связь активности над-и надф-зависимых дегидрогеназ

Оригинальные статьи
616.381-002.3-031.14-008.853.2
СВЯЗЬ АКТИВНОСТИ НАД-И НАДФ-ЗАВИСИМЫХ ДЕГИДРОГЕНАЗ ЛИМФОЦИТОВ
С ИСХОДОМ РАСПРОСТРАНЕННОГО ГНОЙНОГО ПЕРИТОНИТА
Савченко А.А.1,.Здзитовецкий Д.Э.2, Лузан Н.А.1
1
2
ÍÈÈ ìåäèöèíñêèõ ïðîáëåì Ñåâåðà, ã. Êðàñíîÿðñê
Êðàñíîÿðñêèé ãîñóäàðñòâåííûé ìåäèöèíñêèé óíèâåðñèòåò èì. ïðîô. Â.Ô. Âîéíî-ßñåíåöêîãî, ã. Êðàñíîÿðñê
РЕЗЮМЕ
Öåëüþ èññëåäîâàíèÿ ÿâèëîñü èçó÷åíèå óðîâíåé àêòèâíîñòè ÍÀÄ(Ô)-çàâèñèìûõ äåãèäðîãåíàç ëèìôîöèòîâ ïðè ðàçëè÷íûõ èñõîäàõ ðàñïðîñòðàíåííîãî ãíîéíîãî ïåðèòîíèòà (ÐÃÏ). Àêòèâíîñòü ôåðìåíòîâ
â ëèìôîöèòàõ êðîâè îïðåäåëÿëàñü áèîëþìèíåñöåíòíûì ìåòîäîì. Óñòàíîâëåíî, ÷òî ó áîëüíûõ ñ íåáëàãîïðèÿòíûì èñõîäîì ÐÃÏ â ëèìôîöèòàõ êðîâè áîëåå âûðàæåííî îñóùåñòâëÿþòñÿ ðåàêöèè ëèïèäíîãî àíàáîëèçìà è êàòàáîëèçìà êñåíîáèîòèêîâ. Íåçàâèñèìî îò èñõîäà çàáîëåâàíèÿ â ëèìôîöèòàõ
êðîâè áîëüíûõ ÐÃÏ ñíèæåíû óðîâíè àêòèâíîñòè ôåðìåíòîâ, îïðåäåëÿþùèõ èíòåíñèâíîñòü àíàýðîáíîãî è àýðîáíîãî äûõàíèÿ, à òàêæå óðîâåíü ïëàñòè÷åñêèõ ïðîöåññîâ ïðè àêòèâàöèè ðåàêöèé ëèïèäíîãî êàòàáîëèçìà è ïåðåíîñà ïðîäóêòîâ ÷åðåç ãëèöåðîë-3-ôîñôàòäåãèäðîãåíàçó íà îêèñëèòåëüíîâîññòàíîâèòåëüíûå ðåàêöèè ãëèêîëèçà. Èñõîäÿ èç èíôîðìàòèâíîñòè óðîâíåé àêòèâíîñòè ÍÀÄ(Ô)çàâèñèìûõ äåãèäðîãåíàç â íåéðîñåòåâîé ìîäåëè ïðè êëàññèôèêàöèè ïî èñõîäó çàáîëåâàíèÿ, ïðåäëàãàåòñÿ ìåòàáîëè÷åñêèé êîýôôèöèåíò, îáëàäàþùèé ïðîãíîñòè÷åñêîé çíà÷èìîñòüþ.
КЛЮЧЕВЫЕ СЛОВА: ðàñïðîñòðàíåííûé ãíîéíûé ïåðèòîíèò, èñõîä çàáîëåâàíèÿ, ÍÀÄ-çàâèñèìûå
äåãèäðîãåíàçû, ÍÀÄÔ-çàâèñèìûå äåãèäðîãåíàçû, ëèìôîöèòû, ìåòàáîëèçì.
Введение
Íåñìîòðÿ íà äîñòèæåíèÿ â ìåäèöèíå, ëåòàëüíîñòü
ïðè ðàñïðîñòðàíåííîì ãíîéíîì ïåðèòîíèòå (ÐÃÏ),
ÿâëÿþùàÿñÿ ãëàâíûì êðèòåðèåì îöåíêè ýôôåêòèâíîñòè ïðèìåíÿåìûõ ñïîñîáîâ ëå÷åíèÿ, óäåðæèâàåòñÿ íà
óðîâíå 20–30%, äîñòèãàÿ íàèáîëåå âûñîêèõ öèôð (50%
è áîëåå) ïðè òðåòè÷íîì ïåðèòîíèòå è ïåðèòîíèòå, ñîïðîâîæäàþùåìñÿ ðàçâèòèåì ïîëèîðãàííîé íåäîñòàòî÷íîñòè è ñåïòè÷åñêîãî øîêà [1, 2].  ñâÿçè ñ ýòèì
ïîÿâëÿåòñÿ íåîáõîäèìîñòü ïîäðîáíîãî èññëåäîâàíèÿ
ìîëåêóëÿðíî-êëåòî÷íûõ ìåõàíèçìîâ âîñïàëèòåëüíîé
ðåàêöèè ïðè ïåðèòîíèòå.
Îäíèì èç ïåðñïåêòèâíûõ íàïðàâëåíèé, ïîçâîëÿþùèõ îõàðàêòåðèçîâàòü ïàòîãåíåç íàðóøåíèÿ ðåàêòèâíîñòè èììóííîé ñèñòåìû ïðè èíôåêöèîííî-âîñïàëèòåëüíûõ ïðîöåññàõ, ÿâëÿåòñÿ èçó÷åíèå ìåòàáîëèçìà
êëåòîê èììóííîé ñèñòåìû. Íà ñåãîäíÿøíèé äåíü óñòàíîâëåíî, ÷òî ôóíêöèîíàëüíûå ïðîÿâëåíèÿ ëèìôîöèòîâ, íàïðèìåð, òàêèå êàê äèôôåðåíöèðîâêà, ïðîëèôåðàöèÿ, ñèíòåç ðåöåïòîðîâ è öèòîêèíîâ, îñóùåñòâëÿþòñÿ òîëüêî ïðè ñîîòâåòñòâóþùåì èçìåíåíèè èõ
Ñàâ÷åíêî Àíäðåé Àíàòîëüåâè÷, òåë.: +7-9059713715;
e-mail: [email protected]
ìåòàáîëèçìà [3–5]. Â ñâÿçè ñ òåì ÷òî ôóíêöèîíàëüíàÿ
àêòèâíîñòü ëèìôîöèòîâ âî ìíîãîì îïðåäåëÿåò òå÷åíèå è
èñõîä èíôåêöèîííî-âîñïàëèòåëüíûõ çàáîëåâàíèé [6, 7],
íåîáõîäèìî îöåíèòü ñòåïåíü íàðóøåíèÿ âíóòðèêëåòî÷íûõ ìåòàáîëè÷åñêèõ ïðîöåññîâ ïðè ïåðèòîíèòå.
