Systematic evaluation of plasma signaling cascades by functional proteomics approaches: SARS-CoV-2 infection as model.

PURPOSE: Acute phase reactants (APRs) play a critical role in inflammation. The difference in their physiological functions or the different dynamic ranges of these proteins in plasma makes it difficult to detect them simultaneously and to use several of these proteins as a tool in clinical practice. EXPERIMENTAL DESIGN: A novel multiplex assay has been designed and optimized to carry out a high-throughput and simultaneous screening of APRs, allowing the detection of each of them at the same time and in their corresponding dynamic range. RESULTS: Using Sars-CoV-2 infection as a model, it has been possible to profile different patterns of acute phase proteins that vary significantly between healthy and infected patients. In addition, severity profiles (acute respiratory distress syndrome and sepsis) have been established. CONCLUSIONS AND CLINICAL RELEVANCE: Differential profiles in acute phase proteins can serve as a diagnostic and prognostic tool, among patient stratification. The design of this new platform for their simultaneous detection paves the way for them to be more extensive use in clinical practice.

The Neuroinflammatory Acute Phase Response in Parkinsonian-Related Disorders.

BACKGROUND: Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings. OBJECTIVES: The aim was to measure a panel of neuroinflammatory acute phase response (APR) proteins in the cerebrospinal fluid (CSF) of participants with PD and related disorders. METHODS: Eleven APR proteins were measured in the CSF of 867 participants from the BioFINDER cohort who were healthy (612) or had a diagnosis of PD (155), multiple system atrophy (MSA) (26), progressive supranuclear palsy (PSP) (22), dementia with Lewy bodies (DLB) (23), or Parkinson's disease with dementia (PDD) (29). RESULTS: CSF APR proteins were mostly unchanged in PD, with only haptoglobin and α1-antitrypsin significantly elevated compared to controls. These proteins were variably increased in the other disorders. Certain protein components yielded unique signatures according to diagnosis: ferritin and transthyretin were selectively elevated in MSA and discriminated these patients from all others. Haptoglobin was selectively increased in PSP, discriminating this disease from MSA when used in combination with ferritin and transthyretin. This panel of proteins did not correlate well with severity of motor impairment in any disease category, but several (particularly ceruloplasmin and ferritin) were associated with memory performance (Mini-Mental State Examination) in patients with DLB and PDD. CONCLUSIONS: These findings provide new insights into inflammatory changes in PD and related disorders while also introducing biomarkers of potential clinical diagnostic utility. © 2022 International Parkinson and Movement Disorder Society.

Acute-phase protein concentration in bronchoalveolar lavage fluid from healthy horses / Proteínas de fase aguda do lavado broncoalveolar de equinos hígidos

Bronchoalveolar lavage fluid (BALF) was analyzed to obtain information on leakage of acute-phase proteins from the blood into the respiratory lumen and about local synthesis. Ceruloplasmin, transferrin, albumin, α1-antitripsin, immunoglobulin G heavy, immunoglobulin G light, immunoglobulin A, haptoglobin, acidic glycoprotein, and P23 were measured in BALF from 30 horses without inflammatory disease by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). In serum, the same proteins were identified except for α1-antitrypsin. In conclusion, this study demonstrated that polyacrylamide gel electrophoresis (SDS-PAGE) can be used for the determination of acute-phase proteins in BALF samples from horses. In healthy horses, the values are very low, but they can be compared with reference values to assist in the diagnosis of animals with respiratory diseases.(AU)

O líquido obtido através da lavagem broncoalveolar (LBA) foi analisado para obter informações sobre as proteínas da fase aguda. Ceruloplasmina, transferrina, albumina, α1-antitripsina, imunoglobulina G pesada, imunoglobulina G leve, imunoglobulina A, haptoglobina, glicoproteína ácida e P23 foram medidas nos LBA de 30 cavalos sem doença inflamatória por eletroforese em gel de poliacrilamida com dodecilsulfato de sódio (SDS-PAGE). No soro, as mesmas proteínas foram identificadas, exceto a α1-antitripsina. Em conclusão, este estudo demonstra que a eletroforese em gel de poliacrilamida (SDS-PAGE) pode ser usada para a determinação de proteínas de fase aguda em amostras de LBA em cavalos. Em cavalos saudáveis, os valores são muito baixos, no entanto, podem ser comparados e auxiliar no diagnóstico de animais com doenças respiratórias.(AU)

Osteoporosis in the age of COVID-19.

