We carried out an epidemiological study on lower respiratory tract infections, concerning the respiratory syncytial virus (RSV) infection, in northern Hokkaido, Japan, during the 2-year-study period from April 1991 to March 1993. There were 467 hospitalized patients with lower respiratory tract infections. We examined the presence of RSV antigen in their nasopharyngeal specimens of 456 out of 467 patients (97.6%) by enzyme immunoassay. The diagnosis of Mycoplasma pneumoniae infection was done by the rise of antibody titer, performed with complement fixation method, in the sera of the acute and convalescent phases. There were 133 patients with RSV infection (28.9%), 45 patients with Mycoplasma pneumoniae infection (9.8%) and 7 patients with measles virus infection (1.5%). RSV played an important role in the lower respiratory tract infections in northern Hokkaido, Japan. The epidemic of RSV infection was observed in spring and early winter in 1991 and only in early winter in 1992. The number of patients with RSV infection from April 1991 to March 1992 was greater than that from April 1992 to March 1993. In contrast with RSV infection, the epidemic of Mycoplasma pneumoniae infection was observed in 1992. We speculated that the RSV and Mycoplasma pneumoniae infections might interfere with each other.

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A newly described Vibrio cholerae 0139 was isolated from a patient who had traveled in India on April 1993. The patient experienced 5 to 6 watery diarrhea per day after he returned to Japan. The isolated strain registered as K111 did not agglutinate with O1-O138 antiserum and agglutinated with O 139 antiserum. This strain resembled V. cholerae O1 strain in biochemical characters and had ctx and zot, although was resistant to the vibrio static agent O/129.
This is the first report of choleralike illness by the newly described toxigenic V. cholerae 0139 strain in Japan.

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We treated 125 patients with strongyloidiasis (78 males and 47 females) by 2 oral doses of ivermectin (6 mg) at 2-week interval, and obtained the following results:
1. Eradication rate after treatment was 86.4%(108 of 125 patients), responsively. Out of the total 17 patients were resistant (non-responsive) to treatment, 8 patients received a further course of ivermectin and all Strongyloides stercoralis in their feces were eradicated.
2. Side effects were observed in 7.2% of the patients after the first dose treatment and in 3.2% after the second dose. But all symptoms were mild and self-limited. Although liver disfunction developed in 13.6% of the patients, no symptoms occurred and no special treatment was required.
3. Positive rate of anti-HTLV-I antibody in the resistant group was significantly higher (80.0%) than in the eradicated group (29.2%) and in the stool-negative group (0%).
4. Although eosinophils before treatment in the eradicated group was significantly higher than that of controls, there was no significant difference between the resistant group and controls. IgE levels in the resistant group was significantly lower than in the eradicated group.
We w0uld like to conclude that IVM is the best drug for treatment of the patient with Strongyloides stercoralis not only from this results but also our previous reports which had investigated the clinical efficacy on thiabendazole, mebendazole and albendazole.

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MRSA has been isolated frequently from patients in the neurologic ward of Minami-Okayama Hospital. We examined the flora in the anterior nares of 37 patients in the neurologic ward and 36 patients in the medical ward.
Existence of dysphagia and nasogastric intubation is considered to make a marked difference between nasal flora of neurologic patients and that of medical patients. Patients with nasogastric intubation had higher incidences of colonization with S. aureus, and gram-negative rods. All patients colonized with MRSA had received nasal tube-feeding. Nasogastric intubation is considered to be a significant risk factor for MRSA colonization.
The study in patients with nasogastric intubation demonstrated that patients with mechanical ventilation had a significantly higher incidence of colonization with gram-negative rods, such as P. aeruginosa, and a lower incidence of colonization with S. aureus. A incidence of MRSA colonization in patients with mechanical ventilation was significantly low. Mechanical ventilation is not necessarily considered to be a risk factor for MRSA colonization.

