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Leber congenital amaurosis (LCA), although rare, is one of the most severe forms of early-onset inherited retinal dystrophy (IRD). Here, we review the molecular genetics and phenotypic characteristics of patients with NMNAT1-associated IRD. The longitudinal clinical and molecular findings of a Japanese girl diagnosed with LCA associated with pathogenic variants in NMNAT1 c.648delG, (p.Trp216Ter*) and c.709C>T (p.Arg237Cys) have been described to highlight the salient clinical features of NMNAT1-associated IRD.

Purpose: To determine the effect of low-dose cyclosporine (CyA) treatment for patients with chronic Vogt-Koyanagi-Harada (VKH) disease resistance to systemic corticosteroid treatment. Methods: We retrospectively evaluated patients diagnosed with chronic VKH disease resistance to systemic corticosteroid treatment at Japan Community Health Care Organization (JCHO) Osaka Hospital between March 2013 and March 2016. We followed the observation with systemic low-dose CyA (100 mg once daily) treatment of these patients. The patients were divided into two groups, anterior ocular inflammation group and posterior ocular inflammation group. Demographic data were reviewed, including age, gender, the existence of inflammation at the initial visit and three months after CyA treatment, and side effect. Results: Twenty-three eyes of thirteen patients with chronic VKH disease were included in this study (11 women, 2 men; mean age, 54.6±11.9 years). Nine cases showed anterior ocular inflammation and seven cases showed posterior ocular inflammation (includes overlapping cases). Thirteen of fourteen eyes in the anterior ocular inflammation group subsided at three months after CyA treatment, and ten of thirteen eyes in the posterior ocular inflammation group subsided at three months after treatment. We had to stop the treatment in one patient because of severe increase of serum triglyceride. Conclusions: Low-dose CyA treatment was effective in patients with chronic VKH resistance to systemic corticosteroid treatment. Our results suggest that this treatment was more effective in the anterior ocular inflammation group than in the posterior ocular inflammation group; however, a larger number of patients and longer observation periods are needed to confirm these results.

ObjectiveTo report four cases of new onset or exacerbation of uveitis following administration of infliximab.MethodsThis retrospective observational case series includes four patients who developed new onset or exacerbation of uveitis paradoxically during infliximab treatment.ResultsFour patients were assessed, including three women, with a mean age of 33 (14–84) years. Infliximab was introduced for the treatment of scleritis associated with rheumatoid arthritis (two cases), chronic anterior uveitis associated with juvenile idiopathic arthritis (JIA) (one case) and Crohn’s disease (one case). Anterior scleritis associated with rheumatoid arthritis successfully improved following infliximab administration; however, macular oedema or dense vitritis paradoxically developed in two cases. In one case, infliximab was switched to tocilizumab. In another case, infliximab was discontinued, and additional corticosteroids and immunosuppressive medications were added. In one patient with JIA, new-onset macular oedema and exacerbation of anterior uveitis were observed during infliximab treatment, so the patient was switched to adalimumab. In the patient with Crohn’s disease treated with infliximab, severe vasculitis and macular oedema occurred, requiring intravitreal triamcinolone injection. The patient was switched to adalimumab. Given that these reactions were paradoxical effects of infliximab, infliximab treatment was discontinued in all cases, and additional corticosteroids or immunosuppressive medications were added. All cases remained free of ocular inflammation at the last visit.ConclusionUveitis rarely occurs de novo or is exacerbated during infliximab treatment. Cessation of infliximab led to resolution of this paradoxical adverse effect.

