ISO-1 Binding to the Tautomerase Active Site of MIF Inhibits Its Pro-inflammatory Activity and Increases Survival in Severe Sepsis

MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis, arthritis, and other inflammatory diseases. Antibodies against MIF are effective in experimental models of inflammation, and there is interest in strategies to inhibit its deleterious cytokine activities. Here we identify a mechanism of inhibiting MIF pro-inflammatory activities by targeting MIF tautomerase activity. We designed small molecules to inhibit this tautomerase activity; a lead molecule, "ISO-1 ((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester)," significantly inhibits the cytokine activity in vitro. Moreover, ISO-1 inhibits tumor necrosis factor release from macrophages isolated from LPStreated wild type mice but has no effect on cytokine release from MIFdeficient macrophages. The therapeutic importance of the MIF inhibition by ISO-1 is demonstrated by the significant protection from sepsis, induced by cecal ligation and puncture in a clinically relevant time frame. These results identify ISO-1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis

Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation

The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNF alpha) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer\u27s disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation

КЛИНИЧЕСКИЙ СЛУЧАЙ ЭНДОВАСКУЛЯРНОГО ЛЕЧЕНИЯ ПОСТТРАВМАТИЧЕСКОЙ АНЕВРИЗМЫ ПОЧЕЧНОЙ АРТЕРИИ

Introduction. Aneurysm of renal artery is a rare and complex pathology of renal bloodstream. Large percentage of observations show that renal artery aneurysms are iatrogenic and happen due to urological interventions. Traumatic aneurysms are much less frequent. By the nature of the blood supply arterial aneurysms are subdiveded into those, which occur when the injured organ is only artery and arteriovenous aneurysms that occur while an artery is damaged along with the accompanying veins. Aneurysms may be treated only surgically, and the only exception is pregnancy. It is possible to use the open treatment option such as aneurysm resection with prosthetics, reanastomosing or its collateral plastics of the renal artery; exclusion of aneurysm with shunting of renal artery or its branches; resection of aneurysm with anastomosing of artery with azygos splanchnic arteries; complex reconstruction using autovein or internal iliac artery segment; including kidney resection at local infarction or nephrectomy in the case of evident nephrosclerosis.Materials and methods. This paper presents a clinical case of successful minimally invasive surgical treatment of traumatic aneurysm of renal artery. It was carried out through stenting of the right lowpolar renal artery: a coronary sheath was used to transfuse and implant the Explorer-Itgimedical Aneugraft 3.0 * 18.0 mm graft-system; the stent-graft was implanted into the right lowpolar renal artery so that it covers the aneurysm ostium. Results. The above case shows the possibility to successfully apply the endovascular method to treat posttraumatic aneurysms of renal arteries with derivative circulation.Conclusion. This technique can be safely and successfully used as an alternative to the traditional «open» surgery, as it is minimally invasive, and allows performing a complete blockade of the pathological blood flow and to avoid an additional operating trauma and compromenation of distal branches. Введение. Аневризма почечных артерий – редкая и сложная патология сосудистого русла почки. В большом проценте наблюдений аневризмы почечных артерий являются ятрогенными, возникающими в результате интервенционных урологических вмешательств. Травматические аневризмы встречаются значительно реже. По характеру кровоснабжения различают артериальные аневризмы, возникающие при ранении только артерии, и артериовенозные аневризмы, возникающие при одновременном повреждении артерии и сопутствующей вены. Лечение аневризм возможно только хирургическим способом, исключением является только беременность. Возможно применение открытых методов лечения, таких как резекция аневризмы с протезированием, реанастомозированием или ее боковой пластикой почечной артерии; выключение аневризмы с шунтированием почечной артерии или ее ветвей; резекция аневризмы с анастомозированием артерии с непарными висцеральными артериями; сложные реконструкции с использованием аутовены или сегмента внутренней подвздошной артерии; в том числе применение резекции почки при локальном инфаркте или нефрэктомии в случае выраженного нефросклероза. Материалы и методы. В данной работе представлен клинический случай успешного малоинвазивного хирургического лечения травматической аневризмы почечной артерии. Для этого выполнено стентирование правой нижнеполюсной почечной артерии: по коронарному проводнику проведена и имплантирована графт-система Itgimedical Aneugraft 3,0*18,0 мм – стент-графт имплантирован в нижнеполюсную правую почечную артерию с перекрытием шейки аневризмы.Результаты. Приведенный случай показывает возможность успешного применения эндоваскулярного метода для лечения посттравматических аневризм почечных артерий с артериовенозным сбросом.Заключение. Данная методика может безопасно и с успехом применяться в качестве альтернативы традиционного «открытого» хирургического вмешательства, поскольку она малоинвазивна, позволяет выполнять полную блокаду патологического кровотока, избегать дополнительной операционной травмы и компрометации дистальных ветвей.

Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation

The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation

Cardiovascular Changes during Robot-Assisted Pelvic Surgery

The application of robotic assistance in pelvic surgery has become popular across multiple specialties during the past decades, facilitating minimally invasive surgery. The most remarkable challenges regarding these procedures are the carbon dioxide pneumoperitoneum and steep Trendelenburg position. The combination of two factors affects the patient additionally or synergistically and have important physiological effects on cardiovascular system. All those changes are usually well tolerated in patients with normal cardiac function, but it can be different in elderly patients or even in patients with underlying heart conditions. In order to provide the proper management of patients undergone the robotic surgery, we aim to thoroughly understand these effects and overview the risks and possible related cardiovascular complications. Further, a short introduction on dangerous areas of robot-assisted pelvic surgery will be briefly reviewed

A CLINICAL CASE OF ENDOVASCULAR TREATMENT OF POST-TRAUMATIC ANEURYSMS OF RENAL ARTERIES

Introduction. Aneurysm of renal artery is a rare and complex pathology of renal bloodstream. Large percentage of observations show that renal artery aneurysms are iatrogenic and happen due to urological interventions. Traumatic aneurysms are much less frequent. By the nature of the blood supply arterial aneurysms are subdiveded into those, which occur when the injured organ is only artery and arteriovenous aneurysms that occur while an artery is damaged along with the accompanying veins. Aneurysms may be treated only surgically, and the only exception is pregnancy. It is possible to use the open treatment option such as aneurysm resection with prosthetics, reanastomosing or its collateral plastics of the renal artery; exclusion of aneurysm with shunting of renal artery or its branches; resection of aneurysm with anastomosing of artery with azygos splanchnic arteries; complex reconstruction using autovein or internal iliac artery segment; including kidney resection at local infarction or nephrectomy in the case of evident nephrosclerosis.Materials and methods. This paper presents a clinical case of successful minimally invasive surgical treatment of traumatic aneurysm of renal artery. It was carried out through stenting of the right lowpolar renal artery: a coronary sheath was used to transfuse and implant the Explorer-Itgimedical Aneugraft 3.0 * 18.0 mm graft-system; the stent-graft was implanted into the right lowpolar renal artery so that it covers the aneurysm ostium. Results. The above case shows the possibility to successfully apply the endovascular method to treat posttraumatic aneurysms of renal arteries with derivative circulation.Conclusion. This technique can be safely and successfully used as an alternative to the traditional «open» surgery, as it is minimally invasive, and allows performing a complete blockade of the pathological blood flow and to avoid an additional operating trauma and compromenation of distal branches

Correlation of the imbalance in the circulating lymphocyte subsets with C-reactive protein and cardio-metabolic conditions in patients with COVID-19

The immune system is severely compromised in patients with COVID-19. The representative group of 43 patients were selected from the cohort of 342 patients with COVID-19 and pneumonia. This group of 43 patients was examined for the levels of C-reactive protein, biomarker of systemic inflammation, and for the subsets of adaptive immune cells. The immunological parameters were correlated with the metabolic parameters and cardiovascular pathology history. We identified that a decrease in the absolute number of T-lymphocytes, T-cytotoxic, T-activated and B-lymphocytes correlated with the higher levels of CRP. The absolute number of T-helpers and the absolute number of double positive T-lymphocytes positively correlated with the levels of iron in serum (Z= 0,310 and Z=0,394). The absolute numbers of T-activated lymphocytes positively correlated with serum levels of LDH (Z = 0,422), ferritin (Z = 0,407) and iron (Z = 0,418). When studying subpopulations of lymphocytes, depending on the combined pathology, we found that the absolute numbers of B-lymphocytes and double positive T-lymphocytes in the peripheral blood were significantly reduced in patients with arterial hypertension (p=0,0074 and p=0,0227, correspondingly). The increased levels of NK cell were found in patients with a history of coronary heart disease (p=0,0108). In addition, we found that deficiencies in the adaptive immune system correlated with the deficiencies in iron metabolism. The cardiovascular pathology upsets the balance in the adaptive and innate immune system in the circulation of patient with severe COVID-19