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Thalidomide is a TNF-alpha inhibitor and has been administrated for erythema nodosum leprosum (ENL, Type II leprosy reaction) which is one of leprosy reactions and can cause serious illness to patients oflepromatous pole among the immune spectrum. Twenty live cases (at May, 2011) were identified to whom thalidomide had been administrated since 1978 for their ENL reactions. Data were collected from their clinical records in order to evaluate the usage and effectiveness of thalidomide in National Sanatorium Oku-Komyoen, Okayama, Setouchi-city, Japan. Individual data includes bacillary index (BI), total dose, average daily dose, maximum daily dose, minimum daily dose, methods of thalidomide administration and change of symptoms of ENL. Results: No adverse effect was found among 20 cases. Average daily dose of 20 cases was 19 mg. Regarding to the maximum daily dose, in 3 cases (15%) more than 100 mg, in 3 cases (15%) 50 mg, and in 14 cases (70%) less than 40 mg was administrated. Dose was gradually tapered in most cases. From clinical records, thalidomide was found effective for ENL in 19 cases and clinicians concerned were trying to adjust the proper dose of the drug carefully depending on the current symptoms, because there was no guideline of thalidomide administration for ENL. This data suggests that even less than 50-100 mg as the initial daily dose was still effective, though 50-100 mg daily dose is recommended in the current guideline of Japan (2011) and more dose had been administrated in USA and India.

ad hoc committee of Japanese Leprosy Association recommends revised standard treatment protocol of leprosy in Japan, which is a modification of World Health Organization's multidrug therapy (WHO/MDT, 2010). For paucibacillary (PB) leprosy, 6 months treatment by rifampicin and dapsone (MDT/PB) is enough. However, for high bacterial load multibacillary (MB) leprosy, 12 months treatment seems insufficient. Thus, (A) For MB with bacterial index (BI)3 before treatment, 2 years treatment by rifampicin, dapsone and clofazimine (MDT/MB) is necessary. When BI becomes negative and active lesion is lost within 2 years, no maintenance therapy is necessary. When BI is still positive, one year of MDT/MB is added (3 years in total), followed by maintenance therapy by dapsone and clofazimine until BI negativity and loss of active lesions. (B) For MB with BI3 or fresh MB (less than 6 months after the onset of the disease) with BI3, 1 year treatment by MDT/MB is necessary. When BI becomes negative and active lesion is lost within one year, no maintenance therapy is necessary. When BI is still positive or active lesion is remaining, additional therapy with MDT/MB for one more year is recommended. Brief summary of diagnosis, purpose of therapy, character of drugs, and prevention of deformity is also described.

The origin, history, sensitivity to anti-leprosy drugs and genotypic characteristics for 27 strains maintained at the Leprosy Research Center in Tokyo are described. Strains are isolated and passaged in nude mouse footpads, and frozen bacillary suspensions with different generations are also maintained. The Leprosy Research Center provides bacillary materials as experimental resources at researchers' request.

The main principles of leprosy control, based on timely detection of new cases and their treatment with effective chemotherapy in the form of multidrug therapy, will not change over the coming years. The emphasis will remain on sustaining the provisions for quality patient care that are equitably distributed, affordable and easily accessible. The Enhanced Global Strategy for Further Reducing the Disease Burden due to Leprosy: 2011-2015 together with the updated Operational Guidelines of the Enhanced Global Strategy. The Strategy will require endorsement and commitment from everyone working towards the common goal of reducing the disease burden due to leprosy and its detrimental physical, social and economic consequences in order to move closer to achieving the common dream of "world without leprosy".

