Published papers

薬剤性腎障害の原因は多岐にわたるが,漢方薬やサプリメントなど医薬品以外の物質の関与も多く,病歴を漏れなく聴取することが重要である。近年,機能性表示食品「紅麹コレステヘルプ」(小林製薬,大阪,日本)による健康被害の報告が多数のぼり,腎機能障害や尿所見異常などを呈し,一部の症例では末期腎不全に至るなどの臨床像が報告されているが,原因物質は未詳である。今回われわれは,以前より軽度の推算糸球体濾過量(estimated glomerular filtration rate:eGFR)低下を指摘されていたところへ同サプリメントを3年間内服継続し,発症2ヵ月前から非ステロイド性抗炎症薬(non-steroidal anti-inflammatory drugs:NSAIDs)を使用していたところに発症した急性腎障害(acute kidney injury:AKI),後天性完全型Fanconi症候群を伴った急性尿細管障害(acute tubular injury:ATI)の1例を経験した。初診時には尿中β2ミクログロブリン(β2 microglobulin:β2MG)および好中球ゼラチナーゼ結合リポカリン(neutrophil gelatinase-associated lipocalin:NGAL)の上昇と,汎アミノ酸尿,尿糖陽性,高カルシウム尿症,高リン尿症,高尿酸尿症,II型尿細管性アシドーシスといった近位尿細管機能異常を認め,Fanconi症候群を呈したATIによるAKIと考えられた。腎生検組織所見では尿細管上皮の傷害像はみられたが,炎症性細胞浸潤は乏しかった。足突起消失(foot process effacement)は部分的であった。ステロイドを含めた免疫抑制治療は行わず保存的治療のみで腎機能障害やFanconi症候群は軽快し,現在経過観察中である。全国的に使用されているサプリメントであり,原因物質の究明が待たれるが,同サプリメントにより惹起される腎機能障害や蛋白尿などの尿所見異常の病態を中心に,文献的考察を踏まえて報告する。(著者抄録)

当院において、半月体形成性糸球体腎炎を呈したMPO-ANCA、抗糸球体基底膜(glomerular basement membrane:GBM)抗体共陽性かつ膜性腎症を合併した急速進行性糸球体腎炎(rapidly progressive glomerulonephritis:RPGN)を経験した。血清Crの上昇がみられた早期に副腎皮質ステロイド、静注シクロホスファミドパルス療法(intravenous cyclophosphamide:IVCY)に加え選択的血漿交換(selective plasma exchange:SePE)を行ったところ、2抗体の陰性化を得られ肺障害を生じることなく腎機能障害も改善した。発症早期に、免疫抑制療法に加えて凝固因子補充不要なSePEを行うことが新規抗体産生抑制および抗体除去に有用であると考えられた。(著者抄録)

The 90-kDa heat shock protein, HSP90, is an abundant molecular chaperone which functions in cellular homeostasis in prokaryotes and eukaryotes. It is well known that HSP90 plays a critical and indispensable role in regulating cell growth through modulations of various signal transduction pathways, but its roles in cell cycle control are not so well known. We transferred human HSP90 (wild-type or mutated types) expression vectors into NTH-3T3 cells in order to study certain functions of HSP90 in the cell cycle and cell growth under physiological conditions. We found that the exogenous expression of HSP90 (wild-type) induced a decrease in cell growth via retardation of the G1/S transition. The inhibition of cell growth was caused by reduced expressions of cyclin D3 and cyclin A mRNA and protein. On the other hand, no stable transfectants with the three types of mutated HSP90 were obtained. Unexpectedly, exogenous HSP90 expression impaired the heat shock response by inhibiting both heat shock transcription factor 1 (HSF1) activation and transportation of HSF1 into the nucleus. The HSF1 function was disrupted by the direct association between HSF1 and exogenous HSP90, which was present as a monomer. These results reveal important roles of HSP90 in cell cycle control and in the stress response of nontransformed cells. (C) 2002 Elsevier Science (USA).