Öåëü èññëåäîâàíèÿ – èçó÷èòü óðîâíè àêòèâíîñòè
ÍÀÄ(Ô)-çàâèñèìûõ äåãèäðîãåíàç ëèìôîöèòîâ êðîâè
ó áîëüíûõ ðàñïðîñòðàíåííûì ãíîéíûì ïåðèòîíèòîì ïðè
áëàãîïðèÿòíîì è íåáëàãîïðèÿòíîì èñõîäàõ çàáîëåâàíèÿ.
 êà÷åñòâå ïîêàçàòåëåé âíóòðèêëåòî÷íîãî ìåòàáîëèçìà âûáðàíû ÍÀÄ(Ô)-çàâèñèìûå äåãèäðîãåíàçû, òàê
êàê, âî-ïåðâûõ, îñíîâíûìè ïåðåíîñ÷èêàìè ýëåêòðîíîâ
â êëåòêàõ ÿâëÿþòñÿ ïèðèäèíîâûå íóêëåîòèäû, à îòñþäà – àêòèâíîå ó÷àñòèå îêñèäîðåäóêòàç â áèîýíåðãåòè÷åñêèõ ïðîöåññàõ; âî-âòîðûõ, ÍÀÄ(Ô)-çàâèñèìûå äåãèäðîãåíàçû, ó÷àñòâóÿ â íàïðàâëåííîé êîîðäèíàöèè
ñîïðÿæåííûõ ìåòàáîëè÷åñêèõ ïîòîêîâ, â çíà÷èòåëüíîé
ñòåïåíè îáóñëàâëèâàþò àäàïòèâíûå èçìåíåíèÿ êëåòî÷íîãî îáìåíà âåùåñòâ [8–10].
Материал и методы
Ïîä íàøèì íàáëþäåíèåì íàõîäèëñÿ 51 áîëüíîé ñ
ÐÃÏ (23 ìóæ÷èí è 28 æåíùèí) âíåáîëüíè÷íîãî è ãîñïèòàëüíîãî ïðîèñõîæäåíèÿ, ïðîõîäèâøèé ëå÷åíèå â
Бюллетень сибирской медицины, 2014, том 13, № 5, с. 79–86
79
Савченко А.А.,.Здзитовецкий Д.Э., Лузан Н.А.
Связь активности НАД-и НАДФ-зависимых дегидрогеназ лимфоцитов с исходом РГП
îòäåëåíèè ãíîéíîé õèðóðãèè è îòäåëåíèè ðåàíèìàöèè
è èíòåíñèâíîé òåðàïèè ÌÓÇ «ÃÁÑÌÏ èì. Í.Ñ. Êàðïîâè÷à» ã. Êðàñíîÿðñêà. Ñðåäíèé âîçðàñò ïàöèåíòîâ
ñîñòàâèë (54,2 ± 19,2) ãîäà. Èç èññëåäîâàíèÿ áûëè
èñêëþ÷åíû áîëüíûå, ó êîòîðûõ ïåðèòîíèò áûë îñëîæíåíèåì ïàíêðåîíåêðîçà, íåîïåðàáåëüíûõ îíêîëîãè÷åñêèõ çàáîëåâàíèé îðãàíîâ áðþøíîé îáëàñòè è íåîïåðàáåëüíîãî íàðóøåíèÿ ìåçåíòåðèàëüíîãî êðîâîîáðàùåíèÿ.
Èñõîäíóþ ñòåïåíü òÿæåñòè áîëüíûõ îïðåäåëÿëè ïî
øêàëå SAPSII [11], òÿæåñòü ÐÃÏ èñõîäíî – ïî Ìàíãåéìñêîìó èíäåêñó ïåðèòîíèòà è èíäåêñó áðþøíîé
ïîëîñòè [12, 13]. Íàëè÷èå è ñòåïåíü âûðàæåííîñòè
ïîëèîðãàííîé íåäîñòàòî÷íîñòè èñõîäíî è â äèíàìèêå
îïðåäåëÿëè ïî øêàëå SOFA [14]. Ïðè îöåíêå òÿæåñòè
ñèíäðîìà ñèñòåìíîé âîñïàëèòåëüíîé ðåàêöèè ïðèäåðæèâàëèñü êðèòåðèåâ ACCP/SCCM [15].  êà÷åñòâå
êîíòðîëÿ îáñëåäîâàíî 75 çäîðîâûõ ëþäåé àíàëîãè÷íîãî âîçðàñòíîãî äèàïàçîíà.
