荒川 敏

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 x 10(-15)) and ARMS2 (rs3750847, P = 8.67 x 10(-29)) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 x 10(-12), odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 x 10(-8), odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathophysiology of exudative AMD.

Morise Z, Sugioka A, Kawabe N, Umemoto S, Nagata H, Ohshima H, Kawase J, Arakawa S, Yoshida R, Asian journal of endoscopic surgery, 2011, vol. 4, no. 3, pp. 143-146, 2011

Purpose: To assess the association between serum total bilirubin levels and diabetic retinopathy prevalence in participants of the Hisayama Study who had diabetes and impaired glucose metabolism. Design: Population-based, cross-sectional study. Participants: Of 3119 participants of the Hisayama Study Eye Examinations in 2007, Japan, 1672 aged >= 40 years with either diabetes or impaired glucose metabolism (defined by a 75-g oral glucose tolerance test) were enrolled in the present study. Methods: Diabetic retinopathy was assessed via ophthalmic examination after pupil dilatation. The presence and the severity of diabetic retinopathy were determined by grading of color fundus photographs using the modified Airlie House classification system. Association of diabetic retinopathy with serum bilirubin quartiles was assessed using logistic regression model adjusting for age and known risk factors for diabetic retinopathy. Main Outcome Measures: Prevalent diabetic retinopathy. Results: Diabetic retinopathy was present in 70 of 1672 (4.2%) participants. The prevalence of diabetic retinopathy in persons with the highest bilirubin quartile (>= 0.9 mg/dL) was 2.7%, compared with the prevalence of 3.4%, 5.1%, and 5.1% in those with the first (<0.6 mg/dL), second (0.6-0.69 mg/dL), and third quartiles (0.7-0.89 mg/dL). After adjusting for factors known to be associated with diabetic retinopathy, the prevalence was significantly lower among persons with the highest bilirubin quartile compared with those with the lowest quartile (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.09-0.72) or compared with those in the 3 lower quartiles (OR, 0.25; 95% CI, 0.11-0.58). Conclusions: Elevated serum bilirubin levels may be protective against diabetic retinopathy among persons with either diabetes or impaired glucose metabolism, independent of known risk factors for diabetic retinopathy.

PURPOSE. To estimate the long-term cumulative incidence and risk factors for retinal vein occlusion (RVO) in a population-based cohort study of Japanese. METHODS. In 1998, a total of 1775 individuals aged 40 years or older underwent a baseline eye examination. Of those, 1369 subjects (77.1%) took part in the follow-up eye examination in 2007 and were enrolled in the present study. Each participant underwent a comprehensive examination. The diagnosis of RVO, including branch (BRVO) and central RVO (CRVO), was determined by grading color fundus photographs. Logistic regression analysis was performed to determine risk factors for RVO. RESULTS. The 9-year cumulative incidence of RVO was 3.0% (2.7% for BRVO and 0.3% for CRVO). The age-specific cumulative incidence of RVO significantly increased with age (P for trend = 0.03). After adjusting for age and sex, higher diastolic blood pressure and chronic kidney disease (CKD) were significantly associated with RVO. In multivariate analysis, higher diastolic blood pressure (per 10 mm Hg) (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.14 to 2.01) and CKD (OR, 2.23; 95% CI, 1.02 to 4.89) remained independently significant risk factors for RVO. In stratified analysis, the risk of RVO was higher in subjects with CKD than that in subjects without CKD in both the nonhypertension and the hypertension groups. CONCLUSIONS. These findings suggest that the incidence of RVO is higher in Japanese than that in other Asians and Caucasians, and that higher blood pressure and CKD are independent risk factors for RVO in the Japanese. (Invest Ophthalmol Vis Sci. 2011;52:5905-5909) DOI: 10.1167/iovs.11-7775

