Glycoproteoform Profiles of Individual Patients’ Plasma Alpha-1-Antichymotrypsin are Unique and Extensively Remodeled Following a Septic Episode

Sepsis and septic shock remain the leading causes of death in intensive care units (ICUs), yet the pathogenesis originating from the inflammatory response during sepsis remains ambiguous. Acute-phase proteins are typically highly glycosylated, and the nature of the glycans have been linked to the incidence and severity of such inflammatory responses. To further build upon these findings we here monitored, the longitudinal changes in the plasma proteome and, in molecular detail, glycoproteoform profiles of alpha-1-antichymotrypsin (AACT) extracted from plasma of ten individual septic patients. For each patient we included four different time-points, including post-operative (before sepsis) and following discharge from the ICU. We isolated AACT from plasma depleted for albumin, IgG and serotransferrin and used high-resolution native mass spectrometry to qualitatively and quantitatively monitor the multifaceted glycan microheterogeneity of desialylated AACT, which allowed us to monitor how changes in the glycoproteoform profiles reflected the patient’s physiological state. Although we observed a general trend in the remodeling of the AACT glycoproteoform profiles, e.g. increased fucosylation and branching/LacNAc elongation, each patient exhibited unique features and responses, providing a resilient proof-of-concept for the importance of personalized longitudinal glycoproteoform profiling. Importantly, we observed that the AACT glycoproteoform changes induced by sepsis did not readily subside after discharge from ICU.

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Temporal gene expression profiling of liver from periparturient dairy cows reveals complex adaptive mechanisms in hepatic function

Physiological Genomics ◽

10.1152/physiolgenomics.00132.2005 ◽

2005 ◽

Vol 23 (2) ◽

pp. 217-226 ◽

Cited By ~ 154

Author(s):

Juan J. Loor ◽

Heather M. Dann ◽

Robin E. Everts ◽

Rosane Oliveira ◽

Cheryl A. Green ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acids ◽

Dairy Cows ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Physiological State ◽

Expression Patterns ◽

Hepatic Function ◽

Mrna Levels ◽

Nonesterified Fatty Acids

Long-term molecular adaptations in liver from high-producing dairy cows are virtually unknown. Liver from five Holstein cows was biopsied at −65, −30, −14, +1, +14, +28, and +49 days relative to parturition for transcript profiling using a microarray consisting of 7,872 annotated cattle cDNA inserts. More than 5,000 cDNA elements represented on the microarray were expressed in liver. From this set we identified 62 differentially expressed genes related to physiological state, with a false discovery rate threshold of P = 0.20. The dominant expression pattern consisted of upregulation from day −30 through day +1, followed by downregulation through day +28. There was a threefold decrease from day −65 through day +14 in expression of IGFBP3, GSTM5, and PDPK1. These genes mediate IGF-I transport, oxidative stress, and glucose homeostasis, respectively. IGFBP3, EIF4B, and GSTM5 mRNA levels were positively correlated with blood serum total protein. Correlation analysis showed positive associations between serum nonesterified fatty acids and mRNA expression for SAA1, CPT1A, ACADVL, and TFAP2A. Transcript levels of ACSL1, PPARA, and TFAP2A were positively correlated with serum β-hydroxybutyrate. Expression patterns for certain genes (e.g., IGFBP3, HNF4A, GPAM) revealed adaptations commencing well ahead of parturition, suggesting they are regulated by factors other than periparturient hormonal environment. Results provide evidence that hepatic inflammatory responses occurring near parturition initiate or augment adipose catabolism. In this context, cytokines, acute-phase proteins, and serum nonesterified fatty acids are key players in periparturient cow metabolism. We propose a model for integrating gene expression, metabolite, and liver composition data to explain physiological events in placenta, adipose, and liver during the periparturient period.

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Efferocytosis during myocardial infarction

The Journal of Biochemistry ◽

10.1093/jb/mvaa051 ◽

2020 ◽

Vol 168 (1) ◽

pp. 1-6

Author(s):

Chikashi Yoshimura ◽

Akiomi Nagasaka ◽

Hitoshi Kurose ◽

Michio Nakaya

Keyword(s):

Myocardial Infarction ◽

Cell Death ◽

Crucial Role ◽

Molecular Mechanisms ◽

Causes Of Death ◽

Inflammatory Responses ◽

Heart Cells ◽

Dead Cell ◽

Related Cell

Abstract Myocardial infarction is one of the major causes of death worldwide. Many heart cells die during myocardial infarction through various processes such as necrosis, apoptosis, necroptosis, autophagy-related cell death, pyroptosis and ferroptosis. These dead cells in infarcted hearts expose the so-called ‘eat-me’ signals, such as phosphatidylserine, on their surfaces, enhancing their removal by professional and non-professional phagocytes. Clearance of dead cells by phagocytes in the diseased hearts plays a crucial role in the pathology of myocardial infarction by inhibiting the inflammatory responses caused by the leakage of contents from dead cells. This review focuses on the rapidly growing understanding of the molecular mechanisms of dead cell phagocytosis, termed efferocytosis, during myocardial infarction, which contributes to the pathophysiology of myocardial infarction.