Âûäåëåíèå îáùåé ôðàêöèè ëèìôîöèòîâ îñóùåñòâëÿëè ïî îáùåïðèíÿòîìó ìåòîäó â ãðàäèåíòå ïëîòíîñòè
ôèêîëë-óðîãðàôèíà ñ ïîñëåäóþùåé î÷èñòêîé îò ïðèëèïàþùèõ êëåòîê. Èññëåäîâàíèå àêòèâíîñòè ÍÀÄ(Ô)çàâèñèìûõ äåãèäðîãåíàç â ëèìôîöèòàõ êðîâè ïðîâåäåíî
ñ ïîìîùüþ áèîëþìèíåñöåíòíûõ ìåòîäîâ [16]. Ìåòàáîëèçì ëèìôîöèòîâ îöåíèâàëè ïî àêòèâíîñòè ñëåäóþùèõ
ôåðìåíòîâ:ãëþêîçî-6-ôîñôàòäåãèäðîãåíàçû (Ã6ÔÄÃ),
ãëèöåðîë-3-ôîñôàòäåãèäðîãåíàçû (Ã3ÔÄÃ), ìàëèê-ôåðìåíòà (ÍÀÄÔÌÄÃ), ÍÀÄ- è ÍÀÄÍ-çàâèñèìîé ðåàêöèè
ëàêòàòäåãèäðîãåíàçû (ËÄÃ è ÍÀÄÍ-ËÄÃ), ÍÀÄ- è
ÍÀÄÍ-çàâèñèìîé ðåàêöèè ìàëàòäåãèäðîãåíàçû (ÌÄÃ
è ÍÀÄÍ-ÌÄÃ), ÍÀÄÔ- è ÍÀÄÔÍ-çàâèñèìîé ãëóòàìàòäåãèäðîãåíàçû (ÍÀÄÔÃÄÃ è ÍÀÄÔÍ-ÃÄÃ), ÍÀÄè ÍÀÄÍ-çàâèñèìîé ãëóòàìàòäåãèäðîãåíàçû (ÍÀÄÃÄÃ
è ÍÀÄÍ-ÃÄÃ), ÍÀÄ- è ÍÀÄÔ-çàâèñèìûõ èçîöèòðàòäåãèäðîãåíàç (ÍÀÄÈÖÄÃ è ÍÀÄÔÈÖÄÃ) è ãëóòàòèîíðåäóêòàçû (ÃÐ). Àêòèâíîñòü ÍÀÄ(Ô)-çàâèñèìûõ äåãèäðîãåíàç âûðàæàëè â ôåðìåíòàòèâíûõ åäèíèöàõ íà 104
êëåòîê, ãäå 1 Å = 1 ìêìîëü/ìèí [8]. Èññëåäîâàíèå
ïðîâîäèëè íà ôåðìåíòàòèâíîì ïðåïàðàòå NÀD(Ð):
FMN-îêñèäîðåäóêòàçà-ëþöèôåðàçà èç Photobacterium
leiognathi (ïîëó÷åí â Èíñòèòóòå áèîôèçèêè ÑÎ ÐÀÍ,
Êðàñíîÿðñê).
Âñå èññëåäîâàíèÿ âûïîëíåíû ñ èíôîðìèðîâàííîãî
ñîãëàñèÿ èñïûòóåìûõ è â ñîîòâåòñòâèèñ Õåëüñèíêñêîé
äåêëàðàöèåé Âñåìèðíîé ìåäèöèíñêîé àññîöèàöèè
«Ýòè÷åñêèå ïðèíöèïû ïðîâåäåíèÿ íàó÷íûõ ìåäèöèíñêèõ èññëåäîâàíèé ñ ó÷àñòèåì ÷åëîâåêà» ñ ïîïðàâêàìè
2000 ã. è «Ïðàâèëàìè êëèíè÷åñêîé ïðàêòèêè â Ðîññèéñêîé Ôåäåðàöèè», óòâåðæäåííûìè Ïðèêàçîì Ìèíçäðàâà ÐÔ îò 19.06.2003 ã. ¹ 266.
Ñòàòèñòè÷åñêèé àíàëèç îñóùåñòâëÿëè â ïàêåòå
ïðèêëàäíûõ ïðîãðàìì Statistica 8.0 for Windows
80
(StatSoft Inc., 2007).Îïèñàíèå âûáîðêè ïðîèçâîäèëè ñ
ïîìîùüþ ïîäñ÷åòà ìåäèàíû Ìå è èíòåðêâàðòèëüíîãî
ðàçìàõà â âèäå 25-ãî è 75-ãî ïðîöåíòèëåé (LQ–UQ).
Äîñòîâåðíîñòü ðàçëè÷èé ìåæäó ïîêàçàòåëÿìè íåçàâèñèìûõ âûáîðîê îöåíèâàëè ïî íåïàðàìåòðè÷åñêîìó
êðèòåðèþ Ìàííà–Óèòíè.
Äëÿ ðåøåíèÿ çàäà÷ ïîääåðæêè ïðèíÿòèÿ ðåøåíèé
èñïîëüçîâàëè ìåòîä íåéðîííûõ ñåòåé. Íåéðîñåòåâîé
êëàññèôèêàòîð ïðåäñòàâëÿåò ñîáîé àëãîðèòì, ñïîñîáíûé ê îáó÷åíèþ è ïðèíÿòèþ ðåøåíèé, íà îñíîâå ðàññ÷èòàííûõ âåñîâûõ êîýôôèöèåíòîâ. Íåéðîñåòü âêëþ÷àåò íàáîð âõîäíûõ íåéðîíîâ (14 ïîêàçàòåëåé àêòèâíîñòè ôåðìåíòîâ + 2) è ìàòðèöó ñèíàïñîâ (ñâÿçè
ìåæäó íåéðîíàìè). Êëàññèôèêàöèÿ(ïðèíÿòèå ðåøåíèÿ)
ïðîèñõîäèò â çàâèñèìîñòè îò çíà÷åíèé, ðåãèñòðèðóåìûõ íà âûõîäíûõ íåéðîíàõ. Îáó÷åíèå íåéðîííîé ñåòè
ïðîâîäèëîñü ìåòîäîì îáðàòíîãî ðàñïðîñòðàíåíèÿ
îøèáêè. Äëÿ ðàñ÷åòà ïàðàìåòðîâ ìîäåëè ïðèíÿòèÿ
ðåøåíèé èñïîëüçîâàëàñü îáó÷àþùàÿ âûáîðêà, ñîñòîÿùàÿ èç îáúåêòîâ, êàæäûé èç êîòîðûõ õàðàêòåðèçóåòñÿ
îïðåäåëåííûì íàáîðîì ïîêàçàòåëåé àêòèâíîñòè ôåðìåíòîâ â ëèìôîöèòàõ îäíîãî ÷åëîâåêà. Âñå îáúåêòû
îáó÷àþùåé âûáîðêè íåéðîñåòåâîãî êëàññèôèêàòîðà
ðàçáèòû íà êëàññû (áîëüíûå ñ áëàãîïðèÿòíûì è íåáëàãîïðèÿòíûì èñõîäàìè çàáîëåâàíèÿ), â îòíîøåíèè
êîòîðûõ è ðåøàåòñÿ çàäà÷à êëàññèôèêàöèè. Ïî îêîí÷àíèþ êëàññèôèêàöèè ïîäñ÷èòûâàåòñÿ èíôîðìàòèâíîñòü ââîäèìûõ ïîêàçàòåëåé [17].