PURPOSE. To determine a profile of gene expression in retinas of a murine model of oxygen-induced retinopathy (OIR). METHODS. OIR was induced in C57BL/6N mice by exposing postnatal day (P) 7 pups to 75% oxygen for 5 days and then returning them to room air at P12. Gene microarrays containing more than 47,000 transcripts were used to study the changes in gene expression in retinas isolated immediately (P12) and at 12 hours (P12.5) after exposure to hyperoxia. The retinas of P12 mice raised under normoxic conditions served as control subjects. Quantitative RT-PCR and multiplex ELISA were performed to validate the microarray analyses. RESULTS. The expression of 83 gene transcripts was significantly altered in the hyperoxic P12 retinas. These genes were classified as cellular components or were associated with development, metabolism, transport, stress response, cell adhesion, inflammation, or vision. The genes related to retinal growth, such as Pdgfb and Robo4, which are associated with vascular development, were downregulated. In contrast, the expression levels of 95 genes were significantly altered in the hypoxic P12.5 retinas, which contained several known hypoxia-regulated genes including Vegfa and Hif1a. The differentially expressed genes were broadly clustered into the development, inflammation, metabolism, signaling, antiapoptosis, cellular component, transport, glycolysis, and vision groups. Those associated with organogenesis (e. g., Vegfa, Igfbp3, Tnfrsf12a, and Nestin) and to inflammation (e. g., Ccl3, Ccl4, and MHCs) were upregulated. The results of quantitative RT-PCR and multiplex ELISA were in agreement with the microarray data. CONCLUSIONS. These alterations in gene expression may determine the hyperoxic growth retardation, postischemic inflammation, neovascularization, and remodeling in retinas of murine OIR. (Invest Ophthalmol Vis Sci. 2010; 51:4307-4319) DOI:10.1167/iovs.09-4605

目的:癌化学療法がE-セレクチンの発現に及ぼす影響と,それに対するシメチジンの抑制効果を前向き試験で明らかにする.対象と方法:胃癌6例と大腸癌8例,合計14例を対象とした.化学療法は経口フッ化ピリミジン系薬剤を使用したレジメンとし,シメチジンは6週間以上併用投与した.経時的に静脈血を採取し,血清中の可溶性E-セレクチン濃度を測定した.結果:可溶性E-セレクチン値は,化学療法単独投与で上昇し(p=0.034),化学療法とシメチジンの併用で低下した(p=0.043).さらに併用後,シメチジンのみ中止すると上昇する傾向にあった(p=0.068).結語:化学療法は血清可溶性E-セレクチン濃度を上昇させ,シメチジンはそれを抑制する効果がある.このことから,シメチジンが化学療法による易転移環境の改善に有用である可能性が示唆される.(著者抄録)

We herein report the findings of a 47-year-old Japanese female with chronic myeloid leukemia (CML) with a cryptic BCR-ABL1 transcript on chromosome 9 and a derivative chromosome 22 unrelated to BCR-ABL1. Although she achieved and continued to demonstrate a major molecular response to imatinib treatment following interferon-alpha, there was persistence of a derivative chromosome 22. A detailed chromosome/molecular studies, including serial karyotyping analysis, finally resulted in the karyotyping at the disease onset to be 47,XX,+del(22)(q11.2), with two genetic evens, namely a cryptic BCR-ABL1 transcript on chromosome 9 and derivative chromosome 22 unrelated to BCR-ABL1. This CML case with these two rare genetic events thus raises diagnostic issues such as the difficulty in making a concise evaluation of the chromosomal/molecular events and an accurate disease prognosis, as well as the difficulty in determining the disease remission status after treatment.

目的:GISTの手術症例について診断,治療,予後の特徴を明らかにする.方法:2002年1月から2008年10月の間に手術を施行したGIST 25例の診断,手術,化学療法,予後について検討した.結果:年齢は61.8±13.5歳,男女比は14:11.発生臓器は胃18例,十二指腸・小腸5例,直腸2例で,腫瘍径の中央値はそれぞれ3.4cm,6.5cm,6.8cmであった.術前の組織学的な確定診断は,超音波内視鏡下穿刺吸引生検で7例中6例,通常生検4例中3例において可能であった.胃GIST症例において腹腔鏡下手術では開腹術に比べて出血量が少なく(p=0.004),術後在院期間が短かった(p=0.033).リスク分類は7例(28%)が高リスクであり,高リスク群は4年無再発生存率25.1%と不良であった.結語:胃GISTは予後がよく,術中出血量が少なく術後の早期回復が得られるので,腹腔鏡下手術のよい適応である.(著者抄録)

