The 1951 Tuberculosis Control Law of Japan was amended extensively and has been in effect since April, 2005. The revision of the National Tuberculosis Program (NTP) is to respond to the tremendous changes that have occurred during the last 50 years in tuberculosis epidemiology and in the environment in tuberculosis control implementation. In this review, the main points and framework of the revisions were summarized and the perspective of the development of new technical innovations relevant to each area of the revised TB control legislation is discussed. Also, challenges of Japan's NTP in the recent future are discussed, including the controversies over the proposed abolishment of the Tuberculosis Control Law.
1. Immunization. In the revision of NTP, the BCG vaccination of elementary school and junior-high school entrants was discontinued. In order to strengthen the early primary vaccination for infants, the new Law has adopted the direct vaccination scheme omitting tuberculin testing prior to immunization. This program is implemented to young babies, i.e., less than six months old, as defined by the decree. It is a heavy responsibility for the municipalities to ensure the high coverage of immunization when the period of legal vaccination is rather strictly limited practically to the fourth to sixth months after birth. The safe direct vaccination is another new challenge where appropriate management of the Koch's phenomenon or similar reactions should be warranted.
2. Chemoprophylaxis. Though unfortunately suspended for some legal reason currently, the expansion and improvement of chemoprophylaxis, or treatment of latent tuberculosis infection, to cover anyone with higher risk of clinical development of TB would have a tremendous effect in Japan, especially since 90% of patients who developed TB were infected tens of years ago. The technical innovations in diagnosis of TB infection such as QuantiFERON will be very helpful. Development of new drugs or drug regimens for this purpose is also expected.
3. Case detection. The “indiscriminate” screening scheme in the periodic mass health examination has been replaced with a selective one. Only subjects aged 65 or older are eligible for the screening, supplemented with selected occupational groups who are considered to become source of infection, should they develop tuberculosis, such as health-care providers and school teachers. Local autonomies are also responsible for offering screening to the socio-economic high-risk populations, such as homeless people, slum residents, day laborers, and/or workers in small businesses, as decided by the autonomies at their disposal. Another important mode of active case-finding, i.e., contact investigation has been legally enforced so that anybody cannot refuse to be examined by the Health Center. This investigation service will be greatly enhanced by such new technologies as DNA fingerprinting of TB bacilli and a new diagnostic of TB infection. Regarding the clinical service of the symptomatic patients that detect 75% of new cases currently will be improved in its quality by introducing an external quality assurance system of commercial bacteriological laboratory services.
4. Treatment and patient support The revised NTP clearly states the government's responsibility for treating TB patients in close cooperation with a doctor, in the framework of the DOTS Japan version. While the development of new anti-tuberculosis drugs will be realized in the near future, Japan still has to overcome the issues of improper practice of treatment, as well as the government's slow process for approving drugs to be used for multi-drug resistant TB and non-tuberculous mycobacterioses, such as quinolones, macrolides and others.

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Needless to say, EBM (evidence-based medicine) is of prime importance to medical doctors and others engaged in medical service.
However, now that a lot of disputes over medical treatment or litigations of medical malpractice are occurring more frequently than ever, EBM finds it impossible to remain within the frame of a “medical” problem. In other words, the issue of EBM can be settled for those concerned with medical service only when EBM is understood and practiced not only medically but also “legally” and “from a litigious viewpoint”.
(A lecture on the occasion of the 79th general meetin of the Japanese Association for Infectious Diseases)

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Objective:To review complaints (such as fever, respiratory symptoms, diarrhea, vomiting, and rashes) in the medical records of outpatients as potential sources of data for syndromic surveillance, and to examine the possibility of practical application from a statistical view point.
Materials and Methods: Using data obtained from a certain internal and pediatric clinic, we count the number of patients each day who suffered from one of the above five symptoms from January 1st, 2003 to June 30th, 2005. In order to detect outbreaks prospectively after January 1st, 2005, we at first estimate the baseline using the data from January 1st, 2003 to the day before any given day. We then predict the number of patients there ought to be in any given day and judge whether or not an outbreak has occurred. So as to evaluate the system, we check the sensitivity and specificity in its ability to detect outbreaks other than those seen in previous patterns.
Results: The total number of cases in which each of the above symptoms occurred were respectively: 11, 896 cases of fever, 16, 273 cases of respiratory symptoms, 3, 672 cases of diarrhea, 3, 485 cases of vomiting, and 542 cases of rash. We found prolonged outbreaks of fever and respiratory symptoms in February and March and shorter outbreaks of vomiting and diarrhea in January. The sensitivity and specificity of this system's ability to detect outbreaks was very high and thus we can confirm that it showed satisfactory performance.
Discussion: We found large-scale outbreaks of influenza late in the 2004/2005 season, and small outbreaks of GI that seemed to be particularly related to the Noro virus. In both cases, these outbreaks seemed to be natural phenomena, not artificial, human induced phenomena such as outbreaks caused by bioterrorism attacks. However, since this system was able to detect these outbreaks, we would also be able to use it to detect an outbreak caused by a bioterrorism attack if the size of the outbreak was similar to these cases.
Conclusion: In order to use this system to detect outbreaks in the community on a smaller level we would have to increase the number of medical institutions cooperating in this study. Moreover, we would need to find a way to handle the different electronic medical record systems and different writing styles used by different medical institutions in order to move toward the practical use of Syndromic Surveillance.