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We demonstrated the efficacy of “long term” roxithromycin (RXM) treatment in 15 patients with chronic lower respiratory tract disease (11 with diffuse panbronchiolitis and 4 with sinobronchial syndrome). (1) Fourteen (93.3%) of the 15 patients showed improvement when assessed by the comprehensive improvement score, and they showed significant improvements in PaO₂ (74.2 ± 10.4 Torr to 84.3 ± 10.9 Torr, p<0.01), %VC (86.9 ± 20.2% to 96.0 ± 21.9%, p<0.001) and FEV₁ (1.81 ± 0.87 L to 2.14 ± 1.08 L, p<0.01) after RXM treatment. (2) Neutrophils accumulated in the pre-RXM treatment bronchoalveolar lavage (BAL) fluid and decreased in BAL fluid of patients responding to RXM treatment (49.8 ± 28.3% to 17.1 ± 15.7%, p<0.01). Additionally, the levels of interleukin 1β and interleukin 8 were significantly higher in BAL fluid of these patients than those in the healthy volunteers (p<0.025, p<0.01 respectively), and correlated with the neutrophil accumulation (r=0.619, p<0.05). These cytokines showed a decrease after RXM treatment. These results indicated that RXM acts by reducing pulmonary inflammation through reduction of neutrophil migration to inflammatory sites, and is effective on chronic lower respiratory tract disease.

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Thirty cases of bacteremia out of 1512 patients who had been admitted to our Department between February 1988 and June 1991 were reviewed.
They consisted of 22 males and 8 females and their age ranged from 32 to 88 years (mean 62.7). 25 of the patients (83.3%) had malignant diseases of which bladder cancer (15 cases) was predominant and 5 had benign diseases.
Gram positive bacteria were isolated in 18 cases (56.2%) and fungi in 4 cases (12.5%) from blood culture. Of these MRSA was most prevalent: 6 cases (18.8%), followed by S. epidermidis: 4 cases (12.5%), P. aerginosa: 3 cases: E. faecalis: 3 cases and Corynebacterium: 3 cases (9.4%). Analysing the onset of bacteremia for each case, in three cases urinary tract infections, in one case a surgical wound infection and in one case a skin infection were prominent before the diagnosis of bacteremia. From their background, 23 cases (76.7%) were so-called compromised hosts. A total of 7 cases had died, 6 cases of bladder cancer and one case of testicular cancer, five of them were on systemic anti-cancer chemotherapy.
Of those cases who expired, P. aeruginosa was isolated in two cases, Candida in two cases, MRSA in one case and E. faecium in one case, Corynebacterium in one case. It was noteworthy that in two cases where blood cultures were positive for P. aeruginosa and one case where the blood culture proved positive for Candida, drastic decrease of the peripheral leukocyte number during anti-caner chemotherapy was seen.
It was also noteworthy that only one out of six cases where blood cultures had proved positive for MRSA had died and the remainder of the cases survived by the administration of Vancomycin.

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A DNA amplification assay using PCR, which consists of amplification of genus specific mycobacterial 16S rRNA gene as the 1st step and reamiplification of the amplicon with species specific primers as the next step, could detect M. avium, M. intracellular and M. kansasii in the sputum.
The results with type or standard strains showed that M. avium PCR and M. intracellular PCR were highly specific for identification of each species but M. kansasii PCR detected M. gastri besides M. kansasii.
Among 22 clinical samples which were positive by PCR, the 17 results were confirmed by culture.
The PCR detected 27 (7.5%) of nontuberculous mycobacteria from 360 sputum and showed that the 27 of NTM consists of 9 M. avium, 8 M. intracellulare, 5 M. kansasii, 1 reacted both M. avium and M. intracellulare and 4 unidentified.

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To compare the differences in the severities, host defense responses and clinical courses C. pneumoniae respiratory tract infections between the initial and second challenge of chlamydia, an experimental C. pneumoniae respiratory infection model using mice was established and the following studies were carried out.
For the initial infection mice were challenged with C. pneumoniae, strain TW-183, by nasal instillation. No animals died from this initial infection. The second exposure to C. pneumoniae, in the same manner, was done 35 days after the first challenge. Serial observation in the two groups of mice were done on the anti-C. pneumoniae IgG and IgM antibody titers of their sera, histopathological evaluations of their lungs and the formation of inclusion bodies in the lung sections. Focal inflammatory changes consisting of neutrophil and macrophage infiltration in the alveolar spaces of mice lungs three days after the initial challenge were observed, but there were no remarkable inflammatory changes in the lung sections of mice with the second challenge, with the exception of marked formation of bronchus-associated lymphoid tissues and perivascular accumulation of lymphoid cells. The numbers of inclusion bodies were very small in the lungs of mice with reinfection with chlamydia. These histopathological findings all disappeared within ten and five days after the initial and the second challenge, respectively. Anti-C. pneumoniae IgG antibodies showed a remarkable increase from seven days after the initial challenge and peak value was 1: 512-1024 at 28-35 days. Second exposure on day 35, caused another increase in IgG antibody titers up to 1: 2048-4096 21 days after the second exposure. IgM antibody titers also showed the same response as that of IgG. Based on the above results, we considered that the second exposure of animal respiratory tracts to C. pneumoniae might result in a milder infection, because of protective immunoresponses activated by the previous exposure to C. pneumoniae.