Результаты и обсуждение
Êëèíè÷åñêèå ïðîÿâëåíèÿ ñèíäðîìà ñèñòåìíîé âîñïàëèòåëüíîé ðåàêöèè ïåðåä ïåðâè÷íîé îïåðàöèåé ïî
ïîâîäó ïåðèòîíèòà îòìå÷àëèñü ó 47 áîëüíûõ
((94,0 ± 3,4)%). Ïðåîáëàäàëè áîëüíûå ñ òÿæåëûìè
ïðîÿâëåíèÿìè ñèíäðîìà ñèñòåìíîé âîñïàëèòåëüíîé
ðåàêöèè (òÿæåëûé ñåïñèñ è ñåïòè÷åñêèé øîê) – 34
((68,0 ± 6,6)%). Òÿæåñòü ñîñòîÿíèÿ ïî øêàëå SAPS II
ñîñòàâèëà 29 (16–37) áàëëà. Âûðàæåííîñòü ïîëèîðãàííîé íåäîñòàòî÷íîñòè ïî øêàëå SOFA – 2 (1–4) áàëëà.
Èíòðàîïåðàöèîííàÿ îöåíêà òÿæåñòè ïåðèòîíèòà äàëà
ñëåäóþùèå ðåçóëüòàòû: Ìàíãåéìñêèé èíäåêñ ïåðèòîíèòà â ñðåäíåì ñîñòàâèë 28 (25–33), èíäåêñ áðþøíîé
ïîëîñòè – â ñðåäíåì 14 (13–14).
Ïðè èññëåäîâàíèè óðîâíåé àêòèâíîñòè ÍÀÄÔçàâèñèìûõ äåãèäðîãåíàç ëèìôîöèòîâ êðîâè ó áîëüíûõ
ïåðèòîíèòîì â çàâèñèìîñòè îò èñõîäà çàáîëåâàíèÿ îáíàðóæåíî, ÷òî àêòèâíîñòü ÍÀÄÔÌÄÃ â ëèìôîöèòàõ
êðîâè áîëüíûõ ïåðèòîíèòîì ñíèæåíà îòíîñèòåëüíî êîíòðîëüíûõ çíà÷åíèé êàê ïðè áëàãîïðèÿòíîì, òàê è ïðè
íåáëàãîïðèÿòíîì èñõîäå (ðèñ. 1, à). Îäíàêî ó áîëüíûõ ñ
íåáëàãîïðèÿòíûì èñõîäîì ïîíèæåíèå óðîâíÿ àêòèâíîñòè áîëåå âûðàæåíî, ÷åì ïðè áëàãîïðèÿòíîì èñõîäå.
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Оригинальные статьи
Ðèñ. 1. Àêòèâíîñòü ÍÀÄÔ-çàâèñèìûõ äåãèäðîãåíàç â ëèìôîöèòàõ êðîâè ó áîëüíûõ ÐÃÏ â çàâèñèìîñòè îò èñõîäà çàáîëåâàíèÿ. Çäåñü è íà
ðèñ. 2 è 3: ð1 – ñòàòèñòè÷åñêè äîñòîâåðíûå ðàçëè÷èÿ ñ àêòèâíîñòüþ ôåðìåíòîâ êîíòðîëüíîé ãðóïïû; ð2 – ñòàòèñòè÷åñêè äîñòîâåðíûå ðàçëè÷èÿ
ñ àêòèâíîñòüþ ôåðìåíòîâ áîëüíûõ ñ áëàãîïðèÿòíûì èñõîäîì ÐÃÏ
Óðîâíè àêòèâíîñòè Ã6ÔÄÃ, ÍÀÄÔÃÄÃ, ÍÀÄÔÈÖÄÃ,
ÃÐ è ÍÀÄÔÍ-ÃÄà â ëèìôîöèòàõ ó áîëüíûõ ïåðèòîíèòîì ñíèæåíû îòíîñèòåëüíî êîíòðîëüíûõ çíà÷åíèé
íåçàâèñèìî îò èñõîäà çàáîëåâàíèÿ (ðèñ. 1, á–å).
Ïðè èññëåäîâàíèè óðîâíåé àêòèâíîñòè ÍÀÄçàâèñèìûõ äåãèäðîãåíàç ëèìôîöèòîâ êðîâè ó áîëüíûõ
ïåðèòîíèòîì îáíàðóæåíî, ÷òî àêòèâíîñòü Ã3ÔÄÃ ïîâûøåíà, òîãäà êàê àêòèâíîñòü ËÄÃ, ÌÄÃ è ÍÀÄÃÄÃ
ñíèæåíà îòíîñèòåëüíî êîíòðîëüíûõ óðîâíåé íåçàâèñèìî îò èñõîäà çàáîëåâàíèÿ (ðèñ. 2, à–ã). Àíàëîãè÷íûì îáðàçîì èçìåíÿåòñÿ àêòèâíîñòü ÍÀÄÍ-
çàâèñèìûõ ðåàêöèé äåãèäðîãåíàç â ëèìôîöèòàõ êðîâè áîëüíûõ ïåðèòîíèòîì: ñíèæåíà îòíîñèòåëüíî
êîíòðîëüíûõ óðîâíåé íåçàâèñèìî îò èñõîäà çàáîëåâàíèÿ (ðèñ. 3, à–â).
Âàðèàáåëüíîñòü èçìåíåíèé óðîâíåé àêòèâíîñòè
ÍÀÄ(Ô)-çàâèñèìûõ äåãèäðîãåíàç â ëèìôîöèòàõ ó
áîëüíûõ ïåðèòîíèòîì â çàâèñèìîñòè îò èñõîäà çàáîëåâàíèÿ îêàçàëàñü èíôîðìàòèâíà â ìîäåëè íåéðîñåòåâîãî àíàëèçà (ðèñ. 4). Îáíàðóæåíî, ÷òî íàèáîëåå èíôîðìàòèâíûìè ïîêàçàòåëÿìè ìîäåëè ÿâëÿþòñÿ óðîâíè
àêòèâíîñòè ËÄÃ, ÌÄÃ, ÃÐ, ÍÀÄÔÍ-ÃÄÃ è ÍÀÄÔÌÄÃ.