The number of ex-leprosy patients has reduced rapidly who were forced to be admitted under leprosy prevention/segregation law and are staying at national sanatoriums with different disabilities due to different physical and social reasons for long time in Japan. Most of them have been of clinically cured status for decades after effective chemotherapy. Some have still been suffering from acute or chronic neuralgic pains which are supposed to be long standing consequences of nerve damage of leprosy and getting medications for long period. Pharmacy department of National Suruga Sanatorium has studied the amount of prescriptions of some medicines for last 11 years, which were thought to be prescribed for pain including neuralgic pain. There seem to be some tendencies of medications during last decade. VitaminB12 (Mecobalamine) is one of the commonest drugs for neuralgic pain at this sanatorium and the amount of prescription had almost been unchanged through the years. Prescription of non-steroid anti-inflammatory drugs (NSAIDs) increased year by year, which may reflect the increasing age of ex-patients who need more pain killers for their painful joints or back. Loxoprofen is the most popular pain killer here and increased by ten times for last decade. The number of prescription for Pentazocine and Hydroxyzine Hydrochloride injection increased for last several years, which reflects a few patients who were still suffering from severe chronic neuralgia for years. It is desirable that a standard regimen for chronic neuralgic pain as a consequence of nerve impairment in leprosy will be developed as soon as possible.

UNLABELLED Gene mutation of Mycobacterium leprae was studied on bacilli-positive multibacillary leprosy patients since 2000 in Japan. SUBJECTS LL 31 cases, BL 7 cases. RESULTS gene mutation of folP was found in 19/36 cases (52.8%), that of rpoB in 13/33 cases (39.4%), that of gyrA in 6/31 cases (16.8%). Five cases showed both mutations of folP and rpoB, and one case showed those of fol/P and gyrA. Mutations of folP, rpoB andgyrA all were found in 4/36 cases (10.3%). High incidence of resistance to DDS or rifampicin was observed, and incidence of resistance to of loxacin was considerably high. These results reveal existence of multidrug-resistant bacilli in Japanese leprosy patients. Treatment of these cases was arranged according to the result of gene mutation analysis and satisfactory effects were obtained in 34/38 cases. One case did not response to newer treatment. Three cases refused use of improved treatment and their disease activities are not controlled. This study proved that gene mutation analysis is a rapid and accurate method to know the drug resistance against DDS, rifampicin and new quinolones, and important in chemotherapy of leprosy.

This reports a long-term follow-up study on clinical effects of ofloxacin (OFLX)-combined therapy to 14 leprosy patients with various types and stages. Combined drugs were diaminodiphenyl sulfone (DDS), rifampicin (RFP) and clofazimine. Clinical evaluation of the treatment after OFLX-combined therapy was remarkable improvement 10 cases, improvement 3 and re-exacerbated after improvement 1 to whom clofazimine and minocycline were prescribed. The evaluation during the follow-up was remarkable improvement 10, improvement 1; three cases died of traffic accident or complications not related to chemotherapy and none of them showed relapse of leprosy. Bacterial negativity after onset of OFLX-combined therapy was achieved in about the same periods as RFP-combined therapy. OFLX-combined therapy was effective and safe. This follow-up study supports the efficacy of clinical guideline for the use of new quinolones published by Japanese leprosy Association.

Antimicrobial susceptibility testing of Mycobacterium leprae by non-radioactive bioluminescence assay was developed. Optimization of the assay conditions such as temperature and time for ATP extraction, bacteria dose, preparation of bacteria suspension and pH of culture medium was carried out using M. leprae Thai 53 strain. Samples of bacterial suspension of M. leprae were first treated with filamentous cell treatment reagent at room temperature for 30 minutes and ATP was extracted from the leprosy bacilli by heating at 60 degrees for five minutes. Luciferin luciferase was added to the extract after cooling to room temperature followed by measurement of relative light units (RLU) of each sample using a luminometer. The concentrations of the drugs used for the evaluation of antimicrobial activities of rifampin (RFP), clofazimine (CLF), ofloxacin (OFLX) and clarithromycin (CAM) were 0.125, 0.50, 2.0 and 8.0 microg/ml respectively. Middlebrook 7H9 broth medium was used (pH6.6) as the basal medium and the bacilli were cultivated at 32 C for 0-14 days. ATP was extracted from 0.1 ml of culture suspension and inhibition of the luminescent activity was calculated. The results were compared to that obtained by radio-active CO2 detection system, Buddemeyer method which is commonly used for measuring anti-M. leprae activity. There was a good correlation between the results obtained by ATP method on the tenth day of culture and the results obtained by Buddemeyer method on the seventh day of culture. ATP method may be useful for the determination of drug susceptibility ofM. leprae.

