JP6104265B2 - 石灰化の傾向を判定する方法 - Google Patents
石灰化の傾向を判定する方法 Download PDFInfo
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/47—Scattering, i.e. diffuse reflection
- G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
- G01N21/51—Scattering, i.e. diffuse reflection within a body or fluid inside a container, e.g. in an ampoule
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Description
(i) 可溶性カルシウム塩および可溶性リン酸塩を該流体の試料に添加する段階;
(ii) カルシプロテイン粒子 (CPP) の形成を可能にする条件で、該試料をインキュベートする段階;ならびに
(iii) (a) 一次および/もしくは二次CPPの形成の速度;
(b) 一次および/もしくは二次CPPの量;ならびに/または
(c) 一次CPPの二次CPPへの移行の速度
のうちの1つまたは複数を決定する段階
を特徴とし、
段階 (iii) の (a)、(b)、および/または (c) のうちの1つまたは複数の増加により、該流体が石灰化する傾向が高いことが示される、方法に関する。
[本発明1001]
流体が石灰化する傾向を判定する方法であって、以下の段階:
(i) 可溶性カルシウム塩および可溶性リン酸塩を該流体の試料に添加する段階;
(ii) カルシプロテイン粒子 (CPP) の形成を可能にする条件で、該試料をインキュベートする段階;ならびに
(iii) (a) 一次および/もしくは二次CPPの形成の速度;
(b) 一次および/もしくは二次CPPの量;ならびに/または
(c) 一次CPPの二次CPPへの移行の速度
のうちの1つまたは複数を決定する段階
を特徴とし、
段階 (iii) の (a)、(b)、および/または (c) のうちの1つまたは複数の増加により、該流体が石灰化する傾向が高いことが示される、方法。
[本発明1002]
段階 (iii) が、光学的方法、特に、
吸光光度法、
光散乱の検出、
相関分光法、
またはこれらの2つもしくはそれ以上の組み合わせ
からなる群より選択される光学的方法によって行われる、本発明1001の方法。
[本発明1003]
光学的方法で用いられる励起光がレーザービームである、本発明1002の方法。
[本発明1004]
光学的方法が、光散乱を検出することにより、好ましくは動的光散乱により、より好ましくは相互相関動的光散乱により、さらにより好ましくは三次元相互相関動的光散乱により、特に比濁法により行われる、本発明1002または1003の方法。
[本発明1005]
段階 (iii) が、
沈降技法、
濾過解析、
サイズ排除クロマトグラフィー、
粒度分析、
音響分光法、
またはこれらの2つもしくはそれ以上の組み合わせ
からなる群より選択される任意の方法によって行われる、本発明1001の方法。
[本発明1006]
流体が体液であり、特にここで、流体は血液、血液血漿、血液血清、リンパ液、および/または尿である、本発明1001〜1005のいずれかの方法。
[本発明1007]
流体が患者から得られた体液であり、好ましくはここで、該患者は石灰化を発症しており、かつ/または石灰化を発症するリスクがあり、特にここで、該患者は透析患者である、本発明1006の方法。
[本発明1008]
患者が、血管、弁、および/または軟部組織の石灰化を患っており、好ましくはここで、該患者はリウマチ性疾患、悪性疾患、および/または感染症をさらに患っており、特にここで、該患者は、
腎機能障害、
高血圧症、
真性糖尿病、
脂質異常症、
十分なミネラル化の欠如、特に骨粗鬆症および/または骨軟化症、ならびに
アテローム性動脈硬化症
からなる群より選択される症候群のうちの少なくとも1つを示す、本発明1007の方法。
[本発明1009]
流体が人工体液および/または輸液である、本発明1001〜1005のいずれかの方法。
[本発明1010]
一定温度および/または一定pHで行われる、本発明1001〜1009のいずれかの方法。
[本発明1011]
(a) マルチウェル形式、より好ましくは8ウェルチャンバープレート、16ウェルチャンバープレート、96ウェルマイクロタイタープレート、もしくは384ウェルマイクロタイタープレート、特に96ウェルマイクロタイタープレート;
(b) フロースルーセル;または
(c) マイクロ流体デバイス
のうちの1つで行われる、本発明1001〜1010のいずれかの方法。
[本発明1012]