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A clinical Phase I study of E5, edobacomab, an anti-endotoxin monoclonal IgM antibody was carried out to evaluate its efficacy, safety and pharmacokinetics and in parallel, explore an optimum dosage in the treatment of patients with gram-negative sepsis (incl. those suspected). A total of 10 patients were administered a dose of 1 mg/kg, 2 mg/kg or 4 mg/kg of E5 by infusion over one hour.
1. Peak blood levels after an intravenous dose of 1 mg/kg, 2 mg/kg and 4 mg/kg of E5 were 9.9, 11.5 and 35.6 μg/ml, respectively and the half-lives of elimination were 8.7, 11.7 and 10.8 hours, respectively, about the same at all dose levels. The area under the blood concentration-time curve (AUC) were 129.8, 200.8 and 574.4 μg ·hr/ml, respectively, showing an increase in proportion with the dosage.
2. Urinary E5 concentration was not detectable in all the patients and renal excretion of unchanged E5 was not observed.
3. Out of the 8 patients with a positive pre-treatment endotoxin level with a value of above 9.8 pg/ml, those who showed its reduction to a level of below 9.8 pg/ml within one hour after dosing of E5 were 0 of 2 patients (0%) at a dose of 1 mg/kg, 3 of 3 (100%) at a dose of 2 mg/kg and 1 of 3 (33.3%) at a dose of 4 mg/kg.
4. The clinical efficacy following a single intravenous dose of E5 was rated as being “good” or “excellent” for 3 of 3 patients (100%) at a dose of 1 mg/kg, 4 of 4 (100%) at a dose of 2 mg/kg and 2 of 3 (66.7%) at a dose of 4 mg/kg.
5. As for antipyretic effect as assessed by the mean value of temperature, a fall in fever to the level of 36C was noted from 12 hours after administration of E5 in the patients treated with 2 mg/kg. The degree of improvement in WBC, platelet count and CRP was also more evident in this 2 mg/kg group.
6. The safety was rated as “no problem in safety” for all 10 patients. No adverse reaction and clinical laboratory abnormalities suspected of their relation to E5 was observed.
7. Positive antibody (HAMA) response to E5 was observed in 2 of the 10 patients. In one patient (4 mg/kg) of them, response because negative 9 weeks later and in the other patient (1 mg/kg) it tended to decrease.
8. The usefulness was rated as being either “very useful” or “useful” in 3 of 3 patients (100%) at a dose of 1 mg/kg, 4 of 4 (100%) at a dose of 2 mg/kg and 2 of 3 (66.7%) at a dose of 4 mg/kg.
9. The findings on reduction of blood endotoxin and improvement in temperature, WBC, platelet count and CRP allows us to conclude that the optimum dosage of E5 is 2 mg/kg.
The foregoing results suggest the that E5 is effectiveness for the treatment of endotoxemia associated with gram-negative sepsis.

