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Background Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. Methods This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. Results Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0–7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. Conclusions The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).

This study was performed to determine the prevalence, antimicrobial susceptibility, and genetic relatedness of Salmonella enterica subsp. enterica and Campylobacter spp. in poultry meat, and to analyze the association of genetic types of these bacteria with their geographical distribution and antimicrobial resistance profiles. Salmonella and Campylobacter isolates have been detected, respectively, in 54 and 71 samples out of 100 samples tested. Nine Salmonella serotypes were found, including S. enterica subsp. enterica serovar Infantis (33%), Schwarzengrund (12%), Manhattan (9%), and others. Campylobacter jejuni and C. coli were detected in 64 (64%) and 14 (14%) samples, respectively. S. enterica subsp. enterica isolates were very frequently resistant to tetracycline (78.3%) and streptomycin (68.3%). Many C. jejuni and C. coli isolates were resistant to sulfamethoxazole/trimethoprim (90.5%), nalidixic acid (47.3%), ampicillin (45.9%), and ciprofloxacin (40.5%). Cluster analysis was performed for the Salmonella isolates using pulsed-field gel electrophoresis (PFGE) data. For Campylobacter isolates, the cluster analysis was based on both PFGE and comparative genomic fingerprinting. The molecular typing results were compared with the information about antimicrobial resistance and geographical locations in which the poultry meat was produced. This analysis revealed that C. jejuni strains with a particular genotype and antimicrobial resistance profile are spreading in specific areas of Japan.

Salmonella is a major causative agent of food borne diseases. Recently, monophasic strains of Salmonella, such as S. enterica 4: i: -, have been frequently reported. Here, we investigated the genetic background of S. enterica 4: b: - using multilocus sequence typing (MLST) and pulsed-field gel electrophoresis. A total of 10 strains of S. enterica (I) 4: b: - were examined and compared with 34 strains including serovar Paratyphi B and Paratyphi B var Java, Schleissheim, and II b: -. All I 4: b: - strains were negative for hin which encodes an invertase that converts the H phases, and six were also negative for fljB, which encodes the second phase of the H antigen. An MLST analysis identified 12 sequence types (ST) and 6 ST complexes (STC) from the 44 strains. A clustering analysis of PFGE patterns almost corresponded to the STC. The monophasic I 4: b: - strains were assigned to 3 STCs (19, 32 and 155), corresponding to those of Paratyphi B var. Java or a monophasic strain according to the data of this and previous studies. These findings suggest that the monophasic strains examined in this study might have been derived from multiple clones of Paratyphi B var Java. This study shows the usefulness of molecular typing as complementation tools of the conventional serotyping system.

The Japanese Gastric Cancer Association (JGCA) started a new nationwide gastric cancer registry in 2008. Approximately 50 data items, including surgical procedures, pathological diagnoses, and survival outcomes, for 12004 patients with primary gastric cancer treated in 2001 were collected retrospectively from 187 participating hospitals. Data were entered into the JGCA database according to the JGCA Classification of gastric carcinoma, 13th edition and the International Union Against Cancer (UICC) TNM Classification of malignant tumors, 5th edition by using an electronic data collecting system. Finally, data of 11261 patients with gastric resection were analyzed. The 5-year follow-up rate was 83.5%. The direct death rate was 0.6%. TNM 5-year survival rates (5YSRs)/JGCA 5YSRs were 91.8/91.9% for stage IA, 84.6/85.1% for stage IB, 70.5/73.1% for stage II, 46.6/51.0% for stage IIIA, 29.9/33.4% for stage IIIB, and 16.6/15.8% for stage IV. The proportion of patients more than 80 years old was 7.0%, and their 5YSR was 48.7%. Compared to the JGCA archived data, though the follow-up rate needs to be improved, these data suggest that the postoperative results of patients with primary gastric carcinoma have improved in those with advanced disease and in the aged population in Japan.