少なくとも段階 (iii) が自動化されており、好ましくはここで、少なくとも段階 (ii) および (iii) が自動化されており、特にここで、段階 (i)、(ii)、および (iii) のすべてが自動化されている、本発明1001〜1011のいずれかの方法。
[本発明1013]
一次CPPが100 nmよりも小さい平均直径を有し、二次CPPが100 nmよりも大きい平均直径を有する、本発明1001〜1012のいずれかの方法。
[本発明1014]
段階 (iii) の (a)、(b)、および/または (c) のうちの1つまたは複数が1つまたは複数の対照試料と比較される、本発明1001〜1013のいずれかの方法。
[本発明1015]
段階 (iii) の (c) が、一次CPPの二次CPPへの移行の最大半数移行時間 (T 50 ) の時点を決定することにより決定される、本発明1001〜1014のいずれかの方法。
吸光光度法、
光散乱の検出、
相関分光法、
またはこれらの2つもしくはそれ以上の組み合わせ
からなる群より選択される光学的方法によって行われる。
粒子の運動量 (p) = [プランク定数 (h)]/[波長 (λ)]
である。ここで、ゆっくりと動く粒子については、粒子の運動量はその速度を乗じたその質量に相当する。
沈降技法、
濾過解析、
サイズ排除クロマトグラフィー、
粒度分析、
音響分光法、
またはこれらの2つもしくはそれ以上の組み合わせ
からなる群より選択される任意の方法によって行われる。
腎機能障害、
高血圧症、
真性糖尿病、
脂質異常症、
十分なミネラル化の欠如、特に骨粗鬆症および/または骨軟化症、ならびに
アテローム性動脈硬化症
からなる群より選択される症候群のうちの少なくとも1つを示す。
(a) マルチウェル形式、より好ましくは8ウェルチャンバープレート、16ウェルチャンバープレート、96ウェルマイクロタイタープレート、もしくは384ウェルマイクロタイタープレート、特に96ウェルマイクロタイタープレート;
(b) フロースルーセル;または
(c) マイクロ流体デバイス
のうちの1つで行われる。
血清標本のサンプリングおよび調製
健常ボランティア8名からの静脈血をSarstedt Monovette(登録商標)バイアル中に採取した。30分間の凝固の後、試料を室温で3,000 x gで10分間遠心分離した。全個体からの血清をプールし、一定量に分割した。10〜16週齢のDBA/2フェチュインAノックアウトマウス、ヘテロ接合性マウス、および野生型マウス(Schafer et al, 2003;Jahnen-Dechent et al, 1997)からの血液を、屠殺時に心臓からサンプリングした。
Nephelostar(登録商標)比濁計はbmg labtech、Offenburg, Germanyから購入し、Liquidator96(商標)卓上ピペッティングシステムはMettler Toledo GmbH、Giessen, Germanyから購入した。96ウェルプレートはBrand GmbH、Wertheim, Germany製であり、96ウェルプラスチックカバーはCarl Roth GmbH、Karlsruhe, Germany製であった。化学物質(例えば、NaCI、Hepes、CaCl2、NaH2P04、Na2HP04、およびNaOH)はすべて、「解析支持 (pro analysi)」等級の品質で、AppliChem、Darmstadt, Germanyから購入した。
溶液中のタンパク質を定量するには、Pierce BCAタンパク質アッセイキットを製造業者の説明書に従って使用した。BSA(2 mg/ml、Pierce)を標準物質として使用した。ウェスタンブロットは、レーン当たり1 mgのタンパク質または0.4 mgの純粋フェチュインAまたはアルブミンを負荷して、SDS-PAGE(4%〜12%)を用いて標準的プロトコールに従って行った。フェチュインAおよびアルブミンに対する以下の一次抗体を使用した:ポリクローナルウサギ抗ヒトフェチュインA抗血清5359(Behring AG、Marburg, Germany)およびマウス抗ヒトアルブミン(1:2500、カタログ番号0300-0080;AbD Serotec)。蛍光検出のために、以下の西洋ワサビペルオキシダーゼ結合二次抗体を使用した:ブタ抗ウサギIgG(1:5000、カタログ番号P0217;Dako)およびウサギ抗マウスIgG(1:2000、カタログ番号P0260;Dako)。タンパク質染色は、Imperial Protein Stainを用いて製造業者の説明書 (Thermo Scientific) に従って行った;レーン当たり6.0 mgの全タンパク質または2.5 mgの純粋フェチュインAもしくはアルブミンを負荷した。