To determine the vitreous levels of erythropoietin and vascular endothelial growth factor (VEGF) in eyes with retinopathy of prematurity (ROP) and to study the correlation between the 2 levels.Retrospective case-control study.Forty eyes of 27 infants with stage 4 ROP (4A, 30 eyes; 4B, 10 eyes) were studied. Five eyes of 4 patients with congenital cataract were used as controls.The eyes with ROP were classified by the vascular activity into 3 groups: highly vascular-active ROP (n = 16), moderately vascular-active ROP (n = 10), and mildly vascular-active ROP (n = 14). Eyes with highly vascular-active ROP initially received an intravitreal injection of 0.5 mg bevacizumab and underwent vitrectomy approximately 1 week after the injection. The eyes in the other groups underwent vitrectomy without bevacizumab. Undiluted vitreous samples were obtained at the beginning of vitrectomy, and the vitreous concentrations of erythropoietin and VEGF were measured by enzyme-linked immunosorbent assay.The vitreous concentrations of erythropoietin and VEGF were determined and compared among the 4 groups.The vitreous level of erythropoietin was significantly higher (P0.05) in the highly and moderately vascular-active ROP eyes than in control eyes. The median concentration of erythropoietin was 744.6 mIU/ml in the highly vascular-active ROP eyes, 729.9 mIU/ml in the moderately vascular-active ROP eyes, 478.0 mIU/ml in the mildly vascular-active ROP eyes, and 0 mIU/ml in control eyes. The vitreous VEGF level was significantly higher (P0.05) in the moderately vascular-active ROP eyes than in control eyes. The median concentration of VEGF was 44.7 pg/ml in the highly vascular-active ROP eyes that had received an intravitreal bevacizumab injection, 360.8 pg/ml in the moderately vascular-active ROP eyes, 0 pg/ml in the mildly vascular-active ROP eyes, and 11.4 pg/ml in control eyes. There was a significant positive correlation (r = 0.410; P = 0.047) between the erythropoietin and VEGF levels in moderately and mildly vascular-active ROP eyes.The elevated level of erythropoietin and its correlation with the VEGF level in eyes with stage 4 ROP suggest that not only VEGF but also erythropoietin may contribute to the pathogenesis of ROP.The author(s) have no proprietary or commercial interest in any materials discussed in this article.

To determine whether transcorneal electrical stimulation (TES) can improve the visual function of patients with nonarteritic ischemic optic neuropathy (NAION) or traumatic optic neuropathy (TON).Eight consecutive patients at the Osaka University Hospital were studied. TES (600-800 microA, 20 Hz, 30 min) was applied once each to three eyes with NAION and to five eyes with TON, using a contact lens-type stimulating electrode. The primary outcome measurement was the change in visual acuity at 1 to 3 months after TES. An improvement in visual acuity was defined as a change ofor =0.3 log (minimum angle of resolution) (logMAR) units. The side effects of TES were also investigated.After TES application, the visual acuity improved in two patients with NAION and in four patients with TON. Visual acuity did not worsen in any of the eyes. Only a mild superficial punctuate keratopathy was observed in all eyes immediately after TES, and it healed by the next day.Visual acuity can be improved after TES without major complications in some patients with NAION or TON. These results suggest that TES should be considered as a new treatment for eyes with optic neuropathy.

