КЛИНИКО-ДИАГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ УРОВНЯ ПРОКАЛЬЦИТОНИНА У ПОСТРАДАВШИХ С ТЯЖЁЛОЙ СОЧЕТАННОЙ ТРАВМОЙ

Mortality due to pyoseptic complications after severe mechanical injury is rather high. Some hopes for its reduction are associated with the timely detection of infectious complications. In this case an important role is, in terms of early diagnosis, attached to the calcitonin prohormone procalcitonin that is positioned itself as a marker for the progression of a bacterial infectious process. At the same time, there is evidence for elevated PCT levels after extensive surgical interventions and in massive injuries directly unassociated with the development of an infectious process. Objective: to estimate the significance of its changes early after injury. A prospective investigation was conducted, which enrolled 76 victims of severe concomitant mechanical injury (patients with severe brain injury and victims whose death had occurred within the following few days were excluded from the study). The time course of changes in the blood levels of PCT, C-reactive protein, activated monocytes expressing receptors for lipopolysaccharide and other bacterial antigens (CD14+ and HLA-R+), cytokines (IL-6, IL-10), glucose, and lactate was studied on admission, at 12 and 24 hours, 3, 7, and 10 days. The diagnosis of bacteremia involved blood microbiology tests for sterility and polymerase chain reaction to detect antigens of blood opportunistic microorganisms. The findings were analyzed in view of injury severity scores (ISS), the development of infectious complications, and an outcome. PCT concentrations were shown to rise significantly within the first 24 hours after injury in the absence of clinical manifestations of infectious complications. The increase in PCT levels was preceded by the highest rise of HLA-DR+ within the first 24 hours and CD14+ just 12 hours after injury, which could not preclude the bacterial translocation inducing, along with other factors, the development of a systemic inflammatory response. At the same time, the findings could suggest that the role of this indicator must not boil down exclusively to the function of that of infectious complications. Смертность в результате гнойно-септических осложнений после перенесённой тяжёлой механической травмы довольно высока. Определённые надежды на её снижение связывают со своевременным выявлением инфекционных осложнений. При этом с точки зрения ранней диагностики важную роль придают прогормону кальцитонина - прокальцитонину, который позиционируется в качес­тве маркёра прог­рессирования инфекционного процесса бактериальной природы. В то же время есть данные об увеличении уровня прокальцитонина после обширных оперативных вмешательств и при массивных повреждениях, не связанном напрямую с развитием инфекционного процесса. Цель работы - оценка значимости его изменений в ранние сроки после травмы. Проведено ­проспективное исследование, в которое включено 76 пострадавших с тяжёлой сочетанной механической травмой (пациентов с тяжёлой черепно-мозговой травмой, а также пострадавших, летальный исход у которых наступал в течение ближайших суток, из исследования исключали). Изучена динамика (этапы - при поступлении, через 12 ч, 24 ч, на 3-и, 7-е и 10-е сут) уровня прокальцитонина, С-рективного белка, активированных моноцитов, экспрессирующих рецепторы к липополисахариду и другим бактериальным антигенам (CD14+ и HLA-­DR+), цитокинов (IL-6, IL-10), глюкозы и лактата крови. Диагностика бактериемии предусматривала микробиологическое исследование крови на стерильность и использование ПЦР для выявления антигенов условно-патогенных микроорганизмов в крови. Анализ полученных данных проводили с учётом тяжести полученных повреждений (ISS), факта развития инфекционных осложнений и исхода. Показано, что значимое повышение кон­центрации ПКТ происходило в первые сутки после травмы при отсутствии клинических проявлений инфекционных осложнений. Повышению уровня прокальцитонина предшествовало увеличение до максимальных значений уровня HLA-DR+ в первые часы и CD14+ уже через 12 ч после травмы, что не позволяло исключить возможность бактериальной транслокации, индуцирующей, наряду с другими факторами, развитие системной воспалительной реакции. Вместе с тем полученные данные позволили предположить, что роль этого показателя не должна сводиться исключительно к функции сигнализатора инфекционных осложнений