As the world grapples with the crisis of COVID-19, established economies and healthcare systems have been brought to their knees. Tough decisions regarding redirection of resources away from the management of conditions deemed "nonessential" are being made. How can we balance urgent resourcing of our acute crisis while not abandoning the real need of patients with osteoporosis? This article offers a few practical solutions.

Multi-view radiomics and dosiomics analysis with machine learning for predicting acute-phase weight loss in lung cancer patients treated with radiotherapy.

We propose a multi-view data analysis approach using radiomics and dosiomics (R&D) texture features for predicting acute-phase weight loss (WL) in lung cancer radiotherapy. Baseline weight of 388 patients who underwent intensity modulated radiation therapy (IMRT) was measured between one month prior to and one week after the start of IMRT. Weight change between one week and two months after the commencement of IMRT was analyzed, and dichotomized at 5% WL. Each patient had a planning CT and contours of gross tumor volume (GTV) and esophagus (ESO). A total of 355 features including clinical parameter (CP), GTV and ESO (GTV&ESO) dose-volume histogram (DVH), GTV radiomics, and GTV&ESO dosiomics features were extracted. R&D features were categorized as first- (L1), second- (L2), higher-order (L3) statistics, and three combined groups, L1 + L2, L2 + L3 and L1 + L2 + L3. Multi-view texture analysis was performed to identify optimal R&D input features. In the training set (194 earlier patients), feature selection was performed using Boruta algorithm followed by collinearity removal based on variance inflation factor. Machine-learning models were developed using Laplacian kernel support vector machine (lpSVM), deep neural network (DNN) and their averaged ensemble classifiers. Prediction performance was tested on an independent test set (194 more recent patients), and compared among seven different input conditions: CP-only, DVH-only, R&D-only, DVH + CP, R&D + CP, R&D + DVH and R&D + DVH + CP. Combined GTV L1 + L2 + L3 radiomics and GTV&ESO L3 dosiomics were identified as optimal input features, which achieved the best performance with an ensemble classifier (AUC = 0.710), having statistically significantly higher predictability compared with DVH and/or CP features (p < 0.05). When this performance was compared to that with full R&D-only features which reflect traditional single-view data, there was a statistically significant difference (p < 0.05). Using optimized multi-view R&D input features is beneficial for predicting early WL in lung cancer radiotherapy, leading to improved performance compared to using conventional DVH and/or CP features.

An analysis of plasma reveals proteins in the acute phase response pathway to be candidate diagnostic biomarkers for depression.

Globally, depression is one of the most serious debilitating psychiatric mental disorders. In this study, we validated the expression levels of fibrinogen alpha (FGA), fibrinogen beta (FGB), fibrinogen gamma (FGG), Complement factor B (CFB) and serpin family D member 1(SERPIND1) in the acute phase response signaling pathway in plasma samples using enzyme-linked immunosorbent assay (ELISA).Then illuminate the roles of FGA, FGB, FGG, CFB, SERPIND1 in depression using microarray data. Gene expression dataset GSE98793 was downloaded from the Gene Expression Omnibus database. There were 128 whole blood samples included 64 patients with major depressed patients and 64 healthy controls. Differentially expressed genes (DEGs) were identified, and then protein-protein interaction (PPI) network was constructed to screen crucial genes associated with FGA, FGB, FGG, CFB and SERPIND1. Moreover, gene ontology (GO) biological processes analyses was performed. The ELISA data showed that the expression levels of FGA, FGB, FGG, CFB and SERPIND1 were up-regulated in depressed patients. The enriched GO terms were predominantly associated with the biological processes including more genes were inflammation related. The PPI network was found these five genes interacted with 11 genes. FGA, FGB, FGG, CFB and SERPIND1 may be important in the pathogenesis of depression.