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Связь активности НАД-и НАДФ-зависимых дегидрогеназ лимфоцитов с исходом РГП
Ðèñ. 2. Àêòèâíîñòü ÍÀÄ-çàâèñèìûõ äåãèäðîãåíàç â ëèìôîöèòàõ êðîâè ó áîëüíûõ ÐÃÏ â çàâèñèìîñòè îò èñõîäà çàáîëåâàíèÿ
Ðèñ. 3. Àêòèâíîñòü ÍÀÄÍ-çàâèñèìûõ äåãèäðîãåíàç â ëèìôîöèòàõ êðîâè ó áîëüíûõ ÐÃÏ â çàâèñèìîñòè îò èñõîäà çàáîëåâàíèÿ
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Оригинальные статьи
Ðèñ. 4. Èíôîðìàòèâíîñòü ÍÀÄ- è ÍÀÄÔ-çàâèñèìûõ äåãèäðîãåíàç ëèìôîöèòîâ ó áîëüíûõ â çàâèñèìîñòè îò èñõîäà ÐÃÏ â ìîäåëè
íåéðîñåòåâîãî êëàññèôèêàòîðà
Èññëåäóåìûå ôåðìåíòû çàíèìàþò êëþ÷åâûå ïîçèöèè íà ðàçíûõ ìåòàáîëè÷åñêèõ ïóòÿõ êëåòêè, õàðàêòåðèçóÿ îñíîâíûå îáìåííûå ïðîöåññû è òåì ñàìûì îïðåäåëÿÿ ôóíêöèîíàëüíûå âîçìîæíîñòè ëèìôîöèòîâ. Â
öåëîì ìåòàáîëèçì ëèìôîöèòîâ ó áîëüíûõ ïåðèòîíèòîì õàðàêòåðèçóåòñÿ íèçêîé àêòèâíîñòüþ áîëüøèíñòâà
èññëåäóåìûõ ÍÀÄÔ- è ÍÀÄÔÍ-çàâèñèìûõ äåãèäðîãåíàç (ÍÀÄÔÌÄÃ, Ã6ÔÄÃ, ÍÀÄÔÃÄÃ, ÍÀÄÔÈÖÄÃ, ÃÐ
è ÍÀÄÔÍ-ÃÄÃ) è íåêîòîðûõ ÍÀÄ- è ÍÀÄÍ-çàâèñèìûõ
ôåðìåíòîâ (Ã3ÔÄÃ, ËÄÃ, ÌÄÃ, ÍÀÄÃÄÃ, ÍÀÄÍ-ËÄÃ,
ÍÀÄÍ-ÌÄÃ è ÍÀÄÍ-ÃÄÃ). Ïðè ýòîì àêòèâíîñòü
òîëüêî ÍÀÄÔÌÄà ðàçëè÷àåòñÿ â çàâèñèìîñòè îò èñõîäà çàáîëåâàíèÿ. ÍÀÄÔÌÄà – ôåðìåíò, ïðèíèìàþùèé àêòèâíîå ó÷àñòèå â ñèñòåìå ëèïèäíîãî àíàáîëèçìà è êàòàáîëèçìà êñåíîáèîòèêîâ [3, 9]. Ñíèæåíèå åãî
àêòèâíîñòè â ëèìôîöèòàõ êðîâè áîëüíûõ ïåðèòîíèòîì
îïðåäåëÿåò ïîíèæåííóþ èíòåíñèâíîñòü àíàáîëèçìà
ëèïèäîâ. Ïðè÷åì ó áîëüíûõ ñ íåáëàãîïðèÿòíûì èñõîäîì çàáîëåâàíèÿ àêòèâíîñòü ôåðìåíòà çíà÷èòåëüíî
ñíèæåíà, â òîì ÷èñëå è îòíîñèòåëüíî âûÿâëåííîé ó ïàöèåíòîâ ñ áëàãîïðèÿòíûì èñõîäîì çàáîëåâàíèÿ. Ã3ÔÄÃ
– ôåðìåíò, ïðèíèìàþùèé ó÷àñòèå â ïðîöåññàõ ëèïèäíîãî êàòàáîëèçìà è ãëèöåðîëôîñôàòíîì ÷åëíî÷íîì ìåõàíèçìå [8, 18]. Ïîâûøåíèå åãî àêòèâíîñòè ïðåæäå âñåãî
îòðàæàåò âûñîêèé óðîâåíü èíòåíñèâíîñòè êàòàáîëè÷åñêèõ ïðîöåññîâ â ëèìôîöèòàõ ïðè ïåðèòîíèòå. Èíòåíñèâíîñòü àíàýðîáíîãî ãëèêîëèçà â ëèìôîöèòàõ áîëüíûõ ïåðèòîíèòîì ñíèæåíà, òàê êàê ó íèõ âûÿâëÿåòñÿ
íèçêàÿ àêòèâíîñòü àíàýðîáíîé ðåàêöèè ËÄÃ.
Ã6ÔÄà ÿâëÿåòñÿ êëþ÷åâûì è èíèöèàëèçèðóþùèì
ôåðìåíòîì ïåíòîçîôîñôàòíîãî öèêëà, îò àêòèâíîñòè
êîòîðîãî çàâèñèò øèðîêèé ñïåêòð ñèíòåòè÷åñêèõ ïðîöåññîâ [8, 10, 19]. Ñîîòâåòñòâåííî, ñíèæåíèå àêòèâíîñòè ôåðìåíòà â ëèìôîöèòàõ áîëüíûõ ïåðèòîíèòîì
îïðåäåëÿåò çíà÷èòåëüíóþ íåäîñòàòî÷íîñòü ðåàêöèé
ïëàñòè÷åñêîãî îáìåíà. Êðîìå òîãî, èçâåñòíî, ÷òî
ÍÀÄÔÍ, îáðàçîâàííûé íà îêèñëèòåëüíîé ñòàäèè ïåíòîçîôîñôàòíîãî öèêëà, ìîæåò ïðèíèìàòü ó÷àñòèå â
âîññòàíîâëåíèè îêèñëåííîãî ãëóòàòèîíà [20]. Â ñâÿçè
ñ ýòèì ñíèæåíèå àêòèâíîñòè ÃÐ â êëåòêàõ áîëüíûõ
ïåðèòîíèòîì ìîæåò îïðåäåëÿòüñÿ íåäîñòàòî÷íîñòüþ
ÍÀÄÔÍ è îáóñëîâèòü àêòèâàöèþ ïåðåêèñíûõ ïðîöåññîâ.  òî æå âðåìÿ ýòèìè æå àâòîðàìè îòìå÷àåòñÿ
âîçìîæíîñòü ñòèìóëÿöèè ñóáñòðàòíîãî ïîòîêà ïî ïåíòîçîôîñôàòíîìó öèêëó ïðè ïîâûøåíèè ñîäåðæàíèÿ â
êëåòêàõ îêèñëåííîãî ãëóòàòèîíà [21]. Îäíàêî äèñáàëàíñ ìåòàáîëè÷åñêèõ ïðîöåññîâ â ëèìôîöèòàõ êðîâè ó
áîëüíûõ ïåðèòîíèòîì ïðèâîäèò ê íàðóøåíèþ ðåãóëÿòîðíûõ âçàèìîñâÿçåé è, êàê ñëåäñòâèå, ñíèæåíèþ àêòèâíîñòè ÍÀÄÔ- è ÍÀÄÔÍ-çàâèñèìûõ ôåðìåíòîâ
öèòîïëàçìàòè÷åñêîãî êîìïàðòìåíòà êëåòîê.