ИЗМЕНЕНИЯ ПРОКАЛЬЦИТОНИНА В ПОСТТРАВМАТИЧЕСКОМ ПЕРИОДЕ И ЕГО РОЛЬ В СИСТЕМНОМ ОТВЕТЕ НА ТРАВМУ

Procalcitonin is an important marker used in the clinical practice for sepsis diagnostics. However the increase of its concentration can be registered in the early post-traumatic period with no obvious nidus of infection. Goal: to clarify the value of procalcitonin as a biomarker in those with concurrent trauma. Methods. 76 those injured were examined and divided into subgroups depending on the severity of trauma (ISS < 20 and ISS > 20 scores) and outcome (favorable, unfavorable, with infectious complications and no infectious complications). The changes in procalcitonin level in the subgroups were compared with intensity of the systemic response to the injury through changes in IL-6, IL-8, IL-10, CD14, HLA-DR, secretory immunoglobulin A. Blood was collected upon admission to hospital, in 12 hours, on the 1st, 3rd, 7th and 10th days. Results. It has been found out that in case of concurrent trauma the procalcitonin level in blood increased immediately and it was especially intensively expressed in severe trauma (ISS > 20 scores). During first 24 hours it was tens times above the normal and it remained above the normal during the post-traumatic period. And these changes were not related to a generalized infection. During all period of follow up the changes in procalcitonin level coincided with changes in the systemic inflammatory response and anti-inflammatory and pro-inflammatory cytokines though with a certain delay. Procalcitonin level did not increase repeatedly every time as nidus of infection manifested, it occurred more often in those with lethal outcome. High procalcitonin level in the acute post-traumatic period indicated higher chances of septic complications development on the 7-10th day. Conclusion. Along with the role of procalcitonin as an infection marker, changes in its concentration in the early post-traumatic period can be considered as a laboratory sign of the intensity of systemic response to the injury.Прокальцитонин – важный биомаркер, используемый в клинической практике для диагностики сепсиса. Однако в ближайшем посттравматическом периоде повышение его концентрации может регистрироваться и при отсутствии явного очага инфекции. Цель: уточнить значение прокальцитонина как биомаркера у пострадавших с сочетанной травмой. Методика. Обследовано 76 пострадавших, которых разделяли на подгруппы с учетом тяжести травмы (ISS < 20 и ISS > 20 баллов) и исхода (благоприятный, неблагоприятный, с инфекционными осложнениями или без них). Динамику концентрации прокальцитонина в подгруппах сопоставляли с выраженностью системного ответа на повреждение, изменениями IL-6, IL-8, IL-10, CD14, HLA-DR, секреторного иммуноглобулина А. Забор крови производили при поступлении, через 12 ч, на 1, 3, 7, 10-е сут. Результаты. Установлено, что при сочетанной травме повышение концентрации прокальцитонина в крови происходило сразу и особенно заметно при тяжелых (ISS > 20 баллов) повреждениях. Уже в 1-е сут она превышала нормальные значения в десятки раз и оставалась выше нормы в течение ближайшего посттравматического периода. Эти изменения не были связаны с генерализованным инфекционным процессом. На протяжении всего срока наблюдения динамика прокальцитонина, хотя и с некоторым опозданием, но совпадала с изменениями системной воспалительной реакции, а также противо- и провоспалительных цитокинов. Повторное повышение уровня прокальцитонина при манифестации очага инфекции проявлялось не всегда, чаще – у лиц с летальным исходом. Высокий уровень прокальцитонина в остром периоде после травмы указывал на большую вероятность развития септических осложнений на 7–10-е сут. Заключение. Наряду с отводимой прокальцитонину ролью биомаркера инфекции, изменения его концентрации в раннем посттравматическом периоде можно рассматривать в качестве лабораторного признака выраженности системного ответа организма на повреждение.

Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals

The recent identification of the mitochondrial Ca(2+) uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca(2+) uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca(2+) levels following NMDA receptor activation, leading to increased mitochondrial membrane depolarization and excitotoxic cell death. Knockdown of endogenous Mcu expression reduces NMDA-induced increases in mitochondrial Ca(2+), resulting in lower levels of mitochondrial depolarization and resistance to excitotoxicity. Mcu is subject to dynamic regulation as part of an activity-dependent adaptive mechanism that limits mitochondrial Ca(2+) overload when cytoplasmic Ca(2+) levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca(2+) and CaM kinase-mediated induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca(2+) uptake and preventing excitotoxic death. This establishes Mcu and the pathways regulating its expression as important determinants of excitotoxicity, which may represent therapeutic targets for excitotoxic disorders

Влияние отмены ИАПФ/БРА на риск развития послеоперационных осложнений в абдоминальной хирургии

A significant proportion of patients undergoing non-cardiac surgery receive therapy with angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), which are usually prescribed for treatment of arterial hypertension and CHF. Current guidelines fail to provide clear consensus on whether it is worth discontinuing ACEi/ARBs before non-cardiac surgery. The aim of this research was to assess the contribution of pre-op ACEi/ARBs withdrawal to the development of postoperative complications in patients after abdominal surgery using data from STOPRISK database.Materials and methods. Data of 1945 patients from of the STOPRISK database was used for the analysis. Patients were retrospectively divided into two groups: first group (N=471, 24.2%) included patients subjected to ACEi/ARBs withdrawal 24 hours before surgery, second group (N=1474, 75.8%) included patients continuing on ACEi/ARBs therapy. The 30-day outcomes were analyzed — postoperative complications (acute kidney injury, acute respiratory distress syndrome, anastomosis failure, arrhythmias, circulatory arrest, cardiogenic pulmonary edema, postoperative delirium, myocardial infarction, pneumonia, ileus, postoperative bleeding, pulmonary embolism, acute cerebrovascular accident, wound infection) and mortality. We were not evaluating intraoperative and postoperative arterial hypotension and hypertension, we analyzed the use of vasopressors as a surrogate marker. ACEi/ARBs re-initiation after surgery was not evaluated.Results. One or more post-operative complications were documented in 113 patients (5.8%). Only postoperative delirium was more common in patients (1.06% vs. 0.27%, P=0.027) after ACEi/ARBs withdrawal 24 hours before surgery, the difference reached statistical significance. Sub-analysis in the group of patients with arterial hypertension as the only comorbidity showed no statistically significant differences in the outcomes. Sub-analysis in the group of patients with CFH showed higher incidence of postoperative delirium after ACEi/ARBs withdrawal (2.68% vs. 0.6%, P=0.023). The logistic regression analysis showed that the risk of developing postoperative delirium is influenced by age, vasopressor support, and ACEi/ARBs withdrawal (the area under the curve for the model was 0.92 (0.90–0.93).Conclusion. Rates of pre-op ACEi/ARBs withdrawal (24.2%) are consistent with published data. In the entire cohort, ACEi/ARBs withdrawal resulted in higher incidence of postoperative delirium, as well as in the subgroup of patients with CHF, while ACEi/ARBs withdrawal in the subgroup of patients with arterial hypertension had no influence on postop complications.ACEi/ARBs withdrawal, along with hemodynamic instability and older age, contributes to the development of postoperative delirium, which is the subject of future research. Значительное число пациентов, подвергающихся внесердечным операциям, получает терапию ингибиторами ангиотензинпревращающего фермента (ИАПФ)/блокаторами рецепторов ангиотензина II (БРА), которые обычно назначают в качестве антигипертензивных препаратов и для лечения ХСН. В современных руководствах нет единого мнения о том, стоит ли отменять ИПФ/БРА перед внесердечными операциями.Цель работы — изучение вклада отмены ИАПФ/БРА в развитие послеоперационных осложнений у пациентов в абдоминальной хирургии по данным базы STOPRISK.Методы исследования. В анализ включили данные 1945 пациентов базы данных STOPRISK, которых ретроспективно разделили на пациентов, у которых ИАПФ/БРА отменяли за 24 ч до операции (n=471, 24,2%) и остальных пациентов (n=1474, 75,8%), у которых прием продолжался вплоть до оперативного вмешательства. Изучали 30-дневный исход — послеоперационные осложнения (острое повреждение почек, острый респираторный дистресс-синдром, несостоятельность анастомоза, аритмии, остановка кровообращения, кардиогенный отек легких, послеоперационный делирий, инфаркт миокарда, пневмония, парез кишечника, послеоперационное кровотечение, тромбоэмболия легочной артерии, острое нарушение мозгового кровообращения, раневая инфекция) и летальность. В исследовании не оценивали частоту интраоперационной и послеоперационной гипотензии и гипертензии, применяли суррогатный показатель — частоту применения вазопрессоров. Не оценивали возобновление терапии ИАПФ/БРА в послеоперационный период Результаты. Наличие одного и более осложнения регистрировали у 113 пациентов (5,8%). Статистически значимыми были различия только в частоте послеоперационного делирия — он чаще встречался в группе пациентов, у которых ИАПФ/БРА отменяли за 24 часа до операции (1,06% против 0,27%, р=0,027). При проведении субанализа в подгруппе пациентов, где сопутствующие заболевания были представлены изолированной гипертонической болезнью, статистически значимых различий в исходах не отметили.Субанализ у пациентов, в структуре сопутствующих заболеваний которых присутствовала хроническая сердечная недостаточность, показал большую частоту послеоперационного делирия в группе пациентов, у которых ИАПФ/БРА отменяли (2,68% против 0,6%, р=0,023).Проведенный логистический регрессионный анализ показал, что на риск развития послеоперационного делирия влияют возраст, вазопрессорная поддержка, отмена ИАПФ/БРА (площадь под кривой для модели составила 0,92 (0,90–0,93).Заключение. Частота отмены ИАПФ/БРА (24,2%) соотносится с мировыми данными. В общей когорте отмена ИАПФ/БРА приводила к большей частоте развития послеоперационного делирия, субанализ в группе пациентов с хронической сердечной недостаточностью подтвердил эту закономерность, в группе же пациентов с гипертонической болезнью, отмена ИАПФ/БРА, не влияла на исход. Наряду с гемодинамической нестабильностью и пожилым возрастом, отмена ИАПФ/БРА, вносит вклад в развитие послеоперационного делирия, что требует дальнейшего изучения.