高粒子密度を有する溶液中の多重散乱は、標準的な動的光散乱法による特徴決定を妨げる。したがって、本発明者らは、混濁CPP試料を解析するために、3D相互相関動的光散乱 (3D-DLS) 設定を使用した。He-Neレーザー(JDS Uniphase、Koheras GmbH、632.8 nm、25 mW、Type LGTC 685-35)、2つのアバランシェフォトダイオード(Perkin Eimer、Type SPCM-AQR- 13- FC)、およびALV 5000相関器を備えた標準的な光散乱装置(ALV GmbH、Langen, Germany)を用いて、50〜52回の測定を行った。光散乱は90°配置で検出した。試料温度は、Pt-100温度センサーを備えた外部サーモスタットにより調整した。ストークス・アインシュタイン式による二次キュムラント適合から、流体力学半径 Rhを算出した。測定は、2分間隔で1400分の期間に及んだ。以前のTEM調査から、成熟した二次CPPが、およそb/a z 0.3の軸比を有する楕円形状であることが明らかになった。明確にするために、本発明者らは、個々のCPP段階を特徴決定するために、半軸ではなく、流体力学半径を算出した。
三次元相互相関動的光散乱 (3D-DLS) は、溶液中のレーザー散乱を検出し、これらのデータを統合して、粒子サイズの発達に関する経時的な情報をもたらす方法である。
実行の完了後、データはExcel(登録商標)に転送され、行から列に置き換えられた。データ列はGraphPad Prism(登録商標)プログラムにコピーされ、XYグラフが作成された。データは次に、「ロバスト適合」適合化法を用いて「log(アゴニスト) 対 反応‐可変勾配(4パラメータ)」モードで非線形回帰を算出することにより処理された。結果としてT50およびRNUT50に関して得られた値は、必要に応じてさらに処理された。
ここで、本発明者らは、フェチュインA溶液の代わりにヒト血清が使用された場合にも、一次CPPが同様に生成されるかどうかを試験した(図1A、下部)。実際に、いずれの場合にも同等のサイズ(直径約50 nm)の一次CPPが生成され、これらは全く異なる時間枠内であるにもかかわらず二次CPP(直径約150 nm)への自発的移行を起こした(図1A)。これらの極めて異なる移行時間を考えて、本発明者らは、移行の遅れは一次CPPの安定性を反映し得る、およびこの段階を測定することにより、血清に固有の石灰化阻害傾向の定量的推定が提供され得ると推測した。
pH 7.40および37℃において
Ca2+:10 mM
PO4 2-:6 mM
NaCl:140 mM
Hepes:50mM
Claims (18)
- 流体が石灰化する傾向を判定する方法であって、以下の段階:
(i) 可溶性カルシウム塩および可溶性リン酸塩を該流体の試料に添加する段階;
(ii) カルシプロテイン粒子 (CPP) の形成を可能にする条件で、該試料をインキュベートする段階;ならびに
(iii) 一次CPPの二次CPPへの移行の速度を決定する段階
を特徴とし、
段階 (iii) における増加により、該流体が石灰化する傾向が高いことが示される、方法。 - 段階 (iii) が、光学的方法によって行われる、請求項1に記載の方法。
- 光学的方法で用いられる励起光がレーザービームである、請求項2に記載の方法。
- 光学的方法が、光散乱を検出することによって行われる、請求項2または3に記載の方法。
- 段階 (iii) が、
沈降技法、
濾過解析、
サイズ排除クロマトグラフィー、
粒度分析、
音響分光法、または
これらの2つもしくはそれ以上の組み合わせ
からなる群より選択される方法によって行われる、請求項1に記載の方法。 - 流体が体液である、請求項1〜5のいずれか一項に記載の方法。
- 流体が患者から得られた体液である、請求項6に記載の方法。
- 患者が、血管、弁、および/または軟部組織の石灰化を患っている、請求項7に記載の方法。
- 流体が人工体液および/または輸液である、請求項1〜5のいずれか一項に記載の方法。
- 一定温度および/または一定pHで行われる、請求項1〜9のいずれか一項に記載の方法。
- (a) マルチウェル形式;
(b) フロースルーセル;または
(c) マイクロ流体デバイス
のうちの1つで行われる、請求項1〜10のいずれか一項に記載の方法。 - 段階 (iii) における一次CPPの二次CPPへの移行の速度の決定が自動化されている、請求項1〜11のいずれか一項に記載の方法。
- 一次CPPが100 nmよりも小さい平均直径を有し、二次CPPが100 nmよりも大きい平均直径を有する、請求項1〜12のいずれか一項に記載の方法。
- 段階 (iii) における一次CPPの二次CPPへの移行の決定された速度が、1つまたは複数の対照試料と比較される、請求項1〜13のいずれか一項に記載の方法。
- 段階 (iii) が、一次CPPの二次CPPへの移行の最大半数移行時間 (T50) の時点を決定することにより決定される、請求項1〜14のいずれか一項に記載の方法。
- 段階 (iii) が、
吸光光度法、
光散乱の検出、
相関分光法、または
これらの2つもしくはそれ以上の組み合わせ