Antibiotic susceptibility test of Mycobacterium leprae still relies on the time consuming methods based on the growth of M. leprae in the mouse footpad. Thus, the establishment of a rapid, simple and reliable method for the detection of drug-resistant M. leprae is one of the most urgent subjects in the treatment of leprosy patients. Recently, many data on the mutation of specific genes correlating with drug resistance have been accumulated. Application of these data permit the establishment of new gene diagnostic methods for drug susceptibility test of leprosy. In this paper, the method using the low density oligonucleotide array that enables the detection of base substitutions involved in resistance against anti-leprosy drugs on a single platform was discussed. The low density oligonucleotide array described in this paper will open the new perspectives in terms of patient management for leprosy with low cost requirement.

The time of the settlement of leprosy in Mexico is uncertain, however recent studies pointed out that leprosy was probably brought by Asian's migration at about 12,000 years ago and not by the Europeans conquerors during XVI and XVII centuries. Registration of leprosy has been done since the colonial era and the disease was considered as a public health problem until the year 2004 in Mexico when the incidence was achieved to be less than 1 per 10,000 as defined by the world health organization (WHO). Although the national epidemiological parameters like prevalence show the leprosy are controlled well, there are still 49 prefectures with higher prevalence in Mexico. In addition, the incidence in last 10 years has not been stably reduced, in other words the infection cycle has not been interrupted. Therefore, it is necessary to keep the careful epidemiological monitoring, and to increase the search and follow-up of new cases and their contacts in order to eliminate leprosy in this country.

The elimination of leprosy with the advent of multidrug therapy (MDT) is one of the success stories in public health. Elimination will be achieved in the regions of Western pacific and South-East Asia in near future. A biregional consultation between the WHO South-East Asia and Western Pacific regions was held in the end of 2004 in Manila, the Philippines. A strategy document was developed during the consultation, to sustain quality leprosy services in Asia and the Pacific beyond 2005, and to further reduce the leprosy burden. The main strategy involves timely detection of new cases, multidrug treatment, and the key element of integration of leprosy services into general health services.

Due to the advent of multi-drug therapy (MDT) recommended by the WHO, for the treatment of leprosy, presently, leprosy is regarded as a "curable disease". The number of new cases in Japan is relatively very low, due to which the disease is likely to be neglected, but on scientific grounds, there is a necessity to perform in depth studies. Leprosy caused by M. leprae is still unclear on various aspects including transmission, immunology, nerve damage etc. Here we introduce the recent advances in the field of basic leprosy research.

DNA sequences of Mycobacterium leprae in particular regions of the gyrA, rpoB, and folP genes responsible for resistance to new quinolones, rifampicin and dapsone, respectively, were analyzed. Among 88 isolates of M. leprae from leprosy patients in Japan, Haiti, Indonesia, Pakistan, and the Philippines, eleven isolates had mutational changes in 2 genes (resistance to 2 drugs), and 2 isolates (Shinsei-1 and Zensho-4) showed mutations in 3 genes (resistance to 3 drugs). These findings are suggesting emergence of multi-drug resistant M. leprae.

A 68 year-old male presented with painful swelling in the extremities and disseminated small brownish nodules over his entire body. A histological examination of the skin nodules showed multiple granuloma and a thickened peripheral nerve bundle surrounded with foamy macrophages and a few lymphocytes. Fite stain revealed numerous acid fast bacilli within the cytoplasm of the foamy cells. A diagnosis of lepromatous leprosy was thus made and multi-drug therapy following the Japanese guideline with DDS, rifampicin and clofazimine was started. The clinical features improved, and the morphological index decreased after undergoing chemotherapy. Although a severe type 1 reaction developed after four months of treatment, he was treated with oral prednisolone at a dose of 40 mg/day.