[Lower limb venous thrombosis : Management in the acute phase]. / La thrombose veineuse profonde des membres inférieurs : Prise en charge en aigu.

Venous thromboembolism is the third cardiovascular disease in Europe. The cornerstone of the treatment of deep vein thrombosis is anticoagulation. It aims at avoiding harmful complications : thrombosis extension and recurrence, pulmonary embolism and post-thrombotic syndrome. Due to low molecular weight heparins, and recently, to direct oral anticoagulants, most of the patients can get treatment as outpatients. Unfortunately, despite guideline publications, the management of these patients may be complicated in real life and not correspond to evidence-based medicine. This paper aims at helping the practitian when dealing with this potentially dangerous and often misleading disease. The management of the patient after a 3 to 6-month coagulation treatment will be discussed later in a dedicated paper.

La maladie thrombo-embolique veineuse est la troisième maladie cardio-vasculaire en Europe. Le traitement de la thrombose veineuse repose essentiellement sur l'anticoagulation qui vise à prévenir de redoutables complications : extension et récidive de la thrombose, embolie pulmonaire et syndrome post-thrombotique. Grâce aux héparines de bas poids moléculaire et, plus récemment, aux anticoagulants oraux directs, la majorité des patients peut être traitée en ambulatoire. Pourtant, malgré les recommandations qui ont été publiées, force est de constater que celles-ci ne sont pas toujours respectées dans la «vraie vie¼. Le but de cet article est d'aider le praticien dans la prise en charge initiale d'une pathologie potentiellement dangereuse et parfois difficile à cerner. La prise en charge du patient après 3 à 6 mois de traitement sera discutée dans un article ultérieur.

Hypoalbuminemia and Clinical Outcomes: What is the Mechanism behind the Relationship?

Albumin has a number of important physiologic functions, which include maintaining oncotic pressure, transporting various agents (fatty acids, bile acids, cholesterol, metal ions, and drugs), scavenging free oxygen radicals, acting as an antioxidant, and exerting an antiplatelet effect. Hypoalbuminemia in adults, defined by an intravascular albumin level of <3.5 g/dL, is associated with poor postoperative outcomes in patients undergoing surgical intervention. Although the relationship of hypoalbuminemia and poor surgical outcome has been known for many years, the pathophysiology behind the relationship is unclear. Three theoretical constructs might explain this relationship. First, albumin might serve as a nutritional marker, such that hypoalbuminemia represents poor nutritional status in patients who go on to experience poor postoperative outcomes. Second, albumin has its own pharmacologic characteristics as an antioxidant or transporter, and therefore, the lack of albumin might result in a deficiency of those functions, resulting in poor postoperative outcomes. Or third, albumin is known to be a negative acute phase protein, and as such hypoalbuminemia might represent an increased inflammatory status of the patient, potentially leading to poor outcomes. A thorough review of the literature reveals the fallacy of these arguments and fails to show a direct cause and effect between low albumin levels per se and adverse outcomes. Interventions designed solely to correct preoperative hypoalbuminemia, in particular intravenous albumin infusion, do little to change the patient's course of hospitalization. While surgeons may use albumin levels on admission for their prognostic value, they should avoid therapeutic strategies whose main endpoint is correction of this abnormality.

[Transient detection of lupus anticoagulant in acute phase of Kawasaki disease].

  In Kawasaki disease (KD), endothelial damage and an elevation in coagulant factors provoke thrombosis. Lupus anticoagulant (LA) is strongly associated with the risk of thrombosis in patients with antiphospholipid syndrome; however, there has been no report of positive LA in KD patients. A previously healthy, 2-year-old boy was admitted due to fever, bilateral conjunctivitis, redness of the lips, and unilateral cervical lymphadenopathy. Typical Kawasaki disease was diagnosed on day 5 of illness. Adenovirus antigens were detected in his stool. After the KD symptoms were successfully treated with intravenous immunoglobulin, his activated partial thromboplastin time (APTT) increased to 88 seconds at eight days of illness. The cross-mixing test showed an inhibition pattern, and the presence of LA was proved using diluted Russell's viper venom time. APPT elongation improved due to continued low dose aspirin therapy without thromboembolisms. The possibility of contamination by LA was low because six other patients treated with the same immunoglobulin lot showed no APTT elongation. We speculated that KD-related infections led to the presence of LA, which may have triggered the thrombosis. Further accumulation of data is warranted to elucidate the role of LA in KD patients.