症例は70歳の女性で, 脳梗塞症後の寝たきり状態で介護施設に入所中であったが, 腹痛と腹部膨満を主訴に来院した. 来院時血圧は83/33mmHg, 脈拍88回/分, 体温35.0℃であった.腹部膨満と圧痛を認めたが筋性防御はなかった. 血液生化学検査では白血球増多, CRPの上昇を認めた. 腹部X線検査で腹腔内遊離ガスを, 腹部CTでは腹水と肝両葉の門脈ガス, 小腸壁の肥厚と腸管気腫を認めた. 腸管壊死による消化管穿孔, 汎発性腹膜炎を疑い, 緊急手術を施行した. 手術所見では腸管壊死, 腸管穿孔はなく多量の腹水を認めたのみであった. 腹腔洗浄, 盲腸瘻, 空腸瘻, 胃瘻造設術を施行した. 術後は空腸瘻からの経管栄養により栄養状態も改善し介護施設へ転出となった. 本症例は, 明らかな原因は不明であるが, 便秘による腸管内圧の上昇に伴い, 粘膜損傷部から腸管気腫と門脈ガスを発症し, 漿膜のmicroperforationにより腹腔内遊離ガスが生じたと推測された.

Chromosomal 8p23 deletion syndrome is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. The responsible gene for the heart defects in this syndrome has been identified as GATA4 on 8p23.1. Two patients with interstitial deletions of 8p23.1 were investigated; one patient showed moderate developmental delay and Ebstein anomaly, and the other showed mild delay and typical atrioventricular septum defect. The precise deletion sizes, 17 and 2.9 Mb, were determined by FISH analyses using BAC clones as probes. The latter deletion was the smallest deletion including GATA4 in the previously reported patients, and the critical regions and genes for clinical manifestation of 8p23 deletion syndrome, including facial anomalies, microcephaly, behavioral abnormality, and developmental delay, were discussed.

症例は58歳, 女性. 2006年5月に右下腹部痛を主訴に紹介来院した. 腹部超音波, CT, DIC-CTで, 肝S6から肝外に発育した径7cmの嚢胞性腫瘤を指摘された. 嚢胞壁は薄く, 単房性で, 単純性嚢胞の可能性があったが, 有症状であったこと, 肝嚢胞腺腫が否定できなかったことから, 腹腔鏡下に手術を施行し, 完全切除した. 病理組織学的には嚢胞壁は立方円柱上皮からなる肝嚢胞腺腫であった. 一般的に, 肝嚢胞腺腫か腺癌かを術前に診断するのは難しい. また腺腫から癌への移行もあり, 肝嚢胞腺腫自体は良性腫瘍であるが, 悪性腫瘍に準じた完全切除が必要となる. 腹腔鏡下手術は嚢胞の破裂の危険性があり適応は慎重であるべきであり, 本邦での施行例は現在まで極めて稀である. しかし肝外発育型で肝切除の容易なもの, 大きさの小さいものに対しては適応になると思われる. 自験例は鏡視下手術の良い適応であったと思われ, 若干の文献的考察を加え報告する.

症例は54歳, 男性. 腹痛と嘔吐を主訴に来院した. 手術既往歴はなく, 腹部所見では圧痛と軽度の反跳痛を認めたが筋性防御はなかった. 腹部CTで小腸の拡張が著明で内ヘルニアが疑われたが, 症状が軽くイレウス管留置による保存的療法を行った. 連日排液は良好であったがイレウスの改善を認めなかったため, 入院4日目にイレウス管から小腸造影を行った. 左下腹部にループ状の拡張した小腸とその口側, 肛門側の締め付け様の狭窄部が造影された. 腹部CT所見とあわせ, S状結腸間膜ヘルニアを疑い腹腔鏡下手術を施行した. 腹腔鏡下に観察すると, S状結腸間膜左葉に小腸が引き込まれ, 回腸が約4cm嵌入していた. 鉗子によって整復を行い, S状結腸間膜左葉に約3cmのヘルニア門を確認した. ヘルニア門はクリップで縫縮した. 術後経過は良好で術後第12日目に退院となった.

Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid–resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin–induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I–IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.

Medical applications of laser are measurement, laser surgery, in-situ monitoring, and processing of medical devices. In this paper, author briefly reviews the trends of medical applications, describes some new applications, and then discuss about the future trends and problems of medical applications. At present, the domestic market of laser equipment for medical applications is nearly 1/10 of that for industrial applications, which has registered significant growth continuously. Laser surgery as a minimum invasive surgery under arthroscope is expected to decrease the pain of patients. Precise processing such as cutting and welding is suitable for manufacturing medical devices. Pulsed laser deposition has been successfully applied to the thin film coating. The corneal refractive surgery by ArF excimer laser has been widely accepted for its highly safe operation. Laser ablation for retinal implant in the visual prosthesis is one of the promising applications of laser ablation in medicine. New applications with femtosecond laser are expected in the near future.

Diarrheagenic Escherichia coli are differentiated from non-pathogenic members with enterotoxin production, enteroinvasiveness and serotyping. However, the serotypic members are rarely sufficient to reliably identify a strain as diarrheagenic on E. coli. Recently, there are many definite articles which the adhesive E. coli strain against intestinal epithelial cells is enterovirulent. In this study, 1,748 E. coli isolates of diarrheagenic and non-diarrheagenic categories which belonged to EHEC, ETEC, EIEC EPEC and non-EPEC were examinated by PCR method for the presence of eaeA, aggR and bfpA regarding adherence factor genes, and astA of EAST1. The strains examined were recognized to variable carrying geno-patterns, and a large number of EHEC, EPEC and non-EPEC had carried either eaeA or aggR genes. In EHEC isolates, a carrying pattern with the most high frequency was only eaeA, and this type was recognized in the isolates of serotype O157, O26 and O111. EPEC and non-EPEC isolates were recognized eaeA or aggR which harboring with astA or not. Of 508 EPEC isolates from human, a total of 137 isolates (27.0%) carried aggR, and a total of 74 isolates (14.6%) had eaeA, while of the 91 isolates from non-human were recognized aggR and eaeA with 2.2% (2 isolates) and 12.1% (11 isolates), respectively. Also, of 266 non-EPEC isolates from human, a total of 16 isolates (6.0%) carried aggR, and a total of 58 isolates (21.8%) had eaeA. On the other hand, 22 (7.0%) of 316 isolates examined from non-human had eaeA, however no isolate had aggR. Thirteen isolates of EIEC and 218 ETEC isolates were screened, and only 6 ETEC isolates had either eaeA or aggR. The astA gene was recognized in the isolates of all categories, and ETEC strains had more frequently. The bfpA gene was recognized with more frequently in a serotype O157: H45, which is obtained from human with diarrhea, however, this strain was not recognized a member of the EPEC serotype. There is no diagnostic system for the strain of E. coli that cause diarrheal diseases, therefore more laboratories are unable to identify them. The authors had confirmed which PCR technique is a useful simple and rapid method for the detection of adherence factor genes on E. coli strains. From the these results, we showed a differentiation method using PCR technique which have relation with adherence factor, enterotoxin-production and invasiveness, and we firmly believe that application of the procedure is a reasonable and useful method for the identification of diarrheagenic E. coli.

結腸癌術後ダグラス窩腹膜転移に対しpharmacokinetic modulating chemotherapy (PMC)を施行し, 2年経過して根治切除が可能であった1例を経験したので報告する.症例は66歳,男性.平成8年11月上行結腸癌に対し結腸右半切除術を施行(中分化腺癌, se, n2, stage IIIb).平成11年10月CEAの上昇に伴い直腸指診でダグラス窩転移が疑われ,平成12年1月経肛門的に腫瘤生検施行し,高分化腺癌の診断を得た.ダグラス窩腹膜再発に対しPMCを週1回外来通院で施行した. PMCを20カ月施行したところで,腫瘍の増大に伴い直腸RaRbでの腸管狭窄が高度となり,排便障害改善の目的から平成13年10月に開腹術施行.腹膜転移巣と直腸は合併切除可能であり低位前方切除術を施行した. PMCは腹膜再発に対し長期のno change (NC)を得ることができ,人工肛門を回避した根治切除を可能とした.また経過中に有害反応は認められず,再発大腸癌に対してPMCは有効であると考えられた.

Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).

We investigated whether the polycation poly-L-arginine elicited cutaneous vascular hyperpermeability and scratching behavior and, if so, whether these responses involved mast cells and sensory nerves in rats. Intradermal injections of poly-L-arginine induced vascular hyperpermeability and scratching behavior. Combined treatment with chlorpheniramine and methysergide almost completely suppressed the poly-L-arginine (50 microg/site)-induced plasma leakage. Capsaicin desensitization and the tachykinin NK(1) receptor antagonist LY303870, (R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane, partially inhibited the leakage. In mast cell-deficient rats, poly-L-arginine only minimally induced plasma leakage. On the other hand, capsaicin desensitization and LY303870, but not chlorpheniramine or methysergide, suppressed the poly-L-arginine (200 microg/site)-induced scratching. Moreover, poly-L-arginine elicited the scratching even in mast cell-deficient rats. These results suggest that substance P is at least partly involved in both the cutaneous plasma leakage and the scratching behavior induced by poly-L-arginine. Moreover, mast cell-derived amines are suggested to be involved in the plasma extravasation but scarcely, if any, in the scratching behavior.

The effect of erdosteine, a mucoactive drug, on hypochlorous acid (HOCl)-induced lung injury, and the lipopolysaccharide (LPS)-induced increase in tumour necrosis factor-α (TNF-α) production and neutrophil recruitment into the airway, was investigated. Male BALB/c mice were orally administered erdosteine (3–100 mg kg−1), ambroxol hydrochloride (ambroxol) (3–30 mg kg−1), S-carboxymethyl-L-cysteine (S-CMC) (100–600 mg kg−1) or prednisolone (10 mg kg−1), 1h before intratracheal injection of HOC1 or LPS. In the HOCl-injected mice, erdosteine markedly suppressed increases in the ratios of lung wet weight to bodyweight and lung dry weight to bodyweight, whereas the other mucoactive drugs ambroxol and S-CMC had little effect. Erdosteine also inhibited the LPS-induced neutrophil influx, although it did not affect the increased level of TNF-α in the bronchoalveolar lavage fluid. The results suggest that attenuation of reactive oxygen species and neutrophil recruitment is involved in the clinical efficacy of erdosteine in the treatment of chronic bronchitis.

今回われわれは直腸平滑筋腫の1例を経験したので報告する.症例は66歳の女性, 肛門部不快感, 下血を主訴に入院した.注腸造影, 直腸鏡, 骨盤computed tomography, magnetic resonance imagingなどの検査により直腸粘膜下腫瘍 (平滑筋腫疑い) と診断し手術を施行した.全身麻酔下に経仙骨的に腫瘍に達し, 腫瘍を摘出した.摘出標本は4.0×4.0×5.2cmの白色の充実性腫瘍で2.0×3.0×3.0cmのdaughter noduleと一塊になっていた.病理組織学的に平滑筋腫と診断された.直腸平滑筋腫はその良性悪性の鑑別が時に困難で, 悪性化例も報告されており, 慎重な術後経過観察を要するものと思われた.

The Japanese Gastric Cancer Association Registration Committee reported the treatment results and causes of death of patients with primary gastric cancer treated in 1991 at the leading hospitals in Japan. Data of 8851 patients with primary gastric cancer were collected from 113 hospitals, and data of 7935 patients with gastric resection were finally analyzed. The lost-to-follow-up rate was 6.9%; the direct death rate was 1.0%. The cumulative 5-year survival rate (5YSR) of all the patients was 68.2%; 89.9% for Stage I, 69.1% for Stage II, 43.5% for Stage III, and 9.9% for Stage IV. Characteristic findings of the analyzed data were (1) high proportion of early-stage cancer, (2) high resection rate, (3) low mortality rate, (4) low incidence of upper-third cancer, (5) poor treatment results in cases with scirrhous cancer, infiltrating growth, and marked lymphatic or venous invasion, and (6) predominance of systematic (D2) and extended lymphadenectomies possibly resulting in reducing local recurrence and improving survivals.

