Subject(s)
COVID-19/transmission , Immunocompromised Host/immunology , Virus Replication/physiology , Virus Shedding/physiology , Adult , Aged , COVID-19/pathology , Female , Humans , Male , Middle Aged , Patient Isolation/methods , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/metabolism , Young AdultABSTRACT
OBJECTIVE: Hyperglycemia is an independent risk factor in hospitalized patients for adverse outcomes, even if patients are not diabetic. We used continuous glucose monitoring to evaluate whether glycemic control (hyperglycemia) in the first 72 h after an intensive care admission was associated with the need for admission to a post discharge long-term medical facility. RESULTS: We enrolled 59 coronary artery bypass grafting patients. Poor glycemic control was defined as greater than 33% of continuous glucose monitoring values < 70 and > 180 mg/dL (group 1); and then these patients were reevaluated with a less strict definition of poor glycemic control with greater than 25% of continuous glucose values < 70 and > 180 mg/dL (group 2). In group 1 4/10 (40.0%) whose glucose was not well controlled went to an extended care post discharge facility as opposed to 6/49 (12.2%) that were well controlled. In reevaluation as group 2, 5/14 (35.7%) whose glucose was not well controlled went to an extended care post discharge facility as opposed to 5/45 (11.1%) who were well controlled. Admission to a post discharge facility was increased in patients with poor glycemic control p = 0.045 and p = 0.042 for group 1 and group 2, and with odds ratios of 4.8 (95% CI 1.0-22.5) and 4.4 (95% CI 1.0-19.4), respectively.
Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/diagnosis , Hypoglycemic Agents/therapeutic use , Patient Discharge , Aged , Blood Glucose Self-Monitoring , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Hyperglycemia/diagnosis , Insulin/therapeutic use , Male , Middle Aged , Prospective StudiesABSTRACT
Mixed Lineage Kinase 3 (MLK3), a member of the MLK subfamily of protein kinases, is a mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) that activates MAPK signalling pathways and regulates cellular responses such as proliferation, invasion and apoptosis. MLK4ß, another member of the MLK subfamily, is less extensively studied, and the regulation of MLK4ß by stress stimuli is not known. In this study, the regulation of MLK4ß and MLK3 by osmotic stress, thermostress and heat shock protein 90 (Hsp90) inhibition was investigated in ovarian cancer cells. MLK3 and MLK4ß protein levels declined under conditions of prolonged osmotic stress, heat stress or exposure to the Hsp90 inhibitor geldanamycin (GA); and MLK3 protein declined faster than MLK4ß. Similar to MLK3, the reduction in MLK4ß protein in cells exposed to heat or osmotic stresses occurred via a mechanism that involves the E3 ligase, carboxy-terminus of Hsc70-interacting protein (CHIP). Both heat shock protein 70 (Hsp70) and CHIP overexpression led to polyubiquitination and a decrease in endogenous MLK4ß protein, and MLK4ß was ubiquitinated by CHIP in vitro. In untreated cells and cells exposed to osmotic and heat stresses for short time periods, small interfering RNA (siRNA) knockdown of MLK4ß elevated the levels of activated MLK3, c-Jun N-terminal kinase (JNK) and p38 MAPKs. Furthermore, MLK3 binds to MLK4ß, and this association is regulated by osmotic stress. These results suggest that in the early response to stressful stimuli, MLK4ß-MLK3 binding is important for regulating MLK3 activity and MAPK signalling, and after prolonged periods of stress exposure, MLK4ß and MLK3 proteins decline via CHIP-dependent degradation. These findings provide insight into how heat and osmotic stresses regulate MLK4ß and MLK3, and reveal an important function for MLK4ß in modulating MLK3 activity in stress responses.