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The efficacy, safety and unsefulness of murine anti-endotoxin monoclonal IgM antibody “E5, an intravenous dose of 2mg/kg” were evaluated in 88 patients with suspected Gram-negative sepsis from 37 institutes in Japan. Out of these, 74 patients were evaluable for the efficacy, 85 for safety and 75 for clinical usefulness. In assessing the efficacy, the patients were divided into 3 groups based on the plasma endotoxin levels (Endospecy with new PCA treatment of plasma): H group with a level of above 9.8 pg/ml and M group with a level of 3.0-9.8 pg/ml and L group with a level of below 3.0pg/ml.
1. The efficacy rates as assessed following administration of E5 were 73.1% in the H group, 70.4% in the M group and 38.1% in the L group being higher in the groups with significantly high plasma endotoxin levels.
2. In both the H and M groups in whom plasma endotoxin levels were significantly high, the majority of the patients showed rapid reduction of the levels after administration of E5.
3. In all groups, improvement in body temperature, pulse rate, blood TNF-α and blood IL-6 was observed after treatment with E5. In the H and M groups with an endotoxin level of 3.0pg/ml, improvement in platelet count as well as in CRP was noted. The H group showed also improvement in WBC.
4. Improvement in the shock score was noted in all the groups but was more outstanding in the H and M groups in the early stage of treatment.
5. Side effects were seen in 5 (5.9%) of 85 patients and all thought to be allergic in symptoms such as rash, itching, fever and flare.
6. The reaction to the prick test performed before administration of E5 was negative in all these 5 patients. For 3 of the 5 patients, anti-E5 IgE antibody was measured. In all of them, the IgE levels were higher than those of healthy controls. Also, in 47.6% of patients, an elevation of anti-ES IgG antibody was noted two weeks after the administration.
7. Clinical laboratory abnormalities were observed in 3 (3.5%) of 85 patients. They were an elevation of S-GOT · S-GPT and lowering of BUN, increased Al-p and decreased CH₅₀, increased neutrophilia (%) and were all slight in the degree of the changes.
8. The clinical usefulness of E5 was evaluated for 75 patients. The usefulness rates involving “useful” and “very useful” were 69.2% in the H group, 66.7% in the M group and 36.4% in the L group, with the rate being significantly higher in the H and M groups than L group.
9. The blood levels following one-hour intravenous infusion of E5 at a dose of 2mg/kg were obtained by a simulation curve at the end of infusion, 24, 48 and 72 hours later with values of 18.05, 5.26, 1.53 and 0.45μg/ml, respectively. This indicates that a drug concentration of 0.2μg/ml or more which was found to inhibit LPS activity in an in-vitro test was maintained as long as 87.65 hours.
From the foregoing results, an intravenous dose of 2mg/kg E5 was shown to effective by lowering plasma endotoxin level and improving clinical symptoms of patients with endotoxemia due to sepsis. The finding led us to conclude that if ES is used for a patient with such disease profile is mentioned above in consideration of its “Risk-Benefit-Balance”, its therapeutic usefulness will be much expected.

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Recently, two new kits, HITAZYME (Hitachi Chemical Co., Ltd.) and SERO IPALISA (Savyon Diagnostics, Ltd.), for the assay of and-C.trachomatis antibodies by the enzyme immunoassay (EIA) method have been developed and put into clinical application.
In the study reported here, the authors investigated the clinical usefulness of these assay kits, together with the IPAzyme and micro-IF test, in the diagnosis of cases of urogenital tract C.tachomatis infections.
1.The positive rates for IgA antibodies, which are considered to be an indicator of active infection, obtained with the HITAZYME and SERO IPALISA kits in the 82 antigen-positive cases were significantly (p<0.005) higher than the rates obtained with the IPAzyme and micro-IF test.These results showed the usefulness of the HITAZYME and SERO IPALISA kits for detecting C.trachomatis infections.
2.A comparison was made of the assay results obtained with the HITAZYME and SERO IPALISA kits, and it was found that there was a large number of cases (142) that tested negative for IgA antibodies with the HITAZYME but positive with the SERO IPALISA kit.We carried out a confirmatory test on the specimens of cases for which the results obtained with the HITAZYME and SERO IPALISA kits were not in agreement.This test employed the Western blotting method using COMC (the antigen extracted from EB of C.trachomatis strain L₂ and used in the HITAZYME kit) and whole EB of C.trachomatis strain L₂ (the antigen used in the SERO IPALISA kit).The results showed a significantly higher degree of agreement between the HITAZYME kit data and the Western blotting data than between the SERO IPALISA kit data and the Western blotting data.
3.In addition, with the objective of investigating the existence of cross reactivity with anti-C. pneumoniae antibodies, we performed Western blotting using as the antigen crude whole EB of C. pneumoniae strain TW-183.The results showed that anti-C.pneumoniae antibodies were detected in 25 of 35 (71.4%) cases that were negative with C.trachomatis antigen and the HITAZYME kit and positive with the SERO IPALISA kit.These findings indicate a strong possibility that these cases positive with the SERO IPALISA kit are due to a cross reaction with anti-C.pneumoniae antibodies.
It is concluded that the HITAZYME kit is an excellent tool for detecting anti-C.trachomatis antibodies since it present various advantages: high specificity for and-C.trachomatis antibodies, a high degree of objectivity since it employs an EIA method based on evaluation of the absorbance, a simple procedure, and can handle a large number of specimens, etc.
The HITAZYME kit can be used when antigen tests are difficult to perform.It is strongly anticipated that it can be used clinically as a screening test.