からなる群より選択される光学的方法によって行われる、請求項1に記載の方法。 - 流体が、血液、血液血漿、血液血清、リンパ液、および/または尿である、請求項1〜5のいずれか一項に記載の方法。
- 患者が、
腎機能障害、
高血圧症、
真性糖尿病、
脂質異常症、
十分なミネラル化の欠如、および
アテローム性動脈硬化症
からなる群より選択される症候群のうちの少なくとも1つを示す、請求項7に記載の方法。
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PCT/EP2012/071971 WO2013068372A1 (en) | 2011-11-07 | 2012-11-07 | A method for determining the propensity for calcification |
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JPH0972891A (ja) | 1994-07-07 | 1997-03-18 | Hitachi Koki Co Ltd | 等密度分子の分離法 |
JP2003519183A (ja) * | 2000-01-04 | 2003-06-17 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 心臓および動脈の石灰化を抑制する低用量ビスホスホネートの使用 |
JP2002139501A (ja) | 2000-10-30 | 2002-05-17 | Mass Medical Kk | リポ蛋白サブクラスの分析ならびに診断方法 |
WO2005046455A2 (en) * | 2003-11-12 | 2005-05-26 | Ping Gao | Methods for identifying or monitoring a patient with increased risk of cardiovascular calcification |
GB201002382D0 (en) * | 2010-02-12 | 2010-03-31 | King S College London | Assay |
EP2589964A1 (en) * | 2011-11-07 | 2013-05-08 | Rheinisch-Westfälisch-Technische Hochschule Aachen | A method for determining the propensity for calcification |
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US9651566B2 (en) | 2017-05-16 |
JP2014535054A (ja) | 2014-12-25 |
AU2012334149A1 (en) | 2014-04-24 |
US10054601B2 (en) | 2018-08-21 |
EP3002590A1 (en) | 2016-04-06 |
US20140377874A1 (en) | 2014-12-25 |
KR101978346B1 (ko) | 2019-05-14 |
AU2012334149B2 (en) | 2017-08-10 |
ES2570559T3 (es) | 2016-05-19 |
HK1202332A1 (zh) | 2015-09-25 |
EP3002590B1 (en) | 2017-09-06 |
KR20140090246A (ko) | 2014-07-16 |
CN103930788B (zh) | 2016-09-14 |
CA2854587C (en) | 2019-12-03 |
BR112014010869A2 (pt) | 2017-06-13 |
US20170292962A1 (en) | 2017-10-12 |
EP2589964A1 (en) | 2013-05-08 |
NO3002590T3 (ja) | 2018-02-03 |
DK3002590T3 (da) | 2017-11-27 |
BR112014010869A8 (pt) | 2017-06-20 |
PT3002590T (pt) | 2017-12-06 |
CN103930788A (zh) | 2014-07-16 |
BR112014010869B1 (pt) | 2021-07-06 |
CA2854587A1 (en) | 2013-05-16 |
WO2013068372A1 (en) | 2013-05-16 |
EP2776840A1 (en) | 2014-09-17 |
IL232355A0 (en) | 2014-06-30 |
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