The pathological diagnosis of a transplanted kidney is made on Banff Classification in order to gain an accurate understanding of the condition of the kidney. This type of diagnosis is extremely difficult and, thus, a variety of methods for diagnosis, including diagnosis by electron microscope, are being considered at present. Quantification of the diagnostic information derived by image processing is required for such purposes. This study proposes an automatic extraction method for normal glomeruli for the purpose of quantifying Elastica Van Gieson(EVG)-stained pathology specimens. In addition, we provide a report on the package of methods that we have created for the extraction of the glomerulus in the cortex.

DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6Chi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages.

第2世代超音波造影剤(ソナゾイド)の前立腺癌描出に関する有用性につきProspectiveに検討を行った。前立腺全摘術を予定された患者を対象とし、術前に検査を実施し腫瘍局在を同定した。前立腺摘出検体の病理組織結果と比較したところ、高率に癌病巣を描出できていた。Gleason's score高値や被膜浸潤陽性症例においては、正診率はさらに上昇した。前立腺生検時に応用することにより、偽陰性となっていた患者の早期発見に繋がる可能性が示唆された。(著者抄録)

今回われわれは、生体腎移植後1年以内に、持続血糖測定(Continuous glucose monitoring;CGM)を行った2型糖尿病の3例を経験したので報告する。1例目は60歳代の男性、混合型インスリンで治療中に、随時血糖の上昇を認めCGMを施行、昼食後の血糖上昇と血糖変動幅の増大が認められ、超速効型インスリンを追加した。2例目は50歳代の女性、強化インスリン療法中に、食後の低血糖症状を認めCGMを施行、超速効型インスリンの投与時間を食前から食後へと変更する方針となった。3例目は40歳代の男性、BOT(Basal Supported Oral Therapy)治療中に、HbA1cの上昇を認めCGMを施行、食後の血糖上昇に伴う血糖変動幅の増大に対して、超速効型インスリンを開始する方針となった。このように、腎移植後の血糖変動パターンをCGMで評価することで腎移植後糖尿病のより良い治療が行える可能性が示唆された。(著者抄録)

症例は70歳代、女性。微熱、頭重感、両大腿のだるさを契機に他院を受診、腎機能障害を指摘され、精査目的で当院を紹介された。血液検査でミエロペルオキシダーゼ抗好中球細胞質抗体(myeloperoxidase anti-neutrophil cytoplasmic antibody:MPO-ANCA)陽性が判明し、腎生検病理所見の結果、血栓性微小血管症(thrombotic microangiopathy:TMA)を合併した顕微鏡的多発血管炎(microscopic polyangiitis:MPA)と診断した。プレドニゾロン(40mg/日)の投与を開始し、ステロイドパルス療法を2クール、静注シクロホスファミドパルス療法(intravenous cyclophosphamide:IVCY)を1クール行った。また、中等度の高血圧を認めたため、ニフェジピンを投与し、血圧コントロールを行った。その後、両下腿浮腫と両側胸水貯留を認めたため、フロセミドを投与した。患者の病状は安定し、入院37日目に退院した。しかし、退院後に、痙攣と夜間に増悪する呼吸困難を認め、うっ血性心不全の診断で再度入院した。入院後、フロセミドを投与したが、尿量の増加は得られず、急速に呼吸状態の悪化を認めたため、気管内挿管後、人工呼吸器を装着した。14時間にわたる持続低効率血液透析(sustained low efficiency dialysis:SLED)を行い、患者の呼吸状態は著明に改善した。抜管後、意識レベルの低下を伴う痙攣を認め、頭部単純CTでは、両側後頭葉に低吸収域を認めたことから、可逆性後頭葉白質脳症(posterior reversible encephalopathy syndrome:PRES)の関与が示唆された。12誘導心電図検査では、経時的にT波の陰転化を認め、心臓超音波検査では、心尖部に限局した壁運動の低下を認めた。冠動脈造影CTでは、血管病変は認めず、たこつぼ心筋症と診断した。本症例は、重篤で多彩な臨床症状を示した、TMAを合併したMPAの1例である。ANCA関連血管炎に続発したTMA症例では免疫抑制療法開始後も注意深い経過観察が必要である。(著者抄録)