ÍÀÄÔ-çàâèñèìàÿ èçîöèòðàòäåãèäðîãåíàçà îïðåäåëÿåòñÿ êàê âñïîìîãàòåëüíàÿ äåãèäðîãåíàçà öèêëà òðèêàðáîíîâûõ êèñëîò, îñóùåñòâëÿþùàÿ ñóáñòðàòíûé
ïîòîê ïî öèêëó â óñëîâèÿõ ÍÀÄÍ-çàâèñèìîãî èíãèáèðîâàíèÿ ÍÀÄ-çàâèñèìûõ ôåðìåíòîâ öèêëà Êðåáñà [22,
23]. Â íàøåì èññëåäîâàíèè óñòàíîâëåíî, ÷òî àêòèâíîñòü ÌÄÃ (ÍÀÄ-çàâèñèìîé äåãèäðîãåíàçû ëèìîííîãî
öèêëà) â ëèìôîöèòàõ áîëüíûõ ïåðèòîíèòîìñíèæåíà,
òåì ñàìûì îïðåäåëÿÿ íèçêóþ èíòåíñèâíîñòü ñóáñòðàòíîãî ïîòîêà íà òåðìèíàëüíîì ýòàïå öèêëà Êðåáñà.
Ïîäîáíîå ñîñòîÿíèå ìåòàáîëè÷åñêèõ ïðîöåññîâ â ìèòîõîíäðèàëüíîì êîìïàðòìåíòå ëèìôîöèòîâ ïàöèåíòîâ
ñ ïåðèòîíèòîì ìîæåò îïðåäåëÿòüñÿ íèçêîé àêòèâíîñòüþ ïðÿìûõ è îáðàòíûõ ðåàêöèé ÍÀÄ- è ÍÀÄÔçàâèñèìîé ãëóòàìàòäåãèäðîãåíàç. Äàííûå ôåðìåíòû
îñóùåñòâëÿþò âçàèìîäåéñòâèå öèêëà òðèêàðáîíîâûõ
êèñëîò ñ ðåàêöèÿìè àìèíîêèñëîòíîãî îáìåíà, òàêæå
ïðèíèìàÿ ó÷àñòèå â îáìåíå àçîòà [8]. Ñîñòîÿíèå
àýðîáíîãî äûõàíèÿ íå òîëüêî çàâèñèò îò èíòåíñèâíîñòè ñóáñòðàòíîãî ïîòîêà ïî öèêëó Êðåáñà, íî è îïðåäåëÿåòñÿ óðîâíåì âîäîðîäíîãî ãðàäèåíòà â ìèòîõîíäðèÿõ. ÍÀÄÍ-ÌÄà ÿâëÿåòñÿ êëþ÷åâîé â ñèñòåìå ìàëàòàñïàðòàòíîãî øóíòà ìèòîõîíäðèé, ñîîòâåòñòâåííî,
ñíèæåíèå åå àêòèâíîñòè îïðåäåëÿåò âîçìîæíîñòü
ñíèæåíèÿ âîäîðîäíîãî ãðàäèåíòà ñ èíãèáèðîâàíèåì
àýðîáíûõ ïðîöåññîâ â ëèìôîöèòàõ áîëüíûõ ÐÃÏ. Íåîáõîäèìî îòìåòèòü, ÷òî íèçêàÿ àêòèâíîñòü àýðîáíîé
ðåàêöèè ËÄÃ òàêæå ìîæåò îòðèöàòåëüíî âëèÿòü íà
óðîâåíü àýðîáíîãî äûõàíèÿ.
 öåëîì óðîâåíü àêòèâíîñòè èññëåäóåìûõ ôåðìåíòîâ â ëèìôîöèòàõ êðîâè áîëüíûõ ïåðèòîíèòîì
íåçíà÷èòåëüíî ðàçëè÷àåòñÿ â çàâèñèìîñòè îò èñõîäà
çàáîëåâàíèÿ.  ñâÿçè ñ ýòèì, èñõîäÿ èç èíôîðìàòèâíîñòè ôåðìåíòîâ â ìîäåëè íåéðîñåòåâîãî êëàññèôèêàòîðà, ìû ïðåäëàãàåì ðàññ÷èòûâàòü ìåòàáîëè÷åñêèé
êîýôôèöèåíò (ÌÊ), õàðàêòåðèçóþùèé ñîîòíîøåíèå
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Связь активности НАД-и НАДФ-зависимых дегидрогеназ лимфоцитов с исходом РГП
àêòèâíîñòè ðåàêöèé ÍÀÄÔÍ-çàâèñèìîãî âîññòàíîâëåíèÿ ê óðîâíÿì ðåàêöèé ÍÀÄ-çàâèñèìîãî îêèñëåíèÿ:
ÌÊ = (ÃÐ × ÍÀÄÔÍ-ÃÄÃ) / (ËÄÃ × ÌÄÃ) [24]. Ïðè
âåëè÷èíå êîýôôèöèåíòà íèæå 0,005 ïðîãíîçèðóåòñÿ
íåáëàãîïðèÿòíûé èñõîä çàáîëåâàíèÿ, ïðè âåëè÷èíå
êîýôôèöèåíòà ðàâíîé è âûøå 0,005 – áëàãîïðèÿòíûé.
Ïî ðåçóëüòàòàì ïðîâåäåííîãî îïðåäåëåíèÿ ÌÊ è ïåðñïåêòèâíîãî àíàëèçà èñõîäà çàáîëåâàíèÿ óñòàíîâëåíî,
÷òî ó 30 áîëüíûõ íàáëþäàëîñü ñîâïàäåíèå ïðîãíîçà
(96,8% ñîâïàäåíèé).