Characterizing the Acute Phase Response in Healthy Patients Following Total Joint Arthroplasty: Predictable and Consistent.

BACKGROUND: During surgery, trauma to musculoskeletal tissue induces a systemic reaction known as the acute phase response (APR). When excessive or prolonged, the APR has been implicated as an underlying cause of surgical complications. The purpose of this study was to determine the typical APR following total joint arthroplasty in a healthy population defined by the Charlson Comorbidity Index (CCI). METHODS: This retrospective study identified 180 healthy patients (CCI < 2) who underwent total joint arthroplasty by a single surgeon for primary osteoarthritis from 2013 to 2015. Serial measurements of C-reactive protein (CRP) and fibrinogen were obtained preoperative, perioperative, and at 2 and 6 weeks postoperative. RESULTS: Postoperative CRP peaked during the inpatient period and returned to baseline by 2 weeks. Fibrinogen peaked after CRP and returned to baseline by 6 weeks. Elevated preoperative CRP correlated with a more robust postoperative APR for both total hip arthroplasty and total knee arthroplasty, suggesting that a patient's preoperative inflammatory state correlates with the magnitude of the postoperative APR. CONCLUSION: Measurement of preoperative acute phase reactants may provide an objective means to predict a patient's risk of postoperative dysregulation of the APR and complications.

Comparison of the acute-phase response after laparoscopic versus open aortobifemoral bypass surgery: a substudy of a randomized controlled trial.

PURPOSE: Minimally invasive surgical techniques have been shown to reduce the inflammatory response related to a surgical procedure. The main objective of our study was to measure the inflammatory response in patients undergoing a totally laparoscopic versus open aortobifemoral bypass surgery. This is the first randomized trial on subjects in this population. PATIENTS AND METHODS: This is a substudy of a larger randomized controlled multicenter trial (Norwegian Laparoscopic Aortic Surgery Trial). Thirty consecutive patients with severe aortoiliac occlusive disease eligible for aortobifemoral bypass surgery were randomized to either a totally laparoscopic (n=14) or an open surgical procedure (n=16). The inflammatory response was measured by perioperative monitoring of serum interleukin-6 (IL-6), IL-8, and C-reactive protein (CRP) at six different time points. RESULTS: The inflammatory reaction caused by the laparoscopic procedure was reduced compared with open surgery. IL-6 was significantly lower after the laparoscopic procedure, measured by comparing area under the curve (AUC), and after adjusting for the confounding effect of coronary heart disease (P=0.010). The differences in serum levels of IL-8 and CRP did not reach statistical significance. CONCLUSION: In this substudy of a randomized controlled trial comparing laparoscopic and open aortobifemoral bypass surgeries, we found a decreased perioperative inflammatory response after the laparoscopic procedure measured by comparing AUC for serum IL-6.

Early post-operative acute phase response in patients with early graft dysfunction is predictive of 6-month and 12-month mortality in liver transplant recipients.

UNLABELLED: Early allograft dysfunction (EAD) after liver transplantation is mostly a reversible event caused by factors related to ischemia/reperfusion (I/R) injury. EAD represents a hepatic injury associated with pre- and early post-transplant inflammatory cytokine responses. Aim of the present study was to evaluate the prognostic and diagnostic value of CRP in liver transplant recipients with EAD. MATERIALS AND METHODS: Forty-seven patients with EAD were compared with 115 non-EAD patients. Pre- and post-transplant parameters were analyzed. EAD was defined based on postoperative liver function tests such as INR, bilirubin and liver enzymes. Statistical analysis was performed using SPSS version 18.0. RESULTS: Pre-transplant liver enzyme were not significantly different in the two groups. At day 3, 5 and 10 post-transplant CRP was significantly higher in patients with EAD than in non-EAD patients (p⩽0.001 for all investigations) and remained consistently high in patients with EAD and low in non-EAD patients. EAD patients with high CRP at post-transplant days 3 and 5 showed lower survival at 6-month and 12-month post-transplant than patients with low CRP. CONCLUSION: Our results indicate a prognostic and diagnostic value of CRP in patients with early graft dysfunction and predict 6-month and 12-month mortality in liver transplant recipients.

