect of IL-4 was completely neutralized by pretreatment with rabbit anti-IL-4 antiserum. IL-4 also suppressed the production of IL-1 and TNF alpha by monocyte-derived macrophages. As measured by thymocyte co-stimulation assay, the production of cell-associated IL-1 was inhibited by coculture of AM plus LPS with IL-4. Northern blot analysis showed suppression by IL-4 of expression of messenger ribonucleic acid (mRNA) for IL-1 and TNF alpha in LPS-stimulated AM. We conclude that IL-4 is a potent down-regulator for human alveolar macrophages capable of producing IL-1 and TNF alpha.

The alteration ratio of lung field CT numbers in different respiratory phases was studied in 52 patients with chronic pulmonary obstructive disease (COPD) and 20 subjects with normal lung. The 52 patients with COPD consisted of 30 with clinically diagnosed chronic pulmonary emphysema (CPE), 15 with suspected CPE (sCPE) and seven with bronchial asthma (BA). The 20 subjects with normal lung were divided into two groups according to age. CT images were obtained in each case under different respiratory conditions, i.e., full inspiration and end expiration. The following parameters were employed for numerical evaluation: %(I-E)Apex = (MLDApexI-MLDApexE/MLDApexE x 100 %(I-E)Mid = (MLDMidI-MLDMidE)/MLDMidE x 100 %(I-E)Base = (MLDBaseI-MLDBaseE)/MLDBaseE x 100 %(I-E)Whole = (MLDWholeI-MLDWholeE)/MLDWholeE x 100 where MLD is mean lung density and the letters I and E stand for full inspiration and end expiration, respectively. The small letters Apex, Mid, Base and Whole stand for apex cut, mid-thorax cut, base cut and whole lung, respectively. The values of %(I-E)Whole were significantly different between disease groups except for those between the sCPE and BA groups. The values of %(I-E)Whole showed a good positive correlation with FEV1.0% (r = 0.79) and V25/H (r = 0.80) and a good negative correlation RV/TLC (r = -0.75). Diagnostic differentiation of COPDs by %(I-E)Whole values identified 80% of CPE cases and 91% of normal lung cases. In the sCPE group, the values of %DLco in patients with %(I-E)Whole above 9% were smaller than those in patients with %(I-E)Whole under 9%.(ABSTRACT TRUNCATED AT 250 WORDS)

Theophylline is used as a prophylactic agent for controlling bronchospasm in patients with asthma. Sustained-release theophylline (Theodur) is widely used for this purpose. In this report, we describe a patient who developed asthma due to administration of Theodur. A 38-year-old man was referred to our hospital for assessment of the relationship between his respiratory symptoms and theophylline. He had been admitted to the hospital several times for dyspneic attacks. Theophylline ethylenediamine (Aminophylline) and hydrocortisone sodium succinate had been administered intravenously for the acute phase, followed by Theodur orally. Following administration of Theodur, he had developed dyspnea, chest tightness and dizziness. An inhalation challenge test with sulpyline showed a negative reaction. Although an oral challenge test with theophylline also showed a negative reaction, that with Theodur evoked an asthmatic response. We were unable to determined any possible cause or the mechanism for this reaction. We concluded that the vehicle or preservative (i.e., inactive ingredients) contained in Theodur were likely to be related to his asthmatic response.

We conducted these experiments to investigate the differences between continuous portal and one shot portal infusion of 5-fluorouracil (5-FU) using male Donryu rats. Continuous portal infusion of 5-FU (20 mg/kg/day x 5 days) revealed no remarkable side effects on the rats with significant decrease in the number of liver metastases generated by intraportal inoculation of ascites hepatoma AH60C. Consecutive 5-day administration of 5-FU (20 mg/kg x 5) by one shot method via spleen resulted in no metastases but caused death in 75% of rats because of severe leukopenia and dehydration. The rats receiving one shot infusion of 5-FU (33.3 mg/kg x 3, day 1, 3, 5) via spleen showed a significant decrease in the number of metastases without lethal side effects. Continuous portal infusion of 5-FU would be a safe and effective therapy to prevent liver metastases, whereas one shot portal infusion of 5-FU may give rise to severe side effects while preventing liver metastases.

High-resolution computed tomography (HR-CT) was performed on 20 patients with pyrophilitosis. Small nodular opacities in these patients could be divided by HR-CT into two types, namely, tiny irregular branching structures (TIB) and small round opacities (SRO). TIB had a centrilobular distribution and were characteristic of pyrophillitosis. SRO had both centrilobular and perilobular distributions and were considered to be changes modified by the aspiration of silica. Large opacities (LO) of pyrophillitosis were classified into three types, that is, spherical type, flat type parallel to the bronchus and flat type parallel to the thoracic wall. The spherical type was seen in patients exposed to both pyrophillite and silica, while the flat types were seen in patients exposed to only pyrophillite and were characteristic opacities of pyrophillitosis. Pulmonary emphysema was found in only one patient with pyrophillitosis, whereas mediastinal lymph node swelling and calcification were seen in most patients with pyrophillitosis. HR-CT is useful in making a more accurate evaluation of these lesions.