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We studied whether the infectivity of Cryptosporidium parvum oocysts for suckling mice could be inactivated by copper tubing or by other types of tubing used to construct water distribution systems, including stainless steel, rigid polyvinyl chloride (PVC), PVC-lined steel, polyethylene (PE), cross-linked PE, and polybutene (PB), using glass tubing as the control. Oocysts were incubated in each tubings for 24 hours. The extent of inactivation of infectious oocysts by copper tubing was -1.303 log, which significantly inactivated of infectivity. In contrast, other types of tubing had no significant effect on some oocyst infectivity, although. PB did show a maximum inactivation of -0.313 log. 25% of oocysts showed degeneration morphologically after passing through copper tubing, while 0.3% to 1.8% showed degeneration after passing through other tubing. Significant inactivation of infectious oocysts was not caused by water in which copper tubing had been let stand for 24 hours, although it had a cupric ion (Cu²⁺) concentration of 2.4mg/L. The direct contact of oocysts with copper surface resulted in a decrease in the recovery percentage of oocysts and generation of hydrogen peroxide (0.5mg/L) after 24 h of incubation. The percentage of degenerating oocysts was 29%. Such cryptosporidicidal effects of the copper surface on oocysts were completely inhibited by overlaying the surface with a Millipore filter before adding oocysts and incubating oocysts in the presence of catalase, an antioxidant enzyme. These findings suggest that copper tubing inactivates infectious C. parvum oocysts cytotoxically which may be due to oxygen radicals generated by the interaction between Cu²⁺ and hydrogen peroxide on the tubing surface.

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The producibility of thermostable direct hemolysin (TDH) is the most important pathogenic factor in Vibrio parahaemolyticus. TDH (+) V. parahaemolyticus is usually isolated from patients having V.parahaemolyticus food-borne disease. TDH (+) V. parahaemolyticus is, however, very difficult to isolate from food and environmental samples.
In the 5 years from 2000 to 2004 in Tokyo, V.parahaemolyticus was isolated from food samples related to 67 of 227 V.parahaemolyticus food-borne outbreaks. In these outbreaks, TDH (+) strains were also tried to isolate using PCR as the screening methods. TDH (+) V.parahaemolyticus strains were able to isolate from enrichment broth in which toxR, and tdh genes become positive in PCR. TDH (+) strains of the same serotype with patients were able to be isolated from 23 food samples related to 11 outbreaks (16.4%); 3 outbreaks in 2000, 2 in 2001, 2 in 2002, 1 in 2003, and 3 in 2004. The serotypes of V.parahaemolyticus isolated from food were O3: K6 (10 samples), O3: K5 (6 samples), O1: K25 (4 samples), O3: K29 (2 samples), O4: K 8 (1 sample), and O4: K11 (1 sample).
The isolation rate of the TDH (+) strain from enrichment broth differed with samples. In several samples TDH (+) strains were isolated easily only by examining 3 colonies, hence no TDH (+) strains were isolated in spite of the examination of 250 colonies. No correlation was seen between the number of V.parahaemolyticus and the isolation rate of TDH (+) strains in food samples.
Screening using PCR is very effective method for isolating TDH (+) V.parahaemolyticus from food samples.

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Using 41 metallo-β-lactamase producing isolates and 8 metallo-β-lactamase nonproducing and ceftazidime-resistant isolates from Kyushu Island, metallo-β-lactamase was detected by 3 commercial metallo-β-lactamase detection kits, which were Metallo-β-lactamase SMA Eiken (SMA, disk diffusion, Eiken Chemical Co.), dry plate Eiken DPD1 (DPD, two-fold serial broth microdilution, Eiken Chemical Co). and Cica β test I/MBL (CIC, coloring reaction, Kanto Chemical Co.). Detection rate by SMA, DPD, and CIC was 97.5, 100, and 100%. Neither method used in this study produced false-positive or false-negative results. The rates of metallo-β-lactamase nonproducer identification were 37.5%, 62.5%, and 100% for the SMA, DPD, and CIC kits, respectivily.
These three methods have the following features, SMA is useful for routine work because SMA utilizes disk diffusion, which is widely used by medical technologists, and it is the least expensive of the three kits. CIC can detect metallo-β-lactamase after only 15 minutes and can determine the presence of non-metallo-β-lactamase producers at a high rate. DPD can simultaneously identify the MIC of some agents. Consequently these three metallo-β-lactamase detection kits were very useful for detecting metallo-β-lactamase producing isolates.