CLINICAL AND DIAGNOSTIC VALUE OF PROCALCITONIN LEVELS IN VICTIMS OF SEVERE CONCOMITANT INJURY

Mortality due to pyoseptic complications after severe mechanical injury is rather high. Some hopes for its reduction are associated with the timely detection of infectious complications. In this case an important role is, in terms of early diagnosis, attached to the calcitonin prohormone procalcitonin that is positioned itself as a marker for the progression of a bacterial infectious process. At the same time, there is evidence for elevated PCT levels after extensive surgical interventions and in massive injuries directly unassociated with the development of an infectious process. Objective: to estimate the significance of its changes early after injury. A prospective investigation was conducted, which enrolled 76 victims of severe concomitant mechanical injury (patients with severe brain injury and victims whose death had occurred within the following few days were excluded from the study). The time course of changes in the blood levels of PCT, C-reactive protein, activated monocytes expressing receptors for lipopolysaccharide and other bacterial antigens (CD14+ and HLA-R+), cytokines (IL-6, IL-10), glucose, and lactate was studied on admission, at 12 and 24 hours, 3, 7, and 10 days. The diagnosis of bacteremia involved blood microbiology tests for sterility and polymerase chain reaction to detect antigens of blood opportunistic microorganisms. The findings were analyzed in view of injury severity scores (ISS), the development of infectious complications, and an outcome. PCT concentrations were shown to rise significantly within the first 24 hours after injury in the absence of clinical manifestations of infectious complications. The increase in PCT levels was preceded by the highest rise of HLA-DR+ within the first 24 hours and CD14+ just 12 hours after injury, which could not preclude the bacterial translocation inducing, along with other factors, the development of a systemic inflammatory response. At the same time, the findings could suggest that the role of this indicator must not boil down exclusively to the function of that of infectious complications