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Deficits in Identification of Goals and Goal-Concordant Care After Sepsis Hospitalization

Journal of Hospital Medicine ◽

10.12788/jhm.3714 ◽

2021 ◽

Vol October 2021 - Online First ◽

Author(s):

Stephanie Parks Taylor ◽

Marc A Kowalkowski ◽

Katherine R Courtright ◽

Henry L Burke ◽

Sangnya Patel ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Odds Ratio ◽

Causes Of Death ◽

Hospital Medicine ◽

Health Record ◽

Clinical Documentation ◽

Time Points ◽

Expert Review ◽

Sepsis Survivors

In a recent study, identifying and supporting patients’ care goals was named the highest priority in hospital medicine. Although sepsis is one of the leading causes of death and postdischarge morbidity among hospitalized patients, little is known about how frequently care goals are assessed prior to discharge and adhered to in the 90 days after sepsis hospitalization. Evaluating a cohort of 679 high-risk sepsis survivors enrolled in a clinical trial, we found that care goals were documented explicitly in a standardized tool in 130 patients; an additional 139 patients were identified using all available clinical documentation, resulting in only 269 (40%) patients with goals that could be ascertained from the electronic health record (EHR). Among those categorized, goals were classified as prioritizing longevity (35%), function (52%), and comfort (12%). Based on expert review of the care provided during the 90 days subsequent to discharge, goal-concordant care was identified in 184 (68%) cases for which goals were specified. Documentation of goals in a standardized EHR tool was associated with increased likelihood of receiving goal-concordant care (odds ratio, 3.6; 95% CI, 2.4-5.5). Hospitalization and peridischarge time points represent important opportunities to address deficits in the documentation of goals and provision of goal-concordant care for sepsis survivors.

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cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis

Science Advances ◽

10.1126/sciadv.aav5562 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaav5562 ◽

Cited By ~ 16

Author(s):

Ruochan Chen ◽

Ling Zeng ◽

Shan Zhu ◽

Jiao Liu ◽

Herbert J. Zeh ◽

...

Keyword(s):

Metabolic Pathways ◽

Inflammatory Responses ◽

Poly I:C ◽

Inflammasome Activation ◽

Proof Of Concept ◽

Potential Therapeutic Target ◽

Camp Metabolism ◽

Camp Hydrolysis ◽

Insight Into

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11–dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline–induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11–mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11−/−), or Gsdmd inactivation (GsdmdI105N/I105N) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

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Pemeriksaan Laboratorium sebagai Indikator Sepsis dan Syok Septik

JURNAL BIOMEDIK (JBM) ◽

10.35790/jbm.11.1.2019.23204 ◽

2019 ◽

Vol 11 (1) ◽

pp. 1

Author(s):

Diana S. Purwanto ◽

Dalima A.W. Astrawinata

Keyword(s):

Septic Shock ◽

Acute Phase ◽

Laboratory Tests ◽

Acute Phase Proteins ◽

Cell Surfaces ◽

Tissue Hypoperfusion ◽

Organ Systems ◽

Almost All ◽

Sepsis And Septic Shock ◽

Bacterial Products

Abstract: The complexity of the pathogenesis and pathophysiology of sepsis involves almost all types of cells, tissues, and organ systems. Therefore, there are numbers of laboratory tests that can be used as biomarkers of sepsis and septic shock. Some widely used biomarkers are divided into groups of bacterial products, acute phase proteins, tissue hypoperfusion, coagulation mediators, cell surfaces, and cytokines.Keywords: sepsis, septic shock, biomarkersAbstrak: Kompleksnya patogenesis dan patofisiologi sepsis melibatkan hampir semua jenis sel, jaringan, dan sistem organ. Oleh karena itu, terdapat banyak parameter laboratorik yang dapat dijadikan biomarker sepsis dan syok septik. Berbagai biomarker yang banyak digunakan terbagi dalam kelompokan produk bakteri, protein fase akut, hipoperfusi jaringan, mediator koagulasi, permukaan sel, dan sitokin.Kata kunci: sepsis, syok septik, biomarker