To determine the vitreous levels of 27 types of cytokines in eyes with retinopathy of prematurity (ROP).Retrospective case-control study.Twenty-seven eyes of 19 infants with stage 4 ROP were studied. Six eyes of 5 patients with congenital cataract who underwent lensectomy were used as controls.The ROP eyes were divided into 2 groups according to vascular activity: 12 eyes with vascularly active ROP and 15 eyes with vascularly inactive ROP. Undiluted vitreous samples were collected, and the vitreous concentrations of 27 types of cytokines were determined by a multiplex bead analysis system: interleukin (IL)-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, fibroblast growth factor (FGF) basic, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-r, interferon-gamma-inducible protein (IP)-10, monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP)-1a, MIP-1b, platelet-derived growth factor bb, regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor alpha, and vascular endothelial growth factor (VEGF).The vitreous levels of the 27 types of cytokines and a comparison of the levels in the 3 groups.The postmenstrual age at vitrectomy was significantly younger in the vascularly active ROP eyes than in vascularly inactive ROP eyes. The cytokines that had significantly different vitreous levels among the 3 groups were: IL-6, IL-7, IL-10, IL-15, Eotaxin, FGF basic, G-CSF, GM-CSF, IP-10, RANTES, and VEGF (P0.05). The vitreous levels of IL-6, IL-7, IL-15, Eotaxin, G-CSF, IP-10, and RANTES were significantly higher (P0.05) in both vascularly active and inactive ROP eyes than in control eyes, whereas the vitreous level of VEGF was significantly higher (P0.05) only in vascularly active ROP eyes than in control eyes. There was a significantly negative correlation (r = -0.382; P = 0.0495) between the VEGF level and the postmenstrual age at vitrectomy.These results indicate that, although cytokines other than VEGF may be involved in the pathologic changes in eyes with ROP, VEGF is likely to have the strongest correlation with the vascular activity in ROP eyes among these cytokines.

A small multifunctional cytokine, growth-blocking peptide (GBP), from the armyworm Pseudaletia separata larvae was expressed as a soluble and active recombinant peptide in the methylotrophic yeast Pichia pastoris. An expression vector for GBP secretion was constructed using vector pPIC9, and GBP was expressed under the control of the alcohol oxidase (AOX1) promoter. Although we first tried to cultivate GBP in shake flask cultures, the yield was low, probably due to proteolysis of the recombinant protein. To overcome this problem, we utilized a high-density fermentation method. The pH of the medium in the fermenter was kept at 3.0, and the medium was collected within 48 h post methanol shift to minimize exposure of the target peptide to proteases. Recombinant GBP was purified through three reverse-phase HPLC columns. We characterized the 25 amino acid GBP by molecular mass spectrometry and amino acid sequencing. Plasmatocyte spreading, one of the activities of GBP, was similar between chemically synthesized GBP and purified recombinant GBP. Up to 50 mg GBP was recovered per 1 L of yeast culture supernatant.

クロールプロマジン及びアルドメット服用後,肝機能異常が現われ,肝生検にて著明な肝内胆管病変を呈した症例を経験した.症例は71歳,女性で,クロールプロマジンを約18カ月,アルドメットを1カ月服用後肝障害が現われた.肝組織では肝内胆管の破壊像が認められ,同一門脈域に類上皮細胞肉芽腫及びリンパ濾胞を形成する多数の炎症細胞浸潤が認められたが,胆汁うっ滞の所見は認められなかった.組織上では原発性胆汁性肝硬変(PBC)と類似した点もみられたが,門脈域への形質細胞の浸潤がめだたず,肝内胆管の数の減少も認められない点でPBCとは異なっていた.また,抗ミトコンドリア抗体も陰性であった.本例は薬剤の中止により肝機能はすみやかに改善し,リンパ球刺激試験で両薬剤が陽性であったことより,クロールプロマジン,アルドメット両薬剤の関与により多彩な組織像を呈した薬剤性肝障害と考えられた.

A 52-year-old man was admitted to the hospital because of easy fatigability. He didn't have jaundice, itching, hypercholesterinemia and xanthoma. Liver function tests were as follows : total bilirubin, 0.9mg/dl ; GOT, 51IU/l ; GPT, 85IU/l ; alkaline phosphatase, 216IU/l ; γ-GTP, 36IU/l ; total protein, 7.9g/dl ; γ-globulin, 1.79g/dl. HBs antigen and α-fetoprotein were negative. Antimitochondrial antibody and other autoantibody were negative. IgM level was 111mg/dl.Blind liver biopsy specimens showed chronic active hepatitis with changes of interlobular bile ducts. But papillary appearance of the epithelium was not observed, plasma cells were rarely infiltrated and granuloma was never seen. In these points, the present findings differed from the bile duct lesions in CNSDC found in early stage of PBC.