CHANGES OF PROCALCITONIN LEVEL IN THE POST-TRAUMATIC PERIOD AND ITS ROLE IN SYSTEMIC RESPONSE TO TRAUMA

Procalcitonin is an important marker used in the clinical practice for sepsis diagnostics. However the increase of its concentration can be registered in the early post-traumatic period with no obvious nidus of infection. Goal: to clarify the value of procalcitonin as a biomarker in those with concurrent trauma. Methods. 76 those injured were examined and divided into subgroups depending on the severity of trauma (ISS < 20 and ISS > 20 scores) and outcome (favorable, unfavorable, with infectious complications and no infectious complications). The changes in procalcitonin level in the subgroups were compared with intensity of the systemic response to the injury through changes in IL-6, IL-8, IL-10, CD14, HLA-DR, secretory immunoglobulin A. Blood was collected upon admission to hospital, in 12 hours, on the 1st, 3rd, 7th and 10th days. Results. It has been found out that in case of concurrent trauma the procalcitonin level in blood increased immediately and it was especially intensively expressed in severe trauma (ISS > 20 scores). During first 24 hours it was tens times above the normal and it remained above the normal during the post-traumatic period. And these changes were not related to a generalized infection. During all period of follow up the changes in procalcitonin level coincided with changes in the systemic inflammatory response and anti-inflammatory and pro-inflammatory cytokines though with a certain delay. Procalcitonin level did not increase repeatedly every time as nidus of infection manifested, it occurred more often in those with lethal outcome. High procalcitonin level in the acute post-traumatic period indicated higher chances of septic complications development on the 7-10th day. Conclusion. Along with the role of procalcitonin as an infection marker, changes in its concentration in the early post-traumatic period can be considered as a laboratory sign of the intensity of systemic response to the injury

Targeted therapy for tuberous sclerosis complex

The tuberous sclerosis complex genes (TSC1 and TSC2) function as classic tumor suppressor genes in health; a loss of function of these genes results in activation of the kinase m-TOR and to development of benign tumors. Despite their slow progression, renal subependymal giant cell astrocytomas and angiomyolipomas can cause fatal outcomes. Both Phases I–II and III EXIST-1 and EXIST-2 trials demonstrated that the m-TOR inhibitor everolimus had good efficacy and tolerability: the volume of astrocytomas and that of angomyolipomas were reduced by 50% or more in 35 and 41% of patients, respectively. After 3.5 years of the trials, everolimus showed a high retention rate: 80.2 and 79% of the patients, respectively. Virtually all patients were observed to have adverse reactions, most commonly stomatitis, oral ulcers, and nasopharyngitis. Everolimus has been registered in the Russian Federation and Russian patients participated in the EXIST-1 and EXIST-2 trials. The indications for prescribing the drug are tuberous sclerosis complex-associated subependymal giant cell astrocytomas and angomyolipomas in patients older than 3 and in those older than 18 years of age, respectively. Everolimus has the potential for targeted treatment for the spectrum of clinical manifestations of tuberous sclerosis complex

The first results of tuberous sclerosis registry

The purpose of establishing and maintaining a tuberous sclerosis registry is to collect data on the clinical manifestations and outcomes of the disease, and drug and non-drug interventions. The registry includes data on 303 people (156 men and 147 women) aged 4 months to 28 years who are diagnosed as having this disease. Most patients are the residents of Moscow and its Region (102/303; 33,6%). Thirty (9,9%) of the 303 patients are registered to have a family history of tuberous sclerosis. TSC1 and TSC2 gene mutations are detected in 29 (38,6%) and 46 (61,4%) patients, respectively. The TSC2 gene mutations previously undescribed in the world literature are found in 10 patients. There is epilepsy in 86,8% (263/303), intellectual developmental disorders in 39,3% (119/303), subependymal giant cell astrocytomas in 16,2% (49/303), tubers in 61% (81/131), subependymal nodules in 65,7% (86/131), hypopigmentation spots in 66,3% (201/303), facial angtofibromas in 29,4% (89/303), cardiac rhabdomyomas in 44,2% (134/303), and renal angiomyolipomas in 41,6% (126/303). West's syndrome is noted in 68 (25,9%) of the 262 epileptic patients; symptomatic focal epilepsy is seen in 149 (56,9%) patients. Seven patients took everolimus for subependymal giant cell astrocytomas. The registry demonstrates the late diagnosis of tuberous sclerosis, the limitation of genetic testing, and physicians' inadequate attention to the psychiatric manifestations of the disease