With the abolition of Leprosy Prevention Act of 1996, that opportunities examining the Hansen's disease patient with a general medical institution increase is expected. Because we experienced Hansen's disease of a staying in Japan foreigner then in such time, we present it. A case is a man of 50 years old, who is a Filipino of 3 years living in Japan. It recognized infiltrating deep erythema in a face and trunk. Furthermore, in dysesthesia, nerve hyperplasia, and Bl is positive in skin smear. Histopathology is a typical finding. Than the above, we diagnosed it as Hansen's disease of BL-LL type.

In Japan, a cautious definition of clinical cure of leprosy has been used since 1988. This report presents a new definition of clinical cure for leprosy patients after multi-drug treatment is completed. When the patients complete the standard treatment published in 2000, they are defined as "clinically cured". The doctor in charge should inform the patient of the cure of the disease clearly. On the release from the treatment, it is important to explain necessary cares for protection against injuries and prevention from deformities. The patient should be careful about signs of relapse and reactions.

We analyzed the medical and social problems of newly registered leprosy patients in the past 8 years from 1993 to 2000 in a low endemic country, Japan. There were 56 registered Japanese patients (males, 32; females, 24), and 76 registered foreign patients (males, 56; females, 20). The number of Japanese patients in each year was between 5 and 9, and 2/3 of them were from Okinawa Prefecture, located in subtropical zone. But the number of foreign patients in each year was between 5 and 18, and 2/5 of them were from Brazil. The number of foreign patients was greater than that of Japanese patients. Male/female ratio has decreased among the Japanese.

For the effective treatment of leprosy, we should consider that (1) more time is needed for the elimination of bacilli than ordinary bacterial infection, (2) bactericidal therapy often induces host immunity called reactions, (3) rapid treatment is needed for the reactions. Last year, ad hoc committee of Japanese Leprosy Association recommends standard treatment protocol of leprosy in Japan, which is a modification of World Health Organization's multidrug therapy. For multibacillary(MB) with bacterial index (BIor = 3) before treatment, 2 years treatment by rifampicin, dapsone and clofazimine (MDT/MB) is necessary. When BI decrease is not satisfactory(BI value decrease2 steps, or final BIor = 3) after 2 years, MDT/MB should be continued until BI negativity and loss of active lesions. Theoretical background of our proposal is described.

A case of reconstructive surgery for saddle nose deformity is presented in this paper. A 22 year-old Bengali female who had completed WHO/MB regimen for 27 months underwent reconstructive surgery for saddle nose deformity. Since a saddle nose is one of the symbols of leprosy, it often causes serious psychological and social troubles to patients. This happens more often when the patient is a young unmarried woman. In this case the saddle nose seemed to be very serious. After being discharged from hospital she got married and had a baby. This operation gave the patient great relief to live in the community, because she no longer had serious visible evidence of leprosy on the body. Though the correction of the deformity without any dysfunction does not always have priority over other surgeries at a busy leprosy control project in Bangladesh, it has merit both in patients themselves and in the society around them because it leads to the elimination of the stigma of leprosy.

Nephropathy as the sequences of Hansen's disease before and after the introduction of chemotherapy was compared referring to the report by Hayashi in 1943 and the summary of the autopsy reports from 1978 to 1981 at National Hansen's disease hospital Zenseien. Unlike the high rates of tuberculosis as the cause of death before the introduction of chemotherapy (41.3%) those thereafter decreased to be negligible. On the other hand the comparison of the rates of nephropathy with the same way as that of tuberculosis was impossible since the description about nephropathy by Hayashi was not sufficient to characterize each nephropathy since he included arteriolitis, glomerulonephritis and interstitial nephritis together in the term of nephritis. Death rate due to nephritis among Hansen's disease patients according to Hayashi at that time was 21.2% which was twice as many comparing to that in the other cases. According to the report about the cases of Zenseien those reported to have glomerulonephritis was 37.3% though those were not necessarily listed as the cause of death. Also the nephropathy including fibrinoid angitis with occasional microaneurysmal dilatation of afferent arteries, glomerulitis, sclerosis and stricture of efferent arteries likewise ischemic acute tubular necrosis possibly as the result of these angiopathy seemed to be present. These vascular changes partially resemble to that of microscopic periarteritis nodosa but seems to be common in the smaller arteries. In conclusion, unlike the case of tuberculosis the rate of nephritis including glomerulitis, arteriolitis and interstitial nephritis as Hayashi used as his criteria does not seem to have decreased. Therefore, the critical analysis of the nephropathy especially of that relating to the arteriolitis should be done to obtain the knowledge to suppress its occurrence.

