Inter-organ transmission of hepatocellular senescence induces multi-organ dysfunction through the TGFβ signalling pathway.

Cellular senescence is associated with aging but also impacts various physiological and pathological processes such as embryonic development and wound healing. Factors secreted by senescent cells can affect their microenvironment, including local spreading of senescence. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here, using genetic mouse models of hepatocyte-specific senescence, we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence. Additionally, we observe senescence-associated regeneration and reprogramming in the proximal tubules of the kidney. Using single cell transcriptomics and in vitro assays, we identify the Transforming Growth Factor β (TGFβ) pathway as a critical mediator of systemic spread of senescence. Lastly, TGFβ inhibition in our mouse models blocks senescence transmission to other organs and prevents renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence which, independent of aging, contributes to multi-organ dysfunction.

Impact of Comorbidities on Beneficial Effect of Lactated Ringers vs. Saline in Sepsis Patients

Background: Lactated Ringers reduced mortality more than saline in sepsis patients but increased mortality more than saline in traumatic brain injury patients.Method: This prospective cohort study was conducted in a medical intensive care unit (ICU) in central Taiwan. We applied standard sepsis evaluation protocol and identified heart, lung, liver, kidney, and endocrine comorbidities. We also evaluated resuscitation response with central venous pressure, central venous oxygen saturation, and serum lactate level simultaneously. Propensity-score matching and Cox regression were used to estimate mortality. The competing risk model compared the lengths of hospital stays with the subdistribution hazard ratio (SHR).Results: Overall, 938 patients were included in the analysis. The lactated Ringers group had a lower mortality rate (adjusted hazard ratio, 0.59; 95% CI 0.43-0.81) and shorter lengths of hospital stay (SHR, 1.39; 95% C.I. 1.15-1.67) than the saline group; the differences were greater in patients with chronic pulmonary disease and small and non-significant in those with chronic kidney disease, moderate to severe liver disease and cerebral vascular disease. The resuscitation efficacy was the same between fluid types, but serum lactate levels were significantly higher in the lactated Ringers group than in the saline group (0.12 mg/dl/h; 95% C.I.: 0.03, 0.21), especially in chronic liver disease patients. Compared to the saline group, the lactated Ringers group achieved target glucose level earlier in both diabetes and non-diabetes patients.Conclusion: Lactate Ringer's solution provides greater benefits to patients with chronic pulmonary disease than to those with chronic kidney disease, or with moderate to severe liver disease. Comorbidities are important in choosing resuscitation fluid types.

Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5

The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking.

Prevalence of Alcoholic Liver Disease in Port Harcourt, Rivers State

Alcoholic liver disease is a severe liver disease that affects substantial number of people in different parts of the world. However, there is low level of awareness regarding the disease and poor knowledge of the risk factors. The present study aimed to determine the prevalence of alcoholic liver disease among the residents of Port Harcourt, Rivers State, Nigeria, as this will both provide a clear picture of the incidence, as well as, aiding the diagnosis and management of the disease and distinguish it from other forms of liver impairment. This cross-sectional, descriptive study was conducted in the University of Port Harcourt Teaching Hospital; a tertiary health facility serving treatment, teaching, health research and referral purposes for primary and secondary health care facilities within Rivers State and its adjoining states. The relationship between gender and age to the assayed parameters were investigated, shows that age (0.793) and sex (0.591) were not statistically significant for the circulating level of aspartate, with age (0.000) significant and sex (0.217) non-significant for alanine amino transaminase, while age (0.830) and sex (1.52) were not statistically significant for gamma T. the prevalence of liver disease is low (8.1%) in the population and this may be attributed to factors such as poor healthcare-seeking attitude among the residents and effective diagnostic tools to detect the anomaly in the liver, especially, at the earliest stages of the disease condition.

The Spectrum of COVID-19 in Children in Spain

Background: We aimed to identify the spectrum of disease in children with COVID-19, and the risk factors for admission in paediatric intensive care units (PICUs).Methods: We conducted a multicentre, prospective study of children with SARS-CoV-2 infection in 76 Spanish hospitals. We included children with COVID-19 or multi-inflammatory syndrome (MIS-C) younger than 18 years old, attended during the first year of the pandemic.Results: We enrolled 1 200 children. A total of 666 (55.5%) were hospitalized, and 123 (18.4%) required admission to PICU. Most frequent major clinical syndromes in the cohort were: mild syndrome (including upper respiratory tract infection and flu-like syndrome, skin or mucosae problems and asymptomatic), 44.8%; bronchopulmonary syndrome (including pneumonia, bronchitis and asthma flare), 18.5%; fever without a source, 16.2%; MIS-C, 10.6%; and gastrointestinal syndrome, 10%. In hospitalized children, the proportions were: 28.5%, 25.7%, 16.5%, 19.1% and 10.2%, respectively. Risk factors associated with PICU admission were MIS-C (odds ratio [OR]: 37.5,95% CI 22.7 to 57.8), moderate or severe liver disease (OR: 9,95% CI 1.6 to 47.6), chronic cardiac disease (OR: 4.8,95% CI 1.8 to 13) and asthma or recurrent wheezing (OR: 2.8,95% CI 1.3 to 5.8). However, asthmatic children were admitted into the PICU due to MIS-C or pneumonia, not due to asthma flare. Conclusion: Hospitalized children with COVID-19 usually present as one of five major clinical phenotypes of decreasing severity. Risk factors for PICU include MIS-C, elevation of inflammation biomarkers, asthma, moderate or severe liver disease and cardiac disease.