Persistent Fever in the ICU Rehman, Tayyab, MD; deBoisblanc, Bennett P., MD
Chest,
2014, January 2014, 2014-Jan, 2014-01-00, 20140101, Letnik:
145, Številka:
1
Journal Article
Recenzirano
Disorders of elevated body temperature may be classified as either fever or hyperthermia. Fever is caused by a pyrogen-mediated upward adjustment of the hypothalamic thermostat; hyperthermia results ...from a loss of physiologic control of temperature regulation. Fever in the ICU can be due to infectious or noninfectious causes. The initial approach to a febrile, critically ill patient should involve a thoughtful review of the clinical data to elicit the likely source of fever prior to the ordering of cultures, imaging studies, and broad-spectrum antibiotics. Both high fever and prolonged fever have been associated with increased mortality; however, a causal role for fever as a mediator of adverse outcomes during non-neurologic critical illness has not been established. Outside the realm of acute brain injury, the practice of treating fever remains controversial. To generate high-quality, evidence-based guidelines for the management of fever, large, prospective, multicenter trials are needed.
Ghrelin in Critical Illness Narula, Tathagat; deBoisblanc, Bennett P
American journal of respiratory cell and molecular biology
53, Številka:
4
Journal Article
Recenzirano
Ghrelin, a recently described peptide, has attracted significant attention in recent years, primarily in the context of its endocrine- and appetite-regulating effects. The versatility of this peptide ...is manifested in a rapidly expanding body of literature highlighting its nonendocrine functions. This review summarizes the available data on the immunomodulatory as well as the non-immune-mediated effects of ghrelin that form the scientific basis of its role in critical illness.
The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and ...outcomes in patients with acute lung injury.
To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28.
The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up.
Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement.
Ventilator-free days to study day 28.
The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P = .02) (difference, -3.2 95% CI, -5.8 to -0.7) and intensive care unit-free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001).
Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful.
clinicaltrials.gov Identifier: NCT00609180.
Disparities in healthcare access and utilization associated with demographic and socioeconomic status hinder advancement of health equity. Thus, we designed a novel equity-focused approach to ...quantify variations of healthcare access/utilization from the expectation in national target populations. We additionally applied survey-weighted logistic regression models, to identify factors associated with usage of a particular type of health care. To facilitate generation of analysis datasets, we built an National Health and Nutrition Examination Survey (NHANES) knowledge graph to help automate source-level dynamic analyses across different survey years and subjects’ characteristics. We performed a cross-sectional subgroup disparity analysis of 2013-2018 NHANES on U.S. adults for receipt of diabetes treatments and vaccines against Hepatitis A (HAV), Hepatitis B (HBV), and Human Papilloma (HPV). Results show that in populations with hemoglobin A1c level ≥6%, patients with non-private insurance were less likely to receive newer and more beneficial antidiabetic medications; being Asian further exacerbated these disparities. For widely used drugs such as insulin, Asians experienced insignificant disparities in odds of prescription compared to White patients but received highly inadequate treatments with regard to their distribution in U.S. diabetic population. Vaccination rates were associated with some demographic/socioeconomic factors but not the others at different degrees for different diseases. For instance, while equity scores increase with rising education levels for HBV, they decrease with rising wealth levels for HPV. Among women vaccinated against HPV, minorities and poor communities usually received Cervarix while non-Hispanic White and higher-income groups received the more comprehensive Gardasil vaccine. Our study identified and quantified the impact of determinants of healthcare utilization for antidiabetic medications and vaccinations. Our new methods for semantics-aware disparity analysis of NHANES data could be readily generalized to other public health goals to support more rapid identification of disparities and development of policies, thus advancing health equity.
The blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and blood-cerebrospinal fluid barrier (BCSFB) control cerebral/spinal cord homeostasis by selective transport of molecules and cells ...from the systemic compartment. In the spinal cord and brain of both ALS patients and animal models, infiltration of T-cell lymphocytes, monocyte-derived macrophages and dendritic cells, and IgG deposits have been observed that may have a critical role in motor neuron damage. Additionally, increased levels of albumin and IgG have been found in the cerebrospinal fluid in ALS patients. These findings suggest altered barrier permeability in ALS. Recently, we showed disruption of the BBB and BSCB in areas of motor neuron degeneration in the brain and spinal cord in G93A SOD1 mice modeling ALS at both early and late stages of disease using electron microscopy. Examination of capillary ultrastructure revealed endothelial cell degeneration, which, along with astrocyte alteration, compromised the BBB and BSCB. However, the effect of these alterations upon barrier function in ALS is still unclear. The aim of this study was to determine the functional competence of the BSCB in G93A mice at different stages of disease.
Evans Blue (EB) dye was intravenously injected into ALS mice at early or late stage disease. Vascular leakage and the condition of basement membranes, endothelial cells, and astrocytes were investigated in cervical and lumbar spinal cords using immunohistochemistry. Results showed EB leakage in spinal cord microvessels from all G93A mice, indicating dysfunction in endothelia and basement membranes and confirming our previous ultrastructural findings on BSCB disruption. Additionally, downregulation of Glut-1 and CD146 expressions in the endothelial cells of the BSCB were found which may relate to vascular leakage.