慢性甲状腺炎を合併したHBs抗原持続陽性の慢性肝炎例を報告する.症例は23歳の女性で,11歳時,甲状腺腫を指摘されたが放置.入院時,甲状腺腫をみとめたが肝脾は触知しなかった.主な検査成績では,GOT 156, GPT 186, ICG 15分停滞率16.5%, γ-グロブリンは1.86g/dl, RAテスト(+).甲状腺機能検査には異常なく,免疫学的には抗核抗体,抗平滑筋抗体,サイロイドテスト,マイクロソームテストが陽性で,免疫グロブリンではIgGの軽度増加とIgMの上昇がみられだ.HRs抗原は持続陽性でありた.腹腔鏡下肝生検では慢性肝炎活動型の組織所見を示し,甲状腺生検では慢性甲状腺炎と診断された.慢性甲状腺炎に合併する慢性の肝疾患については,その肝病変は甲状腺病変と同じく自己免疫学的な機序に基づくといわれ,肝甲状腺炎症候群という名称が提唱されているが,合併例の肝病変を考える場合ウイルス感染を念頭におくことも必要と思われる.

Propionibacterium acnes加熱死菌をマウスに静注し,7日後にlipopolysaccharideを追加静注すると,肝小葉内に小肉芽腫,sinusoid内に細胞浸潤が認められるようになり,肝細胞壊死が出現する.この急性肝障害モデルにおける浸潤細胞の経時的変化を主にその組織化学的側面から検討した.小肉芽腫数やsinusoid内浸潤細胞数はlipopolysaccharide投与後,次第に増加し,特に18時間後には投与前に比し有意に高値であった.また,小肉芽腫内およびsinusoid内浸潤細胞はそのほとんどがα1-アンチトリプシン陽性細胞とNaphthol AS-D Chloroacetate Esterase陽性細胞であり,前者は経時的に減少し,逆に後者は増加する傾向がうかがわれた.以上の結果より,この急性肝障害モデルにおける肝組織内浸潤細胞の主体はマクロファージ系細胞と好中球系細胞であり,急性肝障害の発現にはこの両者が関与している可能性が示唆された.

In 100 patients with hepatocellular carcinoma (HCC), 79 cases were accompanied by liver cirrhosis and 21 cases were not. In the accompanied (A) and unaccompanied (B) groups by liver cirrhosis, there was no differences about sex, alcohol intake, the serum level of alpha-fetoprotein. B group was widely distributed from 20 to 80 years old in age and more rarely had the history of blood transfusion than A group. The family history of liver disease and the rate of positive HBsAg were frequently observed in B group than A group. Though B group was found in advanced state with subjective and objective symptoms, there was no difference in prognosis between the two groups. The histology of the non-cancerous lesions of the B group included 2 cases of portal fibrosis, 7 cases of chronic active hepatitis, one case of non specific changes. Two young patients under 40 years old of B group were both HBsAg positive, so it seemed to be necessary for HBsAg carriers without liver cirrhosis to be screened as high risk group of HCC.

62才の男性が右季肋部痛にて来院.諸検査にて典型的な多発性骨髄腫(IgG-κ型)が確認された. MCP療法にて38°C台の発熱は下熱し小康を得たが,その後再度発熱し心窩部に圧痛が出現した.エコー, CT等により肝膿瘍と診断し,ドレナージを行ない黄白色の膿汁をえた.細菌培養は陰性,諸種抗生物質治療にも抵抗性で,入院後32病日,麻痺性イレウスの状態で死亡した.剖検にて,回盲部原発のアメーバ性大腸炎と,腹腔内と胃に穿破したアメ一バ性肝膿瘍と判明した.多発性骨髄腫に合併したアメーバ性肝膿瘍の報告は本邦初であり,アメーバ性肝膿瘍自体まれな疾患であるが,今後一種の日和見感染として常に念頭におくべき疾患と考えられ報告した.