前立腺癌の病変において,最大sizeと最高gradeが一致する場合が多いが,一致しないdiscordant caseもある。本研究では,discordant caseにおける最高grade病変のMRI検出能を検討した。結果,discordant caseでは最高grade病変のMRI検出が劣ることが示され,特に腹側に最大size病変がある場合,同側の背側に最高grade病変が隠れている可能性が高いことが示唆された。(著者抄録)

Neurenteric cyst (NC) is a benign epithelial cyst (BEC) of endodermal origin that mostly occurs in the spinal subdural space or posterior cranial fossa. A 28-year-old male presented with a left frontal lobe NC associated with spontaneous repetitive intracystic hemorrhage, which was initially diagnosed and treated as a brain abscess. He presented with headache and disorientation, without underlying diseases. A cystic tumor was suspected because of a hypointense signal on diffusion-weighted magnetic resonance imaging (MRI). One day after admission, his condition deteriorated rapidly and emergency cyst aspiration was performed. A brown viscous liquid like bloody pus comprising many neutrophils and macrophages was obtained. Although culture was negative, we initially started antibiotic treatment because of cyst content characteristics and rapid clinical course compatible with brain abscess. He was discharged without neurological deficits, but occasionally complained of intense headache. Computed tomography/MRI showed repetitive intracystic hemorrhage and gradual re-enlargement of the lesion. He underwent radical cyst excision by frontal craniotomy 34 months after aspiration. The pathological diagnosis was NC. We believe this is the first report of a supratentorial NC with spontaneous repetitive intracystic hemorrhage. BECs, especially with intracystic hemorrhage, are difficult to be distinguished from brain abscesses. In cases of cystic lesions or presumed brain abscesses refractory to treatment with aspiration and/or antibiotics, BECs should be considered, and radical cyst wall removal should be considered a treatment option.

Purpose: We aimed to determine which of the following magnetic resonance (MR) imaging sequences is most effective for detecting prostate cancer: T-2-weighted (T2W), dynamic contrast-enhanced (DCE) T-1-weighted (TOW), or diffusion-weighted (DWI) imaging or apparent diffusion coefficient (ADC) mapping. Materials and Methods: We included 37 male patients with prostate cancer who underwent MR imaging before radical prostatectomy in this retrospective study. Sixty-four foci (>5 mm in size; 35 in the peripheral zone [PZ], 29 in the transitional zone [TZ]) were histopathologically determined to be prostate cancer. We determined the capacity of T2W, DCE-T1W, DWI, ADC mapping alone, and the combination of ADC mapping with DWI, and conventional MR sequences to detect prostate cancer, including their sensitivity and positive predictive value (PPV), with reference to the results obtained in histopathological examinations of whole-mount sections. Results: In the PZ, sensitivities were 31.4% (T2W), 37.1% (DCE-T1W), 51.4% (DWI), and 71.4% (ADC mapping); PPVs were 78.6% (T2W), 92.9% (DCE-T1W), 94.7% (DWI), and 96.0% (ADC mapping). Sensitivity was significantly higher of ADC mapping than other sequences. In the TZ, sensitivities were 55.1% (T2W), 44.8% (DCE-T1W), 82.8% (DWI), and 89.7% (ADC mapping); PPVs were 64.0% (T2W), 46.4% (DCE-T1W), 70.6% (DWI), and 72.2% (ADC mapping). Sensitivity was significantly higher of ADC mapping and DWI than conventional MR imaging, but there was no significant correlation between DWI/ADC mapping and T2W/DCE-T1W with respect to PPVs. Combining sequences did not improve sensitivity; only the PPV in the TZ improved when ADC mapping was combined with DCE-T1W. Conclusion: ADC mapping is the most effective standard MR imaging tool for detecting prostate cancer. The addition of DCE-T1W may improve the PPV of ADC mapping for diagnosing cancer in the TZ.