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Evaluation of Rat Acute Phase Proteins as Inflammatory Biomarkers for Vaccine Nonclinical Safety Studies

Toxicologic Pathology ◽

10.1177/0192623320957281 ◽

2020 ◽

Vol 48 (7) ◽

pp. 845-856

Author(s):

William J. Reagan ◽

Ahmed M. Shoieb ◽

Shelli J. Schomaker ◽

Victoria R. Markiewicz ◽

David W. Clarke ◽

...

Keyword(s):

Injection Site ◽

Acute Phase ◽

Time Course ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Aluminum Phosphate ◽

Positive Control ◽

Meso Scale Discovery ◽

Quillaja Saponaria ◽

Time Course Study

The objectives were to characterize the kinetics of acute phase proteins (APPs) α-2 macroglobulin (A2M), α-1 acid glycoprotein (A1AGP), and fibrinogen (FIB), and injection site macroscopic and microscopic findings following intramuscular administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (TDaP; Adacel); adjuvants (aluminum phosphate [AlPO4]; aluminum hydroxide, Al[OH]3; CpG/Al[OH]3; or Quillaja saponaria 21 [QS-21]); or saline to female Wistar Han rats. Intravascular lipopolysaccharide (LPS) was a positive control. Injection sites and lymph nodes were evaluated microscopically, using hematoxylin and eosin (H&E) stained sections, 48 hours postdose (HPD) and compared with APP concentrations; A2M and A1AGP were measured using Meso Scale Discovery analyzer. Fibrinogen was measured on STA Compact analyzer. In a time-course study, APP peaked at 24 or 48 HPD. In a subsequent study at 48 HPD, injection site microscopic changes included inflammation and muscle degeneration/necrosis, which was different in severity/nature between groups. The APPs were not increased in rats administered saline, Al(OH)3, or AlPO4. Fibrinogen and A1AGP increased in rats administered CpG/Al(OH)3, QS-21, or TDaP; and A2M increased in rats administered QS-21. Fibrinogen, A2M, and A1AGP increased after LPS administration. Acute phase proteins can be used to monitor inflammatory responses to adjuvants; however, some adjuvants may induce inflammation without higher APPs.

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Inflammation: a role for NR4A orphan nuclear receptors?

Biochemical Society Transactions ◽

10.1042/bst0390688 ◽

2011 ◽

Vol 39 (2) ◽

pp. 688-693 ◽

Cited By ~ 109

Author(s):

Jason P. McMorrow ◽

Evelyn P. Murphy

Keyword(s):

Inflammatory Response ◽

Nuclear Receptors ◽

Acute Phase ◽

Immune Cells ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Tissue Injury ◽

Chronic Phase ◽

Psoriatic Skin ◽

Orphan Nuclear Receptors

Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors may contribute to the cellular processes that control inflammation, playing a critical part in the contribution of chronic inflammation or they may have a protective role, where they may mediate pro-resolution responses. Here, we will review the contribution of the NR4A orphan NRs to integration of cytokine signalling in inflammatory disorders.

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Biofilm-coated microbeads and the mouse ear skin: An innovative model for analysing anti-biofilm immune response in vivo

PLoS ONE ◽

10.1371/journal.pone.0243500 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243500

Author(s):

Léo Sauvat ◽

Aizat Iman Abdul Hamid ◽

Christelle Blavignac ◽

Jérôme Josse ◽

Olivier Lesens ◽

...

Keyword(s):