For evaluating hepatic tumors, ultrasonograms using carbon dioxide by arterial injection (CO2US) was performed in 37 patients, including 28 hepatocellular carcinomas, 11 hepatic metastases, and 3 hepatic hemangiomas. Hepatic tumors were enhanced by CO2US and easily identified. CO2US of hepatic tumors were classified into six patients. Generally, on CO2US hepatocellular carcinomas were well enhanced, and hepatic metastases had ring-like enhancement. Hepatic hemangiomas showed peripheral patchy enhancement. In the patients with hepatocellular carcinoma, the primary tumors were better identified on CO2US than conventional sonography. The daughter nodules with hepatocellular carcinoma were also better demonstrated than other examinations. CO2US is helpful in evaluating and differentiating hepatic tumors.

Interferon-gamma (IFN-gamma) acts on a large array of different types of cell and has potent immunomodulatory activities besides cytotoxic effects on tumors. In a phase I study, some immunologic parameters of blood mononuclear cells from healthy volunteers who received intramuscular injections of natural human IFN-gamma were analyzed. The percentage of Leu-11a positive cells, natural killer (NK) activity, lymphokine (interleukin-2)-activated killer (LAK) activity and monokine production were measured either in blood mononuclear cells or in purified samples of lymphocytes or monocytes of the donors before and 24 h after IFN-gamma injection. After IFN-gamma injection, the percentage of Leu-11a positive cells and the LAK activity in the blood were significantly reduced, but NK activity and monokine production remained unchanged. These findings suggest that in vivo IFN-gamma acts directly or indirectly on Leu-11a positive cells and reduces LAK activity by changing the recruitment of LAK precursors in the blood.

Systemic administration of interleukin-2 (IL-2) in patients with malignant diseases induces peripheral eosinophilia. In the present study, to clarify the mechanisms of eosinophilia induced by IL-2, we examined the changes in the number of eosinophils and in eosinophil colony stimulating activity (Eo-CSA) in the pleural fluid of six patients with malignant pleurisy caused by lung cancer or malignant mesothelioma, during and after intrapleural administration of IL-2. Results showed that intrapleural administration of IL-2 induced marked eosinophilia in the pleural fluid and mild eosinophilia in the peripheral blood, and that during IL-2 administration, marked Eo-CSA appeared in the pleural fluid before increase in the number of eosinophils. The Eo-CSA seemed to be a polypeptide or protein because it was trypsin-sensitive and had a molecular weight of 40-60 kDa.

A very rare case of perianeurysmal fibrosis was presented. A 65-year old man was admitted with the complaint of abdominal pulsatile mass and intermittent claudication of right lower limb. Aortography revealed fusiform, calcified aneurysm of the infrarenal abdominal aorta and severe stenosis of right common iliac artery. CT scan demonstrated a soft tissue density structure around the aortic aneurysm which was enhanced after contrast medium injection. At surgery, the aneurysm had a thick, firm, smooth wall which was shiny white in appearance and adherent perianeurysmal fibrosis was marked. In order to avoid injury to surrounding tissue such as the duodenum or vena cava, thrombo-exclusion method was chosen. Histological examination of the aneurysmal wall showed fibrous tissue infiltrated with mononuclear cells such as lymphocytes and plasma cells. The postcontrast enhancement of aortic wall and perianeurysmal sheet disappeared on CT on the post-operative 57th day and no recurrence has been observed.

Using four repetitive sequences, we compared DNAs isolated from Mus caroli, M. cookii, M. hortulanus, M. musculus, M. pahari, M. saxicola, and M. spretus. Except for B1, these probes showed species-specific hybridization patterns. Mouse interspersed fragment (MIF) sequences were present in all species examined, but those defined by the 1.3-kb EcoR1 band were fewer in M. pahari and M. saxicola than in the other species. The Y-chromosomal probe showed male-specific accumulation only in M. hortulanus, M. musculus, and M. spretus, which are known to be closely related. The genetic difference between M. spretus and the other two species (M. hortulanus and M. musculus) was clearly demonstrated by a M. musuclus centromeric sequence that hybridized strongly to M. hortulanus and M. musculus DNA but was underrepresented in the genome of M. spretus. These results may suggest the usefulness of these repetitive sequences in the classification of Mus species that display only subtle morphological differences.

We describe a Canadian family of Czechoslovakian descent that came to our attention because of an HbA2 percentage approximately twice that of an average case of heterozygous beta-thalassemia. This unique phenotype suggested to us the possibility of a novel genetic mechanism being responsible for their beta-thalassemia. To investigate this possibility, we mapped, cloned, and sequenced the mutant beta-globin allele. This molecular analysis demonstrated the presence of a unique 4,237 base pair (bp) deletion extending from 3.3 kilobases (kb) 5' of the beta-globin mRNA cap site to approximately the middle of beta IVS-2. This truncated beta-globin gene further extends the heterogeneity of mutations known to cause beta-thalassemia and delineates new sequences involved in nonhomologous recombination events in the beta-globin gene region.

