Impact of Parenteral Nutrition Versus Fasting on Hepatic Bile Acid Production and Transport in a Rabbit Model of Prolonged Critical Illness

Cholestatic liver dysfunction frequently occurs during critical illness. Administration of parenteral nutrition (PN) is thought to aggravate this. Underlying mechanisms are not clear.status: publishe

Critical illness induces alternative activation of M2 macrophages in adipose tissue

INTRODUCTION: We recently reported macrophage accumulation in adipose tissue of critically ill patients. Classically activated macrophage accumulation in adipose tissue is a known feature of obesity, where it is linked with increasing insulin resistance. However, the characteristics of adipose tissue macrophage accumulation in critical illness remain unknown. METHODS: We studied macrophage markers with immunostaining and gene expression in visceral and subcutaneous adipose tissue from healthy control subjects (n=20) and non-surviving prolonged critically ill patients (n=61). For comparison, also subcutaneous in vivo adipose tissue biopsies were studied from 15 prolonged critically ill patients. RESULTS: Subcutaneous and visceral adipose tissue biopsies from nonsurviving prolonged critically ill patients displayed a large increase in macrophage staining. This staining corresponded with elevated gene expression of "alternatively activated" M2 macrophage markers arginase-1, IL-10 and CD163 and low levels of the "classically activated" M1 macrophage markers tumor necrosis factor (TNF)-alpha and inducible nitric-oxide synthase (iNOS). Immunostaining for CD163 confirmed positive M2 macrophage staining in both visceral and subcutaneous adipose tissue biopsies from critically ill patients. Surprisingly, circulating levels and tissue gene expression of the alternative M2 activators IL-4 and IL-13 were low and not different from controls. In contrast, adipose tissue protein levels of peroxisome proliferator-activated receptor-gamma PPARgamma a nuclear receptor required for M2 differentiation and acting downstream of IL-4, was markedly elevated in illness. In subcutaneous abdominal adipose tissue biopsies from surviving critically ill patients, we could confirm positive macrophage staining with CD68 and CD163. We also could confirm elevated arginase-1 gene expression and elevated PPARgamma protein levels. CONCLUSIONS: Unlike obesity, critical illness evokes adipose tissue accumulation of alternatively activated M2 macrophages, which have local anti-inflammatory and insulin sensitizing features. This M2 macrophage accumulation may contribute to the previously observed protective metabolic activity of adipose tissue during critical illness.status: publishe

Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness

Introduction: Prolonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T3) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T3availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T3syndrome in prolonged critical illness.Methods: Healthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors α (TRα) and β (TRβ) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes.Results: In the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T4) and low-normal T3concentrations, without a change at the thyroid hormone receptor level.Conclusions: Although expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T4and T3content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits. Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators. Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1–5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04–0.04] mmol/L to 0.75 [0.04–2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN sta

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies

Abstract Background Withholding parenteral nutrition (PN) until one week after PICU admission facilitated recovery from critical illness and protected against emotional and behavioral problems 4 years later. However, the intervention increased the risk of hypoglycemia, which may have counteracted part of the benefit. Previously, hypoglycemia occurring under tight glucose control in critically ill children receiving early PN did not associate with long-term harm. We investigated whether hypoglycemia in PICU differentially associates with outcome in the context of withholding early PN, and whether any potential association with outcome may depend on the applied glucose control protocol. Methods In this secondary analysis of the multicenter PEPaNIC RCT, we studied whether hypoglycemia in PICU associated with mortality (N = 1440) and 4-years neurodevelopmental outcome (N = 674) through univariable comparison and multivariable regression analyses adjusting for potential confounders. In patients with available blood samples (N = 556), multivariable models were additionally adjusted for baseline serum NSE and S100B concentrations as biomarkers of neuronal, respectively, astrocytic damage. To study whether an association of hypoglycemia with outcome may be affected by the nutritional strategy or center-specific glucose control protocol, we further adjusted the models for the interaction between hypoglycemia and the randomized nutritional strategy, respectively, treatment center. In sensitivity analyses, we studied whether any association with outcome was different in patients with iatrogenic or spontaneous/recurrent hypoglycemia. Results Hypoglycemia univariably associated with higher mortality in PICU, at 90 days and 4 years after randomization, but not when adjusted for risk factors. After 4 years, critically ill children with hypoglycemia scored significantly worse for certain parent/caregiver-reported executive functions (working memory, planning and organization, metacognition) than patients without hypoglycemia, also when adjusted for risk factors including baseline NSE and S100B. Further adjustment for the interaction of hypoglycemia with the randomized intervention or treatment center revealed a potential interaction, whereby tight glucose control and withholding early PN may be protective. Impaired executive functions were most pronounced in patients with spontaneous or recurrent hypoglycemia. Conclusion Critically ill children exposed to hypoglycemia in PICU were at higher risk of impaired executive functions after 4 years, especially in cases of spontaneous/recurrent hypoglycemia

Reduced Cortisol Metabolism during Critical Illness

Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.status: publishe

Внешнеторговое сотрудничество Республики Корея со странами Северо-Восточной Азии

Вследствие быстрого развития и усложнения мирохозяйственных связей и торгово-экономического взаимодействия государств, тенденции развитие международного сотрудничества приобретают особую актуальность. Северо-Восточная Азия (СВА) – это регион, в котором очень тонко переплетаются исторические, идеологические, политические особенности и экономическая целесообразность торговли. Страновой состав региона Северо-Восточной Азии может рассматриваться с разных точек зрения, в рамках данного исследования под странами данного региона понимаются Республика Корея, Китай, Япония и вся Россия. Взаимодействие Республики Корея с каждым из трех государств имеет уникальную историю, достаточный потенциал для развития торговли, а также свои особенности формирования внешнеэкономических связей. Усиление роли Китая в качестве торгового партнера, снижение значимости Японии и сложная экономическая ситуация в России на текущий момент оказывают существенное влияние на развитие Республики Корея, опорой экономического роста которой традиционно являлась торговля. Эти три страны являются одними из важнейших партнеров для Республики Корея, поэтому изучение процессов формирования внешнеэкономических связей в рамках региона Северо-Восточной Азии необходимо для определения основных тенденций, качественных изменений и факторов, определяющих вектор торговых отношений. Цель исследования – выявить основные тенденции сотрудничества Республики Корея и стран Северо-Восточной Азии в сфере внешней торговли. Практическая значимость работы состоит в возможности получения всестороннего анализа внешнеторгового сотрудничества Республики Корея и стран Северо-Восточной Азии, глубоко раскрытия данной тематики, что может послужить основой для дальнейших исследований торговли Республики Корея со странами региона и определения будущих перспектив в сотрудничестве для формирования внешнеторговой политики страны.The final project is devoted to trade cooperation of the Republic of Korea and North-East Asian countries. This region is influenced by many factors and analyses of dynamics and structure of trade are extremely significant to reveal the reasons of current trends of international cooperation between countries

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α–dependent microRNA (miR)–210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210–based therapeutic and diagnostic strategies

Timing of Parenteral Nutrition Support - The authors reply

status: publishe