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During fifteen months between January 1989 and March 1990, 137 episodes (136 cases) of acute bronchitis were clinically examined in Iki Pubulic Hospital.
From the results of quantitative sputum culture in 99 episodes, 58 epiodes (56.8%) had obviously bacterial infections.
The three major causative bacteria were H. influenzae (45.7%), S. pneumoniae (27.1%) and B. catarrhalis (17.2%). Inflammatory cytology of the sputum revealed that in the patients with acutebronchitis macrophage, vivid neutrophils and bronchial epithelial cells were clearly observed, while in the patients of chronic respiratory infections those cells were fewer in number.
Before and after therapy, respiratory functions and blood gas were evaluated in 45 cases. Significant improvements were observed in PaO₂, FEV_1.0, etc.
During eight years from 1982 to 1989, B. catarrhalis has been gradually increasing, as one of majour causative organisms. Each year, the rate of bacterial infection was approximately fifty percent in acute bronchitis.

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We hypothesized that bacterial biofilm formation could be an important factor that makes some infections intractable, and conducted the following study to confirm the role of bacterial biofilm in airway infection.
We first microscopically examined airway surface in patients with an intractable airway infection and detected bacterial biofilms adhering to the airway surface. Most of the airway biofilm diseases were diffuse panbronchiolitis and bronchiectasia due to Pseudomonas aeruginosa or Klebsiella pneumoniae.
In vivo examination revealed that chemotaxis of neutrophils in atients with biofilm bacteria was less than that in patients with floating type bacteria. Interaction of Pseudomonas biofilm with antibacterial agents was examined in vitro. The rate of survival of biofilm bacteria was higher than that of floating bacteria in contact with twice the minimal bactericidal concentration of ciprofloxacin (CPFX) or two to 10 times the minimal inhibitory concentration of cefclidin and meropenem which are highly potent antibacterial agents against P.aeruginosa.
Additionally, the effects of clarithromycin (CAM) on biofilm bacteria were studied in order to investigate new therapeutic maneuvers against a bacterial biofilm. Also, the combination of CPFX and CAM was more effective in decreasing the bacterial survival rate than CPFX alone. The results suggest that administration CAM can be one of the therapeutic maneuvers against biofilm bacteria.

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We report a case of 40-year-old with chloroquine-and mefloquine-resistant Plasmodium falciparum. He had a single grand mal seizure 37 days following retreatment with qunine intravenously, which resulted in rapid clearance of fever and parasitemia, in addition to mefloquine. He had a long history of seizures, which were well controlled by phenytoin. Because he has never had such a seizure before and computerized tomographic scanning of the brain after admission showed no abnormal findings which caused convulsions, it seemed to be an adverse reaction caused by antimalarial drugs.
It is possible that a double or triple combination treatment for the emergence of multiresistant falciparum malaria might more frequently produce severe side effects, such as psychiatric reactions and convulsions. This case suggests that physicians must have a long follow-up period for chronic toxicity of antimalarial drugs, especially after using drug combinations for falciparum malaria.

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[in Japanese]

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A case of a 53 year old healthy female complaining of diarrhea and abdominal pain after taking raw fish is presented. She immediately went into shock and unconsciousness. Central venous pressure was 8 cmH₂O and her ECG showed a first-degree AV block and ST-T changes in almost all leads. After mechanical ventilation and administration of dopamin, dobtamin, cefotiam, ciprofloxacin, she became alert and recovered from her critical condition.
V. parahaemolyticus which produces thermostable direct hemolysin (TDH) was cultured from the feces on admission. Kanagawa phenomenon was positive.
Arterial blood culture was negative and the titer of serum endotoxin was low. The diagnosis of cardiogenic shock due to exotoxin produced by V. parahaemolyticus was made.
Serological examination by ELISA showed elevation of IgG class antibody against TDH and TRH (TDH related hemolysin). And antibody against TDH was normalized after 180 days.
By review of literature, there are some case reports of cardiogenic shock complicated with V. parahaemolyticus infection, but few showed elevation of antibody against TDH and TRH in the serum of the survived patient.

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