Èñõîä çàáîëåâàíèÿ â çíà÷èòåëüíîé ñòåïåíè îïðåäåëÿåòñÿ èíòåíñèâíîñòüþ ñèñòåìíîãî âîñïàëåíèÿ
è óðîâíåì ïîëèîðãàííîé íåäîñòàòî÷íîñòè. Ñëåäñòâèåì ýòîãî ÿâëÿåòñÿ èçìåíåíèå ñîäåðæàíèÿ â ïåðèôåðè÷åñêîé êðîâè ðÿäà öèòîêèíîâ è äðóãèõ áèîëîãè÷åñêè àêòèâíûõ âåùåñòâ [7]. Ìîæíî ïðåäïîëîæèòü,
÷òî ðåãóëÿòîðíîå âëèÿíèå âñåãî êîìïëåêñà áèîëîãè÷åñêè àêòèâíûõ âåùåñòâ íà ëèìôîöèòû ìîäóëèðóåò
èõ âíóòðèêëåòî÷íûé ìåòàáîëèçì è òåì ñàìûì ôîðìèðóåò õàðàêòåðíûé äëÿ èñõîäà ïåðèòîíèòà ñïåêòð
óðîâíåé àêòèâíîñòè ÍÀÄ- è ÍÀÄÔ-çàâèñèìûõ äåãèäðîãåíàç.
Заключение
Òàêèì îáðàçîì, ó áîëüíûõ ñ íåáëàãîïðèÿòíûì èñõîäîì ÐÃÏ â ëèìôîöèòàõ êðîâè áîëåå âûðàæåííî
ñíèæàåòñÿ àêòèâíîñòü ÍÀÄÔÌÄÃ, õàðàêòåðèçóþùàÿ
èíòåíñèâíîñòü ðåàêöèé ëèïèäíîãî àíàáîëèçìà è êàòàáîëèçìà êñåíîáèîòèêîâ. Íåçàâèñèìî îò èñõîäà çàáîëåâàíèÿ â ëèìôîöèòàõ êðîâè áîëüíûõ ïåðèòîíèòîì
ñíèæåíû óðîâíè àêòèâíîñòè ôåðìåíòîâ, îïðåäåëÿþùèõ èíòåíñèâíîñòü àíàýðîáíîãî è àýðîáíîãî äûõàíèÿ,
à òàêæå óðîâåíü ïëàñòè÷åñêèõ ïðîöåññîâ ïðè àêòèâàöèè
ðåàêöèé ëèïèäíîãî êàòàáîëèçìà è ïåðåíîñà ïðîäóêòîâ
÷åðåç Ã3ÔÄà íà îêèñëèòåëüíî-âîññòàíîâèòåëüíûå ðåàêöèè ãëèêîëèçà. Íåäîñòàòî÷íîñòü îáðàçîâàíèÿ ÍÀÄÔÍ â
öèòîïëàçìàòè÷åñêîì êîìïàðòìåíòå ëèìôîöèòîâ ïðè
ïåðèòîíèòå îïðåäåëÿåò íèçêóþ àêòèâíîñòü ðåàêöèè
âîññòàíîâëåíèÿ ãëóòàòèîíà. Ñíèæåíèå ñóáñòðàòíîãî
ïîòîêà íà óðîâíå òåðìèíàëüíûõ ðåàêöèé öèêëà òðèêàðáîíîâûõ êèñëîò îáóñëîâëåíî íàðóøåíèåì âçàèìîäåéñòâèÿ ñ ðåàêöèÿìè àìèíîêèñëîòíîãî îáìåíà. Èñõîäÿ èç èíôîðìàòèâíîñòè óðîâíåé àêòèâíîñòè ÍÀÄ- è
ÍÀÄÔ-çàâèñèìûõ äåãèäðîãåíàç â íåéðîñåòåâîé ìîäåëè
ïðè êëàññèôèêàöèè ïî èñõîäó çàáîëåâàíèÿ, ïðåäëàãàåòñÿ ìåòàáîëè÷åñêèé êîýôôèöèåíò, îáëàäàþùèé ïðîãíîñòè÷åñêîé çíà÷èìîñòüþ.
Литература
1. Ñóêîâàòûõ Á.Ñ., Áëèíêîâ Þ.Þ., Áóêðååâà À.Å., Åøòîêèí Ñ.À., Èâàíîâ Ï.À., Æóêîâñêèé Â.À. Ïðèìåíåíèå
èììîáèëèçîâàííûõ ôîðì ãèïîõëîðèòà íàòðèÿ â êîìïëåêñíîì ëå÷åíèè ðàñïðîñòðàíåííîãî ãíîéíîãî ïåðèòî84
íèòà // Âåñòíèê õèðóðãèè èì. È.È. Ãðåêîâà. 2011.Ò. 170,
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èììóíèòåòà ó áîëüíûõ ñ ïàòîëîãèåé âåðõíåãî ðåñïèðàòîðíîãî òðàêòà õëàìèäèéíîé ýòèîëîãèè // Æóðíàë ìèêðîáèîëîãèè, ýïèäåìèîëîãèè è èììóíîáèîëîãèè. 2008.
¹ 3. Ñ. 94–95.
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P. 689–693.
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Ein Instrument zur intraoperativen Prognose der Peritonitis
// Chirurg. 1987. V. 58. P.84–91.
14. Vincent J.L., Moreno R., Takala J., Willatts S., De
Mendonça A., Bruining H., Reinhart C.K., Suter P.M.,
Thijs L.G. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf
of the Working Group on Sepsis-Related Problems of the
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Care Med. 1996. V. 22, ¹ 7. P. 707–710.
15. Bone R.S., Balk R.A., Cerra F.B., Dellinger R.P., Fein
A.M., Knaus W.A., Schein R.M., Sibbald W.J. American
college of Chest Physicians. Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ
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16. Ñàâ÷åíêî À.À., Ñóíöîâà Ë.Í. Âûñîêî÷óâñòâèòåëüíîå îïðåäåëåíèå àêòèâíîñòè äåãèäðîãåíàç â ëèìôîöèòàõ ïåðèôåðè÷åñêîé êðîâè áèîëþìèíåñöåíòíûì ìåòîäîì // Ëàá.
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¹ 2. P. 109–119.
Бюллетень сибирской медицины, 2014, том 13, № 5, с. 79–86
Оригинальные статьи
19. Ham M., Lee J.W., Choi A.H., Jang H., Choi G., Park J.,
Kozuka C., Sears D.D., Masuzaki H., Kim J.B. Macrophage glucose-6-phosphate dehydrogenase stimulates proinflammatory responses with oxidative stress // Mol. Cell.
