Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia

Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.

Cortical spreading depolarizations in the context of subarachnoid hemorrhage and the role of ketamine

Delayed cerebral ischemia (DCI) is one of the main complications of spontaneous subarachnoid haemorrhage and one of its causes is the cortical spreading depolarizations (CSDs). Cortical spreading depolarizations are waves of neuronal and glial depolarizations in which there is loss of neuronal ionic homeostasis with potassium efflux and sodium and calcium influx. In damaged brain areas and brain areas at risk, such as those adjacent to subarachnoid haemorrhage (SAH), CSDs induce microvascular vasoconstriction and, therefore, hypoperfusion and spread of ischemia. Several studies have been devoted to minimize secondary injuries that occur hours to days after an acute insult. Ketamine, a drug until recently contraindicated in the neurosurgical population for potentially causing intracranial hypertension, has re-emerged as a potential neuroprotective agent due to its pharmacodynamic effects at the cellular level. These effects include anti-inflammatory mechanisms, and those of microthrombosis and cell apoptosis controls, and of modulation of brain excitotoxicity and CSDs. A literature review was performed at PubMed covering the period from 2002 to 2019. Retrospective studies confirmed the effects of ketamine on the control of CSDs and, consequently, of DCI in patients with SAH, but did not show improvement in clinical outcome. The influence of ketamine on the occurrence/development of DCI needs to be further confirmed in prospective randomized studies.

Effect of TNFAIP8 on the immune function of Th17 cells via p53/ p21/ MDM2 pathway after acute insult

Background: Th17 cells induced immunosuppression plays a vital role during sepsis. Belonging to the tumor necrosis factor α induced protein 8 (TNFAIP8) family, TNFAIP8 associates with different immune cell physiopathological processes, thus its underlying regulatory mechanisms on Th17 cells in the acute insult processes have not been fully elucidated. Result: Sepsis was induced by cecal ligation and puncture (CLP) in the male adult C57BL/6 mice. The stable TNFAIP8 knockdown Th17 cells were established via lentiviral transfection with TNFAIP8-specific SiRNA . CCK-8 assay was conducted for measuring Th17 cell proliferation. Flow cytometric analysis was adopted for examining by flow cytometry. The p53/ p21/ MDM2 pathway was measured through western blot. As a result, high TNFAIP8 expression was related with acute insult and survival rate in septic mice. TNFAIP8 SiRNA reduced Th17 cell proliferation as well as cytokines production in vivo and in vitro. In addition, TNFAIP8 KD increased the Th17 cells apoptosis in WT and septic mice. Further, TNFAIP8 influences immune function of Th17 cell involving the p53/ p21/ MDM2 signaling. Actually, TNFAIP8 KD was suggested to regulate the up-regulation of P21 and MDM2, thereby increasing p53 protein expression during sepsis. P53 gene silencing contributed to reversing cell proliferation and apoptosis regulated by TNFAIP8 KD. Conclusion: Our work concluded that TNFAIP8 affected the immune function of Th17 cells, which is mediated via the p53/ p21/ MDM2 pathway after acute insult.

COVID-19 Associated Large Vessel Thrombosis and Ischemic Stroke: A Case Series

The novel severe acute respiratory syndrome coronavirus (SARS-COV-2) affects different people in different ways. Most infected people will develop mild to moderate respiratory flu-like illness and recover without the need for hospitalization. However, one of the not uncommonly observed extrapulmonary associations with SARS-COV-2 is developing severe large-vessel acute ischemic stroke. Moreover, COVID-19 virus-linked Cerebrovascular Accidents (CVA) were more severe and resulted in a higher risk for severe disability and mortality following acute insult. Although the pathophysiology is not fully understood, the neuro-targeting nature of SARS-COV-2 due to vascular injury and the hyperimmune response were plausible proposed mechanisms. Further research is warranted to have a deep insight into the possible mechanisms. Herein, we review the current literature and describe five patients we have encountered during the SARS-COV-2 viral pandemic.

Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk.

New onset neurologic events in people with COVID-19 in 3 regions in China

ObjectiveTo investigate new-onset neurologic impairments associated with coronavirus disease 2019 (COVID-19).MethodsA retrospective multicenter cohort study was conducted between January 18 and March 20, 2020, including people with confirmed COVID-19 from 56 hospitals officially designated in 3 Chinese regions; data were extracted from medical records. New-onset neurologic events as assessed by neurology consultants based on manifestations, clinical examination, and investigations were noted, in which critical events included disorders of consciousness, stroke, CNS infection, seizures, and status epilepticus.ResultsWe enrolled 917 people with average age 48.7 years and 55% were male. The frequency of new-onset critical neurologic events was 3.5% (32/917) overall and 9.4% (30/319) among those with severe or critical COVID-19. These were impaired consciousness (n = 25) or stroke (n = 10). The risk of critical neurologic events was highly associated with age above 60 years and previous history of neurologic conditions. Noncritical events were seen in fewer than 1% (7/917), including muscle cramp, unexplained headache, occipital neuralgia, tic, and tremor. Brain CT in 28 people led to new findings in 9. Findings from lumbar puncture in 3 with suspected CNS infection, unexplained headache, or severe occipital neuralgia were unremarkable.ConclusionsPeople with COVID-19 aged over 60 and with neurologic comorbidities were at higher risk of developing critical neurologic impairment, mainly impaired consciousness and cerebrovascular accidents. Brain CT should be considered when new-onset brain injury is suspected, especially in people under sedation or showing an unexplained decline in consciousness. Evidence of direct acute insult of severe acute respiratory syndrome coronavirus 2 to the CNS is lacking.

Dengue Infection: A Hidden Cause of Acute Insult in a Case of Acute on Chronic Liver Failure in Endemic Area

Acute on chronic liver failure (ACLF) can be precipitated by several factors such as bacterial infection, alcohol intake, viral hepatitis, surgery, etc. Identification of precipitating factor is an important part of management of ACLF. A middle aged gentleman was presented with features of acute liver failure and after through history and investigations, he was diagnosed as acute on chronic liver failure. Chronic liver disease was first diagnosed after this event of acute insult. Precipitating factor of ACLF was dengue fever in this case report. Therefore, in endemic area of dengue infection, dengue serology tests which are not routinely done should be advised to identify dengue infection as an acute insult in ACLF.

Anterior pituitary function in critical illness

Critical illness is hallmarked by major changes in all hypothalamic–pituitary–peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness by analogy with the fasting state. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body toward a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic–pituitary–peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones or strategies to overcome resistance to anabolic stimuli failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well-controlled RCTs to corroborate these findings are needed.

Acute Liver Failure

Acute liver failure (ALF) is an uncommon condition in which an acute insult results in a rapid deterioration of liver function, encephalopathy, and coagulopathy in the absence of prior underlying liver disease. It is differentiated from rapid deterioration in the setting of underlying liver disease (acute on chronic liver failure) and from the gradual deterioration in liver function that can occur in chronic liver failure.