目的:80歳以上高齢者の大腸手術における手術リスク評価としてPOSSUM(以下P),P-POSSUM(以下P-P),CR-POSSUM(以下CR-P)の有用性を検討した.対象:2001年1月から2007年3月までに局麻手術を除く大腸手術を施行した高齢者60例.方法:P,P-P,CR-Pを術後合併症発生群と非発生群に分けて比較検討した.結果:術後合併症発生群は非発生群に比べてPのすべての項目で高値であり,P-Pでは術後死亡率予測は高値であった.CR-PではOSのみ高値であった.術後合併症発生の高リスク群をPS27以上,OS14以上と設定すると,高リスク群で術後合併症発生は有意に高率となった.考察:術後合併症予測にPは有用である.術後死亡率予測はP-Pの方が有用である.高齢者大腸手術における術後合併症発生と死亡率予測にはCR-PよりもP,P-Pの方が有用である.(著者抄録)

Leiomyoma is the most common submucosal tumor of the esophagus, and accurate preoperative diagnosis is difficult. We report herein on two resected cases of esophageal leiomyoma preoperatively diagnosed accurately with endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB). The first patient, a 34-year-old man, had complained of dysphagia. Following EUS-FNAB, the pathological diagnosis was leiomyoma. Esophagectomy and reconstruction with a gastric tube were performed because the tumor had almost completely encircled the esophageal wall. The second patient, a 60-year-old woman, had complained of dysphagia. Following EUS-FNAB, the pathological diagnosis was leiomyoma. Enucleation of the tumor was performed because the tumor was not located in the entire circumference of the esophageal wall. The postoperative course of both patients was uneventful, and the final pathological diagnosis of each case was leiomyoma. We conclude that EUS-FNAB is a useful method for diagnosing esophageal submucosal tumors and for selecting an appropriate surgical procedure. © 2008 Japan Esophageal Society and Springer.

A 66-year-old male patient visited our hospital with the chief complaints of difficulty in swallowing and vomiting. The upper gastrointestinal radiographic contrast study revealed a diverticulum with a diameter of about 10 cm in the diaphragm to the right of the esophagus. Upper gastrointestinal endoscopy revealed the inlet of the diverticulum on the right wall of the esophagus at a distance of 44-46 cm from the incisors. The patient was diagnosed as having a giant epiphrenic esophageal diverticulum with obstruction dysfunction of the lower esophageal sphincter was also considered. Therefore, he was treated by laparoscopic resection of the diverticulum, followed by Heller myotomy and Dor fundoplication. The postoperative course was satisfactory, and the patient showed substantial improvement in his dysphagia. He was discharged from our hospital on the 9th postoperative day. At present, 2 years after the operation, he remains well without any recurrence of the symptoms. © 2008 Japan Esophageal Soceity and Springer.

食道静脈瘤80例に対し,3種類の直視下直達手術で治療した.8年までの追求で,術後一部症例で避け難い静脈瘤再発の機構とその対策を検討した.1) 56例は静脈瘤消失を持続したが,24例(30%)に再発を生じ,その時期は不定,程度は術前以下であった.2)静脈瘤再発の主因は,術後の肝内と門脈の循環異常増強であり,これに静脈瘤局所血行の特性と手術術式が関与していた.3)直達手術後の再発静脈瘤は,硬化剤の局所注入を含む集学的治療の効果が期待される

肝硬変性門脈圧亢進症37例で末梢血と肝静脈血中のinsulinを比較し,C-peptideとの対比下にglucagon負荷の影響を検討し,肝循環状態の検査成績と対比し,限定された症例で門脈血中insulinを測定した結果,末梢血中insulinが異常高値を呈する主要原因として,門脈副血行路の発達があること,また同時に門脈血の肝内短絡を重視すべきことを認めた.末梢血と肝静脈血中insulinは,門脈副血行路の発達した肝硬変群では正常関係が逆転し,臨床的に重要な判断の根拠となる.端側門脈下大静脈吻合犬においてinsulinの変動を追求した結果,門脈副血行路によって膵臓血をおさめた門脈血が肝臓を迂回し,直接大静脈系に流入する異常血行を生じ,末梢血中のinsulin上昇,insulinの末梢血中濃度と肝静脈血中濃度関係の逆転を生じる主要原因となる