The chronic toxicity of potassium clavulanate (CVA-K) and BRL28500 were evaluated using dogs in 26-week intravenous administration studies followed by a 5-week off-dose period. The doses for CVA-K and BRL28500 were 10, 20, 50 and 100 mg/kg (p.f.a.), and 80, 160, 320 and 800 mg/kg (p.f.a.) respectively. There were no deaths in either of the groups. For general condition, dogs dosed with CVA-K at 100 mg/kg showed reddening of the skin and mucous membranes, shaking of the head, facial oedema, a decrease in food intake and a reduction in body weight. Also some dogs of the same group showed decreased spontaneous activity, emaciation and signs of dehydration. In the BRL28500 treatment groups, there was reddening of the skin and mucous membranes, vomiting and salivation at 800 mg/kg. Urinalysis of dogs dosed with CVA-K showed occasional dark yellow coloration of the urine. There was also a very weak and equivocal response or positive reaction for protein, occult blood, and urine sugar in some animals at 100 mg/kg. Some dogs dosed with BRL28500 also showed either a very weak and equivocal response or slight positive reaction for occult blood at 320 mg/kg and above, and dark yellow coloration of the urine at 800 mg/kg. Haematological examination of the CVA-K groups showed increases in leukocyte count and platelet count at the highest dose of 100 mg/kg. No haematological abnormalities were noted in any of the BRL28500 groups. Serum biochemical studies of dogs dosed with CVA-K revealed a decrease in total protein at 50 mg/kg and above, and increases in Al-P, total bilirubin, GPT, BUN and creatinine at 100 mg/kg. In the BRL28500 treatment groups, there were increases in total cholesterol and triglyceride at 160 mg/kg and above. In dogs dosed with CVA-K there was an increase in liver weight at 100 mg/kg. Histopathological examination showed a ground glass-like appearance of the hepatocyte cytoplasm and also altered distribution of PAS positive material at 50 mg/kg and above. In the BRL28500 groups, there was an increase in liver weight at 320 mg/kg and above. There were the same ground glass-like appearance in hepatocytes and altered distribution of PAS positive material at 800 mg/kg. In view of the above results, the maximum non-effect dose levels in the present studies were considered to be 20 mg/kg for CVA-K and 80 mg/kg for BRL28500.(ABSTRACT TRUNCATED AT 400 WORDS)

In order to evaluate efficacy and safety of L-Keflex (granule form of sustained release cephalexin), a double blind study comparing it with Keflex (capsule of regular cephalexin) was conducted in dental infections. Evaluable cases in adults for efficacy of the drugs were 196 consisting of 97 for L-Keflex and 99 for Keflex. Those in children were 19 (8 for L-Keflex and 11 for Keflex). There were no significant differences in background of the patients and severity of the diseases between both groups (L-Keflex and Keflex groups). The daily doses used in both groups were 1,000 mg in adults and 500 mg in children, respectively. The dose was given in two divided doses for L-Keflex group and in four divided doses for Keflex group. Following are evaluation by the committee members for the study: Adults 1. Clinical response rate at final therapy day was 93.8% in L-Keflex group and 92.9% in Keflex group, showing no significant difference between both groups. 2. No significant difference in severity of subjective and objective symptoms between both groups was observed at each therapy day. 3. Side effects were found in 6.7% of 105 patients receiving L-Keflex and in 5.6% of 107 patients with Keflex, and there was no significant difference between both groups. As the side effects, gastrointestinal symptoms, rash and itching were observed, but no any other side effects were found in both groups. Children 1. As shown in the above, number of the cases enough to evaluate statistically was not obtained, but all of both groups clinically responded to the drugs. 2. As for side effects diarrhea was observed in only one patient of Keflex group consisting of 12 patients. In the patient, however, discontinuation of the drug was not required and the side effect disappeared during the therapy. From the above results, L-Keflex (granule) is judged to have more convenience than Keflex (capsule) in that (1) it can be administered with b.i.d. regimen and (2) it can be easily taken in dental patients such as patients having difficulty in opening mouth of swallowing pain.

Fifty-six reconstructions using Biograft were performed in 45 cases with peripheral arterial occlusion. These consisted of 11 femoro-popliteal bypasses above the knee, 19 femoro-popliteal below the knee, 10 femoro-tibial or peroneal and 16 other miscellaneous procedures including aorto-femoral and extra-anatomic bypasses. Overall patency rates for each type of procedure were 81.8%, 78.9%, 30.0%, and 93.8%, respectively. The cumulative patency rate (calculated by the life table method) for the total group was 70.5% at 56 months. Early failure was thought to relate to technical factors in most instances. The majority of late failures was due to intimal hyperplasia at the distal anastomotic site. One of 9 late failures was successfully treated by patch angioplasty at 23 months following initial operation. Therefore, in order to attain better late results, early discovery of developing stenosis by noninvasive examination techniques and arteriography is important.