CUB (C1r/C1s, urchin embryonic growth factor, BMP1) domain-containing protein 1 (CDCP1) has been implicated in promoting metastasis of cancer cells through several mechanisms, including the inhibition of anoikis, which is cell death triggered by the loss of extracellular matrix interactions. However, the mechanism inhibiting cell death regulated by CDCP1 remains elusive. Inhibition of CDCP1 expression using small interfering RNA (siRNA) induced the cell death of suspended cancer cells without cleaving caspase-3, a marker of apoptosis; cell death was not inhibited by a general caspase inhibitor, suggesting that the loss of CDCP1 induces caspase-independent cell death. In contrast, knockdown of CDCP1 as well as protein kinase C (PKC), a downstream effector of CDCP1, in a suspension culture of lung cancer cells resulted in marked induction of membranous microtubule-associated protein 1 light chain 3 (LC3)-II protein, a hallmark of autophagy, and caused the formation of an autophagosome structure visualized using green fluorescent protein-tagged LC3-II. Expression and phosphorylation of exogenous CDCP1 by Fyn kinase reduced the formation of autophagosomes and inhibited phosphorylation of CDCP1 by PP2, a Src kinase inhibitor or inhibited PKC by rottlerin, stimulating autophagosome formation. Moreover, death of suspended lung cancer cells induced by CDCP1 siRNA or by PKC siRNA was reduced by the autophagy inhibitor 3-methyladenine. CDCP1-PKC signaling plays a critical role in inhibiting autophagy, which is responsible for anoikis resistance of lung cancer cells.

Purpose: Perineural invasion is associated with the high incidence of local recurrence and a dismal prognosis in pancreatic cancer. We previously reported a novel perineural invasion model and distinguished high- and low-perineural invasion groups in pancreatic cancer cell lines. This study aimed to elucidate the molecular mechanism of perineural invasion. Experimental Design: To identify key biological markers involved in perineural invasion, differentially expressed molecules were investigated by proteomics and transcriptomics. Synuclein-gamma emerged as the only up-regulated molecule in high-perineural invasion group by both analyses. The clinical significance and the biological property of synuclein-gamma were examined in 62 resected cases of pancreatic cancer and mouse models. Results: Synuclein-gamma overexpression was observed in 38 (61%) cases and correlated with major invasive parameters, including perineural invasion and lymph node metastasis (P < 0.05). Multivariate analyses revealed synuclein-gamma overexpression as the only independent predictor of diminished overall survival [hazard ratio, 3.4 (95% confidence interval, 1.51-7.51)] and the strongest negative indicator of disease-free survival [2.8 (1.26-6.02)]. In mouse perineural invasion and orthotopic transplantation models, stable synuclein-gamma suppression by short hairpin RNA significantly reduced the incidence of perineural invasion (P = 0.009) and liver/lymph node metastasis (P = 0.019 and P = 0.020, respectively) compared with the control. Conclusions: This is the first study to provide in vivo evidence that synuclein-gamma is closely involved in perineural invasion/distant metastasis and is a significant prognostic factor in pancreatic cancer. Synuclein-gamma may serve as a promising molecular target of early diagnosis and anticancer therapy.

Time-of-flight secondary ion mass spectrometry (MS) provides secondary ion images that reflect distributions of substances with sub-micrometer spatial resolution. To evaluate the use of time-of-flight secondary ion MS to capture subcellular chemical changes in a tissue specimen, we visualized cellular damage showing a three-zone distribution in mouse liver tissue injured by acetaminophen overdose. First, we selected two types of ion peaks related to the hepatocyte nucleus and cytoplasm using control mouse liver. Acetaminophen-overdosed mouse liver was then classified into three areas using the time-of-flight secondary ion MS image of the two types of peaks, which roughly corresponded to established histopathological features. The ion peaks related to the cytoplasm decreased as the injury became more severe, and their origin was assumed to be mostly glycogen based on comparison with periodic acid Schiff staining images and reference compound spectra. This indicated that the time-of-flight secondary ion MS image of the acetaminophen-overdosed mouse liver represented the chemical changes mainly corresponding to glycogen depletion on a subcellular scale. In addition, this technique also provided information on lipid species related to the injury. These results suggest that time-of-flight secondary ion MS has potential utility in histopathological applications. (C) 2015 Elsevier Inc. All rights reserved.