Biol. 2013. V. 33, ¹ 12. P. 2425–2435.
20. Ãàâðèëþê Ë.À., Êîð÷ìàðó È.Ô., Ðîáó Ì.Â. Àêòèâíîñòü
ãëóòàòèîíçàâèñèìûõ ýíçèìîâ è ãëþêîçî-6-ôîñôàòäåãèäðîãåíàçû â êðîâè áîëüíûõ ëèìôîãðàíóëåìàòîçîì // Ãåìàòîëîãèÿ è òðàíñôóçèîëîãèÿ. 2009. Ò. 54, ¹ 2. Ñ. 11–13.
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Ãëóòàòèîí-çàâèñèìûå ôåðìåíòû è ãëþêîçî-6-ôîñôàòäåãèäðîãåíàçà â êðîâè áîëüíûõ ëèìôîñàðêîìîé (Íåõîäæêèíñêîé ëèìôîìîé) // Áèîìåäèöèíñêàÿ õèìèÿ. 2011. Ò.
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2014. V. 1842, ¹ 2. P. 135–143.
23. Lee J.H., Park J.W. Attenuated mitochondrial NADP+dependent isocitrate dehydrogenase activity induces apoptosis and hypertrophy of H9c2 cardiomyocytes // Biochimie. 2014. V. 99. P. 110–118.
24. Ïàò. 2498300 ÐÔ, ÌÏÊ G01N 33/48 (2006.01), G01N 33/68
(2006.01). Ñïîñîá ïðîãíîçèðîâàíèÿ èñõîäà ðàñïðîñòðàíåííîãî ãíîéíîãî ïåðèòîíèòà / À.À. Ñàâ÷åíêî, Ä.Ý. Çäçèòîâåöêèé, Þ.Ñ. Âèííèê, À.Ã. Áîðèñîâ, Í.À. Ëóçàí. Îïóáë.
10.11.2013, Áþë. ¹ 31. 8 ñ.
Ïîñòóïèëà â ðåäàêöèþ 23.04.2014 ã.
Óòâåðæäåíà ê ïå÷àòè 09.10.2014 ã.
뇂˜ÂÌÍÓ Ä̉ÂÈ Ä̇ÚÓθ‚˘ () – ä-ð ìåä. íàóê, ïðîôåññîð, ëàáîðàòîðèÿ ìîëåêóëÿðíî-êëåòî÷íîé ôèçèîëîãèè è ïàòîëîãèè ÍÈÈ ìåäèöèíñêèõ ïðîáëåì Ñåâåðà ÑÎ ÐÀÌÍ (ã. Êðàñíîÿðñê).
á‰ÁËÚӂˆÍËÈ ÑÏËÚËÈ ù‰Û‡‰Ó‚˘ – êàíä. ìåä. íàóê, äîöåíò êàôåäðû è êëèíèêè õèðóðãè÷åñêèõ áîëåçíåé èì. ïðîô. Þ.Ì. Ëóáåíñêîãî ÊÃÌÓ
èì. ïðîô. Â.Ô. Âîéíî-ßñåíåöêîãî (ã. Êðàñíîÿðñê).
ãÛÁ‡Ì ç‡Ú‡Î¸fl Ä̇ÚÓθ‚̇, ëàáîðàòîðèÿ ìîëåêóëÿðíî-êëåòî÷íîé ôèçèîëîãèè è ïàòîëîãèè ÍÈÈ ìåäèöèíñêèõ ïðîáëåì Ñåâåðà ÑÎ ÐÀÌÍ (ã.
Êðàñíîÿðñê).
뇂˜ÂÌÍÓ Ä̉ÂÈ Ä̇ÚÓθ‚˘, òåë.: +7-9059713715; e-mail: [email protected]
COMMUNICATION OF NAD- AND NADP-DEPENDENT DEHYDROGENASE ACTIVITIES
IN LYMPHOCYTES WITH OUTCOME OF PREVALENCE PURULENT PERITONITIS
Savchenko A.A.1, Zdzitovetsky D.E.2, Luzan N.A.1
1
2
Institute of Medical Problems of the North, Krasnoyarsk, Russian Federation
Krasnoyarsk State Medical University named after Prof. V.F. Voyno-Yasenetsky, Krasnoyarsk, Russian Federation
ABSTRACT
Aim of this study was to investigate of NAD(P)-dependent dehydrogenases activity in lymphocytes at
different outcomes widespread purulent peritonitis(WPP). Enzyme activity in blood lymphocytes was
determined by bioluminescent method. Found that patients with a poor outcome of WPP in blood
lymphocytes made more pronounced reaction of lipid anabolism and catabolism of xenobiotics.
Regardless of the outcome of the disease in blood lymphocytes of WPP patients reduced levels of
enzymes activity that determine the intensity of anaerobic and aerobic respiration and the level of
plastic processes, but the activation reactions of lipid catabolism and transport products through
glycerol-3-phosphate dehydrogenase on reactions of glycolysis. Based on the informativeness of the
NAD(P)-dependent dehydrogenases activity in the classification neural network model for the disease
outcome, metabolic coefficient is proposed, which has prognostic significance.
KEY WORDS: widespread purulent peritonitis, disease outcome, NAD-dependent dehydrogenases,
NADP-dependent dehydrogenases, lymphocytes, metabolism.
Bulletin of Siberian Medicine, 2014, vol. 13, no. 5, pp. 79–86
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Luzan N.A. Sposob prognozirovaniya iskhoda rasprostranennogo gnoynogo peritonita [The method of predicting the outcome of widespread purulent peritonitis]. Patent no. 2498300
Russia, MPK G01N 33/48 (2006.01), G01N 33/68 (2006.01),
Published 10.11.2013, Bull. no. 31, 8 p. (in Russian).
Savchenko Andrei A. (), Institute of Medical Problems of the North, Siberian Division, Russian Academy of Medical Sciences, Krasnoyarsk, Russian
Federation.
Zdzitovetsky Dmitry E., Krasnoyarsk State Medical University named after Prof. V.F. Voyno-Yasenetsky, Krasnoyarsk, Russian Federation.
Luzan Natal'ya A., Institute of Medical Problems of the North, Siberian Division, Russian Academy of Medical Sciences, Krasnoyarsk, Russian Federation.
Savchenko Andrei A., Ph. +7-9059713715; e-mail: [email protected]
86
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