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Noroviruses (NVs) cause human gastroenteritis through person-to-person transmission and via contaminated foods. In food poisoning, a major suspected cause is the consumption of raw oysters. We detected NVs from environmental water and oysters around a closed gulf where oysters are cultivated. We collected oyster and water samples once or twice a month for 30 months from October 2001 to March 2004. We then studied monthly changes in virus occurrence and in genetic relationships among 208 NVs isolated from water and oyster samples and from the feces of children suffering from acute gastroenteritis during the same period in the same region.
In the analysis of untreated water flowing into farm sewage, NVs were detected year round. In other water samples -processed sewage, river water, and seawater-, oysters, and children's feces, NVs were detected mainly in winter. A comparison of NV nucleotide sequences showed genetic diversity, but some strains predominated in certain winter seasons. These predominant strains were detected across sample materials. In 2002/03, an identical strain was detected in sewage, river water, seawater, oysters, and feces. We also found that NV genetic types changed at the beginning of the season, in November or December, in both 2001/02 and 2002/03.
This study showed a clear relationship between NVs detected in children's feces and those in environmental water and oysters. These results support the idea that NVs are transmitted from the feces of infected persons to oysters by the flow of water through farm sewage, rivers, and the sea, finally accumulating in the mid-gut gland of oysters.

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Loop-mediated isothermal amplification (LAMP) amplifies a target gene with high specificity and rapidity under isothermal conditions. LAMP assays were developed for the rapid detection of metallo-β-1actamase (MBL) genes such as bla_IMP-1 and bla_VIM-2. We initially designed specific primers to detect MBL genes for LAMP assays and evaluated the specificity and sensitivity of these assays. LAMP assays amplified MBL genes under a constant temperature of 63°Cwithin 1 hour, and were compared to PCR in MBL-producing strains. The results of MBL genes typing by LAMP assays agree completely with PCR results. The lower detection limits of bla_IMP-1-and bla_VIM-2-LAMP assays using real-time turbidimeters were 30cfu/test and 3cfu/test, . After amplification, products were directly observed by the naked eye with a fluorescent detection reagent. In conclusion, LAMP assays are convenient, rapid, and fully feasible for detecting MBL genes in ordinary clinical microbiology laboratories without special apparatus.

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We report case of a 67-year-old alcoholic fisherman who developed infective endocarditis caused by Erysipelothrix rhusiopathiae. The initial manifestations were fever and back pain of approximately three months' duration. Auscultation of the heart revealed a loud systolic murmur at the apex and a diastolic murmur over the aortic valve area. Echocardiographic studies showed vegetations on both the aortic valve and mitral valve. Blood cultures grew Erysipelothrix rhusiopathiae, and it was sensitive to aminobenzyl penicillin. No other bacteria grew aut. A diagnosis of infective endocarditis caused by the Erysipelothrix rhusiopathiae was made, and the patient was treated with aminobenzyl penicillin 12g/day for 6 weeks. His clinical course was complicated by heart failure, multiple cerebral embolism, and renal infarctions. However, he recovered without valve replacement. Although the exact route of infection remains unknown, erosions of the skin, of his palms at the time of tho initial examination appeared to be one possible source of the systemic infection in this case. The serotype of the bacteria was Ib. To our knowledge this is the first case of serotyping of bacterium that caused endocarditis in humans.

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Legionella species have been widely recognized as among the important causative organisms of community-acquired pneumonia in Japan. A delay in the start of adequate treatment has a negative influence on the outcome of the disease. Telithromycin, the first oral ketolide antibacterial, was developed for the treatment of community-acquired pneumonia, including Legionella pneumonia. However, few reports have indicated the efficacy of telithromycin in community-acquired pneumonia caused by Legionella species. We report three cases of Legionella pneumonia, that were improved by early telithromycin therapy. The first patient (67-year-old man) had bronchiectasis as an underlying disease, and the second patient (73-year-old man) had diabetes mellitus and chronic renal failure. The third patient (62-year-old man) developed pneumonia after a spa tour. The diagnosis of Legionella pneumonia was made on the basis of the presence of a single IgG titer of 1/256 in case 1 and positive antigenuria in cases 2 and 3. The patients were classified into a mild group (case 1) and a moderate group (cases 2 and 3) based on the severity of the community-acquired pneumonia according to the 2005 Japanese Respiratory Society Guidelines. The results support the efficacy of telithromycin in mild to moderate Legionella pneumonia.