Leprosy in Federated States of Micronesia is still endemic with incidence rate 221/100,000 and prevalence 33/10,000 in 1996. The disease was introduced by the patients from Nauru. Epidemic of the disease was observed in Pingelap during the 1960's and Kpingamarangi since 1966. Special project for the elimination of the disease by the chemoprophylaxis was launched in 1996. The preventive therapy is consist of one dose of an association of 3 antibiotics (rifampicin, ofloxacine and minocyclin) for adults and rifampicin alone for children. The project is completed for two years and followed by evaluation for 6 years. It is expected to reach the elimination level before year 2000.

バングラデシュの近年のらい事情を疫学調査面からのらい患者の掌握現況,国のらい対策プログラム,らい専門家の養成,多剤併用療法の実施方法およびその進展等について概説した。らい撲滅のためのプログラムの疫学面およびその実施活動面からの評価結果は,必ずしも正確とは思われない情報収集と資料不足のため正しい評価が下せないというのが実情である。また,不適当な所見例,処方通りに薬を服用しない多くの患者達の存在,さらにはプログラムを遂行するのに十分でない予算,専門家不足等,今なお5千余名のらい新患発生数をみるバングラデシュのらい対策は多くの困難の中で行われている。願わくば,"バングラデシュの結核とらい撲滅推進作戦"という名の下に施行されているプロジェクトが,近い将来,これらの病気に病む全ての患者達に行き届くことを望むものである。

As of the year 1991 there were 358 leprosy pa-tients in National Leprosarium Matsuoka Hoyo-En, including 223 patients (62.3%) who had received the injections of chaulmoogra oil before. Calcinosis cutis caused probably from the injections was noted on 73 patients (32.7%): 67 lepromatous and 6 tuberculosis cases. It has never been reported be-fore that the T type patient suffering from calcino-sis cutis was observed in the cases of the chaul-moogra oil injection in Japan.The detectable positions of calcinosis cutis were mostly at the injected sites, that is, outside the right brachium followed by bilateral-branchia and crura. In the group of patients with calcinosis cutis, the anti-PGL antibody was negative for the most part. Urinalyses, peripheral blood figure analyses, histopathological tissue examinations of calcium deposition, X-ray diffraction patterns, dif-ferential thermal and gravitational analyses, and chemical analyses were performed on all patients with this disease.Further, as the result of this study six patients with calcinosis cutis caused by sulpyrine was also found. The major component of the deposit by the drug was calcium phosphate.These calcinosis cutis were considered to be of trophopathic calcinosis based on the disorder of subcutaneous tissue due to the injections of respec-tive drugs : chaulmoogra oil and sulpyrine.