Results suggest that the BSCB is compromised in areas of motor neuron degeneration in ALS mice at both early and late stages of the disease.
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► APOBEC deaminases edit RNA and DNA. ► APOBEC regulation. ► APOBEC restrict foreign genetic elements.
APOBEC1 is a cytidine deaminase that edits messenger RNAs and was the first ...enzyme in the APOBEC family to be functionally characterized. Under appropriate conditions APOBEC1 also deaminates deoxycytidine in single-stranded DNA (ssDNA). The other ten members of the APOBEC family have not been fully characterized however several have deoxycytidine deaminase activity on ssDNAs. Despite the nucleic acid substrate preferences of different APOBEC proteins, a common feature appears to be their intrinsic ability to bind to RNA as well as to ssDNA. RNA binding to APOBEC proteins together with protein–protein interactions, post-translation modifications and subcellular localization serve as biological modulators controlling the DNA mutagenic activity of these potentially genotoxic proteins.
Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial ...premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully understood and include mutation or dysregulation of glycosyltransferases involved in elongation of O-glycans, as well as relocation of glycosyltransferases controlling initiation of O-glycosylation from Golgi to endoplasmic reticulum. Truncated O-glycans have been proposed to play functional roles for cancer-cell invasiveness, but our understanding of the biological functions of aberrant glycosylation in cancer is still highly limited. Here, we used exome sequencing of most glycosyltransferases in a large series of primary and metastatic pancreatic cancers to rule out somatic mutations as a cause of expression of truncated O-glycans. Instead, we found hypermethylation of core 1 β3-Gal-T-specific molecular chaperone, a key chaperone for O-glycan elongation, as the most prevalent cause. We next used gene editing to produce isogenic cell systems with and without homogenous truncated O-glycans that enabled, to our knowledge, the first polyomic and side-by-side evaluation of the cancer O-glycophenotype in an organotypic tissue model and in xenografts. The results strongly suggest that truncation of O-glycans directly induces oncogenic features of cell growth and invasion. The study provides support for targeting cancer-specific truncated O-glycans with immunotherapeutic measures.
Significance Cancer cells characteristically express proteins with immature O-glycosylation, but how and why cancer cells express immature O-glycans has remained poorly understood. Here, we report that one prevalent mechanism in pancreatic cancer is epigenetic silencing, rather than somatic mutations in a key chaperone, core 1 β3-Gal-T-specific molecular chaperone ( COSMC ), required for mature elongated O-glycosylation. We also demonstrate, with the use of well-defined cell systems generated by precise gene editing, that the aberrant O-glycophenotype by itself induces oncogenic features with enhanced growth and invasion. Our study suggests that the characteristic aberrant O-glycophenotype is critical for the development and behavior of cancer and further provides support for immunotherapeutic strategies that target aberrant O-glycans.
Mitochondria are responsible for the majority of energy production in energy-intensive tissues like brain, modulate Ca
signaling and control initiation of cell death. Because of their extensive use ...of oxygen and lack of protective histone proteins, mitochondria are vulnerable to oxidative stress (ROS)-induced damage to their genome (mtDNA), respiratory chain proteins and ROS repair enzymes. Animal and cell models of PD use toxins that impair mitochondrial complex I activity. Maintenance of mitochondrial mass, mitochondrial biogenesis (mitobiogenesis), particularly in high-energy brain, occurs through complex signaling pathways involving the upstream "master regulator" PGC-1alpha that is transcriptionally and post-translationally regulated. Alzheimer disease (AD) and Parkinson disease (PD) brains have reduced respiratory capacity and impaired mitobiogenesis, which could result in beta-amyloid plaques and neurofibrillary tangles. Aggregated proteins in genetic and familial AD and PD brains impair mitochondrial function, and mitochondrial dysfunction is involved in activated neuroinflammation. Mitochondrial ROS can activate signaling pathways that mediate cell death in neurodegenerative diseases. The available data support restoration of mitochondrial function to reduce disease progression and restore lost neuronal function in AD and PD.
ABSTRACT Recently, the discovery of a Venus-mass planet orbiting a brown-dwarf host in a binary system was reported from the analysis of the microlensing event OGLE-2013-BLG-0723. We reanalyze the ...event considering the possibility of other interpretations. From this, we find a new solution where the lens is composed of two bodies, in contrast to the three-body solution of the previous analysis. The new solution better explains the observed light curve than the previous solution with Δχ2 ∼ 202, suggesting that the new solution is a correct model for the event. From the estimation of the physical parameters based on the new interpretation, we find that the lens system is composed of two low-mass stars with ∼0.2 M and ∼0.1 M and located at a distance of ∼3 kpc. The fact that the physical parameters correspond to those of the most common lens population located at a distance with a large lensing probability further supports the likelihood of the new interpretation. Considering that two dramatically different solutions can approximately explain the observed light curve, the event suggests the need for carefully testing all possible lens-system geometries.
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