Real Time ◽

Medical Devices ◽

Immune Cells ◽

Inflammatory Responses ◽

Late Time ◽

Average Cell ◽

Time Points ◽

Mouse Ear

Owing to its ability to form biofilms, Staphylococcus aureus is responsible for an increasing number of infections on implantable medical devices. The aim of this study was to develop a mouse model using microbeads coated with S. aureus biofilm to simulate such infections and to analyse the dynamics of anti-biofilm inflammatory responses by intravital imaging. Scanning electron microscopy and flow cytometry were used in vitro to study the ability of an mCherry fluorescent strain of S. aureus to coat silica microbeads. Biofilm-coated microbeads were then inoculated intradermally into the ear tissue of LysM-EGFP transgenic mice (EGFP fluorescent immune cells). General and specific real-time inflammatory responses were studied in ear tissue by confocal microscopy at early (4-6h) and late time points (after 24h) after injection. The displacement properties of immune cells were analysed. The responses were compared with those obtained in control mice injected with only microbeads. In vitro, our protocol was capable of generating reproducible inocula of biofilm-coated microbeads verified by labelling matrix components, observing biofilm ultrastructure and confirmed in vivo and in situ with a matrix specific fluorescent probe. In vivo, a major inflammatory response was observed in the mouse ear pinna at both time points. Real-time observations of cell recruitment at injection sites showed that immune cells had difficulty in accessing biofilm bacteria and highlighted areas of direct interaction. The average speed of cells was lower in infected mice compared to control mice and in tissue areas where direct contact between immune cells and bacteria was observed, the average cell velocity and linearity were decreased in comparison to cells in areas where no bacteria were visible. This model provides an innovative way to analyse specific immune responses against biofilm infections on medical devices. It paves the way for live evaluation of the effectiveness of immunomodulatory therapies combined with antibiotics.

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Medical Audit of the Management of Patients with Sepsis in the Intermediate Care Unit of Department Internal Medicine School of Medicine Airlangga University/Dr. Soetomo Hospital

Indonesian Journal of Tropical and Infectious Disease ◽

10.20473/ijtid.v1i1.686 ◽

2016 ◽

Vol 1 (1) ◽

pp. 1

Author(s):

Usman Hadi ◽

Erwin Astha Triyono

Keyword(s):

Internal Medicine ◽

Causes Of Death ◽

Age Groups ◽

Intermediate Care ◽

Patient Medical Record ◽

School Of Medicine ◽

Intermediate Care Unit ◽

Number Of Patients ◽

Sepsis And Septic Shock

Sepsis and septic shock is one of the highest causes of death in patients treated in hospitals. Research Objectives: to evaluate the quality of the management of sepsis patients in Intermediate Care Unit, Department of Internal Medicine Dr. Soetomo Hospital Surabaya, Indonesia. This study was a retrospective study to re-evaluate the patient medical record. The number of patients treated: 275 patients, sepsis patients: 80 patients, the number of patients who entered the study 50 patients, 30 (60%) female and 20 (40%) men, most age groups aged 60 -70 years (32%), Mean 54 Median 56. Diagnostic accuracy according to the criteria of sepsis 45 (90%) patients, compliance with taking blood culture 2 (4%) patients, appropriate antibiotic selection 49 (98%) patients, the number of patients who should not be given antibiotics (4 patients), but given the antibiotic is 3 (75%) patients, the number of patients who should be given antibiotics (46 patients) but were not given antibiotics 1 (2%) patient. The reason of patients discharged: 27 had died (54%), 13 cured (26%), not yet recovered 10 (20%). The reason of patients discharged forcibly: to feel recovered 2 (20%), the condition gets worse 3 (30%), no cost 2 (20%), not clear 3 (30%). Patients with sepsis remain a big problem, and it still needs to improve the management of sepsis on existing guidelines.

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Development of a Pressure Measuring Garment to Understand How to Quantify Compression

2020 Design of Medical Devices Conference ◽

10.1115/dmd2020-9024 ◽

2020 ◽

Author(s):

Michael Weber ◽

Abigail Clarke-Sather ◽

Tara Bergeron ◽

Anisa Janko ◽

Alicia Jensen ◽

...

Keyword(s):

General Trend ◽

Autism Spectrum ◽

The Body ◽

Proof Of Concept ◽

Compression Garment ◽

Specific Location ◽

Arm Circumference ◽

Outcomes For Children ◽

The Relationship ◽

Measured Pressure

Abstract Encouraging research shows reductions in the number of disruptive behaviors for children diagnosed with Autism Spectrum Disorder (ASD) when wearing compression shirts. However, current studies do not consider the amount of pressure compression shirts apply to the body and how different amounts of pressure applied to the body may lead to different outcomes for children diagnosed with ASD. The purpose of this proof of concept research project was to develop a method for measuring the pressure applied by a compression shirt at a specific location on the body. This study used conductive thread as the principle element to measure the compression applied by a garment onto the body, specifically the arm. It was found that for the specific stitch and thread tested, the relationship between the displacement the sensor exhibits and the change in resistance was 25.95 Ω/m. With this relation, the pressure applied by a compression garment to a mannequin arm and the arms of four participants was found. A general trend that the measured pressure applied by a garment onto the body directly correlated with increasing individual arm circumference was found.

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