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A 48-year-old man infected with an HIV-1 experienced intermittent bouts of fever, lymphadenopathy, elevated CRP level, and thrombocytopenia, each lasting about 2 weeks, and recurring at 2-3 month intervals. His CD4 count was about 500/μL, and he had never received antiretroviral therapy (ART). In March 2005, he experienced the same symptoms, accompanied by liver damage, splenomegaly, pleural fluid, and a high serum soluble IL-2 receptor level. Examination of a cervical lymph node specimen resulted in a diagnosis of Castleman disease, plasma cell type. Immunohistochemical studies confirmed the presence of HHV-8 and Ebstein-Barr virus (EBV). Since the plasma HHV-8 DNA and serum IL-6 were elevated during the flareup, were negative between episodes, he was treated with ART to control the Castleman disease. He remained asymptomatic for 3 months, but, similar symptoms recurred with a high level of HHV-8 DNA in his PBMCs. Oral valganciclovir was them started at 1, 800mg twice daily, and his symptoms immediately improved. The HHV-8 DNA level in the PBMCs decreased markedly over the course of 4 weeks, and valganciclovir was discontinued. One week later, he experienced another flare-up, and was successfully treated with 10 days of valganciclovir 1, 800mg, followed by maintenance with valganciclovir 900mg. ART was discontinued, because the valganciclovir plus ART caused severe fatigue. No subsequent flare-ups have been observed, and, no HHV-8 DNA has been detected in his PBMCs. Castleman disease is an unusual complication in patients with HIV-1 and HHV-8 infection, but it should be included in the differential diagnosis of patients who exhibit a relapsing systemic inflammatory syndrome and lymphoadenopathy. Further study is needed to determine the appropriate usage and timing of the anti-HHV-8 and HIV-1 medication.

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I detail clinical observation, examination, and treatment of regional otorhinolaryngological infection 3-cases of acute sinusitis and 1 of acute pharyngitis-due to Chlamydia pneumoniae, occurring between January 2002 and December 2004.
Special clinical features by infection with C. pneumoniae were not recognized in the 4 cases, while ordinary clinical features by conventional bacterial infection were recognized, such as pharyngalgia and pyrexia for acute pharyngitis and purulent discharge and headache for acute sinusitis.
I diagnosed an infection for C. pneumoniae for 1 case with acute sinusitis by detecting a causative factor gene of C. pneumoniae by PCR. I diagnosed C. pneumoniae for the 2 other cases of acute sinusitis and the case of acute pharyngitis by confirming antibody titer of C. pneumoniae ascending by serological verification.
The 1 adult acute sinusitis case and the acute pharyngitis case were treated using a new quinolone antimicrobial agent. I administered macrolides antimicrobial agent to the 2 acute pediatric sinusitis cases and attained good outcomes without recurrence.
We wish to emphasize that C. pneumoniae infectionin in the otorhinolaryngological setting has not been adequately reported and has not received the attention it deserved. If a good outcome cannot be attained using the β-lactam antimicrobial agent for otorhinolaryngological infection, it should be sought using a macrolides antimicrobial agent or the new quinolone antimicrobial agent for adults and with the macrolides antimicrobial agent for pediatric cases.

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[in Japanese]

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Group G streptococcus (GGS) is infrequently associated with severe invasive soft tissue infection and toxic shock syndrome. A 74-year-old woman with a history of lymphedema of the lower extremities after surgical and radiation therapy for uterine cancer and diabetic mellitus and admitted for swelling of the right leg, fever, and dyspnea. She presented with shock and necrotizing cellulitis of the right lower extremity. Laboratory tests showed leukocytepenia, acute renal and liver dysfunction, and muscle damage. She rapidly developed multiple organ failure and necrotizing cellulitis. A swab from skin vesicle, throat, and blood culture grew Group G Streptococcus dysgalactiae subsp. equisimilis. Despite endotoxin hemoadsorption therapy, administration of antibiotics, and intravenous immunoglobulin, she died 9 days after admission due to toxic shock syndrome caused by GGS. The M-protein gene (emm) typing of GGS isolated from both blood and skin lesion showed stG 485.0. Three virulence genes, sagA, slo and skcg, were detected from GGS isolated from them.

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