Rhythmical contractions accompanied by an increase in cytosolic Ca2+ concentrations were produced in ring preparations of endothelium-denuded pulmonary arteries from monocrotaline-treated rats, but not in those from vehicle-treated rats, 2-3 h after a resting tension of 15 mN (150-180% of the initial wall length of the artery) was applied. The rhythmical contractions were abolished by nicardipine and ryanodine. Cyclopiazonic acid reduced the relaxation phase of the rhythmical contractions, finally leading to a sustained contraction. Similarly, apamin caused a sustained contraction, whereas charybdotoxin increased the amplitude of the rhythmical contractions. Glibenclamide had no apparent effects on them. Indomethacin and the prostaglandin H2/thromboxane A2 receptor antagonist SQ29548 abolished the rhythmical contractions and reduced the tension, but the thromboxane synthase inhibitor ozagrel had no effect. These results suggest that optimal stretch induces rhythmical contractions in the pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats, to which both Ca2+ influx through voltage-operated Ca2+ channels and Ca2+ release from the endoplasmic reticulum seem to contribute. It is also suggested that small-conductance Ca(2+)-activated K+ channels participate in the relaxation phase of rhythmical contractions. Furthermore, prostaglandin H2 released from nonendothelial cells is likely to play a pivotal role in the induction of rhythmical contractions.

Intradermal injections of poly-L-arginine induce cutaneous vascular hyperpermeability and scratching behavior in rats. Recently, we elucidated that the plasma extravasation involved both histamine and substance P, while the scratching behavior involved substance P, but not histamine. This study examined the effects of olopatadine hydrochloride (olopatadine), an antiallergic drug with histamine H1-antagonistic action, on the poly-L-arginine-induced responses. Olopatadine (1 mg/kg, p.o.) significantly inhibited both the plasma extravasation and the scratching behavior, suggesting that its inhibitory effects are mediated by the suppression of neuropeptidergic action as well as histaminic action. Olopatadine seems to be a novel-type drug for the treatment of dermatitis.

In June, 1984, a large-scale outbreak of type A botulism occurred in 14 different prefectures in Japan, involving 36 cases and 11 deaths, due to consumption of vacuum-packed ‘karashi-renkon’ (deep-fried mustard-stuffed lotus root). The onset of symptoms ranged from June 9th through July 28th and many batches of ‘karashi-renkon’, having been manufactured by a factory during a period of three weeks from June 5th to June 25th, were found to be contaminated with type A spores. Type A spores (1.0 × 104 cfu/g) experimentally inoculated into the mustard-miso stuffing [water activity (aw) 0.92, pH 5.0, NaCl 5.7%] did not multiply. By adjusting the stuffing to aw 0.98 (pH 5.4) growth of type A was still inhibited. When the stuffing with elevated aw and pH was heat-treated for 60 min at 80°C or autoclaved, it supported growth of Clostridium botulinum type A as indicated by the achievement of toxin levels higher than 105 LD50/g. When mustard-miso was stuffed into the holes of lotus roots and refrigerated overnight or a longer period, both aw and pH of the stuffing increased to 0.98 and 5.3, respectively. The changes were apparently due to dialysis between the stuffing and the lotus root. This refrigeration process was actually performed at the plant, where the incriminated foodstuff was manufactured. The dialyzed mustard-miso stuffing, when heat-treated, supported the growth of type A organisms. Thus, we substantiated the possibility of primary multiplication of C. botulinum type A in mustard-miso stuffing subjected to refrigeration in lotus roots and then heat-treated.

Clostridium botulinum type C toxin of 16S was more potent as an oral toxin to geese than that of 12S.