DDS耐性患者の問題が重大化し,DDS耐性菌をマウス足蹠法で検索せねばならないという声が高まっているが,われわれは,薬物耐性といっても,DDS耐性の場合は,DDSの免疫抑制作用とその長期使用によってDDSがらい症状の進行に伴い生じる免疫不全を加速する結果,薬物治効の現われにくい状態に立至らせるのではないかと考えて,実験動物を用いDDS, B663の宿主免疫への影響を調べたところ,次の知見を得た。なお体液性免疫への影響は改良カニンガム法(橋本ら)で,細胞性免疫への影響は遅延型過敏症検査とモルモットリンパ球を用いた兎赤血球とのロゼット形成法(横室ら)により調べた。1. DDSは体液性免疫には影響を示さなかったが,羊赤血球によるマウス足蹠腫脹を弱く抑制し,T細胞ロゼット%を正常モルモットで明瞭に,胸腺摘出後2ヵ月経過したモルモットでは著明に低下させた。これらからDDSの細胞性免疫への低下作用はGheiらの人での所見同様明瞭になった。2. B663は体液性免疫を弱く抑制する一方,DDSを投与後胸腺を摘出1ヵ月以内のモルモットにおいて著明にT細胞ロゼット%を増大させ,胸腺摘出前の無処置モルモットのレベル迄回復した。しかもB663を投与後胸腺を摘出した際,体内に残留する持続性のB663が人為的免疫不全化に抵抗する故か,摘出による細胞性免疫低下が余り見られなかった。しかしこのモルモットに更にB663を投与すると一層なおT細胞ロゼット%が増大した。この新知見は,なぜB663がENLに奏効するかの点と,将来の治療法改善に役立つのではあるまいかと考える。3. 基準物質として用いたレバミゾールは体液性免疫と細胞性免疫の双方を明瞭に亢進したが,B663のように超持続性でないので体内貯留に関しては少量の故か,胸腺摘出による人為的免疫不全化への抵抗作用はB663より弱い傾向が見られた。4. モルモットリンパ球上の対兎赤血球受容体に薬物が結合するとT細胞ロゼット%は低下する。そこで予めDDS, B663を管内でモルモットリンパ球と接触後兎赤血球とロゼットを形成させたところ,DDSには影響が見られず,B663は僅かにT細胞ロゼット%を低下させた。それ故DDSとB663のモルモット免疫への影響は薬物のモルモットリンパ球上受容体との反応により影響されているとは考えられないし,B663の細胞性免疫亢進作用は,少なくとも結果以上のものと推定された。5. モルモットリンパ球と兎赤血球とのロゼット形成法は,当該受容体への被検物質の影響により形成%低下が起る例でもなお多数試料を迅速に検査できる好便な細胞性免疫検査法と考えられるし,今回の実験で胸腺摘出後1カ月は免疫賦活物質の,摘出2カ月以後は免疫抑制物質の検査に適することも判明したので,今後は胸腺摘出モルモットを用いロゼット法を多用して行きたい。6. これら結果に基づき,DDS耐性患者の問題や,らいでの抑制性T細胞の意義,その賦活などが討論され,特に一般的免疫賦活療法と免疫賦活性消炎療法の区別につき論じられた。

1983年にLancasterらは,重症らい菌感染ヌードマウスの足蹠に多型核白血球の集団巣が存在し,また肝にもENLに類似した病巣が見られることを報告している。著者は上記の所見がヒトのENLに相当するものかどうかを解明するために,らい菌感染ヌードマウスに治らい薬を投与したとき,上記の多型白血球集団巣がどのように変化するか,また同病巣部に免疫複合体が存在するかどうかを検索した。らい菌感染ヌードマウスにDDSまたはリファンピシンを投与して組織学的なENL症状を誘導する試みは不成功に終った。また,ENLの発生機序として重視されている免疫複合体をらい菌感染ヌードマウスの病巣内に検出することはできなかった。多型核白血球集団巣の存在だけではENL発生の症状であると結論するには不充分である。ヌードマウスにおいてENLを発生させることは不成功に終ったが,本研究から以下の結論を下すことができた。1) 飼料に0.003%の割合にランプレンを添加し,らい菌感染後18週の比較的早期からヌードマウスに投与しても,多型核白血球集団巣の発生は完全には抑制されなかった。2) 多型核白血球集団巣の発生はDDSまたはリファンピシンの投与では増強されず,ランプレンの長期投与でやや軽減した。3) 早期から開始し,長期間持続したランプレンの投与は,ヌードマウスのらい腫性病変部に明らかな治癒機転をもたらした。ENL反応の発生機序を更に解明するためには,今後ヌードマウスにT cellサブセットを移入して行う実験が有意義であろうということが示唆された。