C-reactive protein and the acute phase reaction in geriatric patients.

The C-reactive protein (CRP), first described as a serum component capable of precipitating the C-polysaccharide of pneumococci, is one of the most important proteins because the serum concentration rises in the acute phase reaction. The acute phase reaction is the nonspecific reaction of the body to noxious stimuli of the most varied kinds, such as infections, burns, neoplasms and tissue trauma. The CRP is synthesized in liver parenchymal cells by cytokines which are derived from stimulated leucocytes and released into the circulation. Because of its molecular structure and in synergy with the complement system, it is able to precipitate and/or lyse microorganisms, thereby rendering them harmless. Measurement of the serum CRP concentration can provide important information with respect to the diagnosis and monitoring of treatment. Due to immunosenescence in geriatric patients the synthesis of CRP appears to be limited to inflammatory stimuli; however, this phenomenon does not appear to be of major clinical relevance. Despite the introduction of new parameters of the acute phase reaction, sometimes with better performance, such as interleukin-6, procalcitonin and the soluble endotoxin receptor sCD14, measurement of CRP for diagnosis and treatment monitoring is still justified even in geriatric patients as testing is rapid, economic and nearly ubiquitously available round the clock. Biochemical markers of the acute phase reaction should always be interpreted together with the clinical picture and their specific limitations.

[How to assess and manage the acute phase of an asthma episode in children]. / Comment je traite ... un asthme bronchique inaugural ou déstabilisé de manière aiguë chez l'enfant.

Asthma is the most common chronic respiratory disease in childhood. An acute crisis can occur during an episode of exacerbation or may be the onset of the disease in a non-asthmatic child. Acute asthma is most often manifested by signs of respiratory distress that will lead the child to the doctor. Regardless of the context, the crisis has to be quickly and efficiently handled. The assessment of the crisis severity, immediate care, treatment and monitoring will be discussed in this article.

Postsurgical Acute Phase Reaction is Associated with Decreased Levels of Circulating Myostatin.

Muscle strength is of importance for postsurgical rehabilitation. Myostatin is a growth factor that regulates the size of muscles and could thus influence muscle mass and function in the postsurgical period. The aim of the present study was to study the changes in myostatin levels during the postsurgical inflammatory period. Myostatin was analysed in serum samples from two elective surgery groups, orthopaedic surgery (n = 24) and coronary bypass patients (n = 21). The samples were collected prior to surgery and 4 and 30 days after surgery. In the orthopaedic group, the median myostatin levels decreased from 3582 ng/L prior to surgery to 774 ng/L at day 4 (p < 0.001) and to 2016 ng/L at day 30 (p < 0.001). Median CRP increased from 2.35 mg/L preoperatively to 117 mg/L at day 4 and decreased to 5.5 mg/L at day 30 in the same group. The coronary bypass group showed a similar pattern with a decrease in myostatin from 4212 ng/L to 2574 ng/L at day 4 (p < 0.001) and to 2808 ng/L at day 30 (p = 0.002). Median CRP increased from 1.80 mg/L preoperatively to 136 mg/L at day 4 and returned to 6.12 mg/L at day 30 in the coronary bypass group. There was a significant decrease in myostatin concentrations both in the early and late postsurgical period. The lowest myostatin concentration time point coincided with the highest CRP concentration time point.

Evaluation of hepatocyte growth factor as a local acute phase response marker in the bowel: the clinical impact of a rapid diagnostic test for immediate identification of acute bowel inflammation.

BACKGROUND: There are no rapid tests that can distinguish contagious gastroenteritis, which requires isolation at its onset, from exacerbation of chronic inflammatory bowel disease (IBD) or bowel engagement in the course of systemic inflammatory response syndrome (SIRS). Hepatocyte growth factor (HGF) is an acute phase cytokine that is produced at the site of injury. It has high affinity to sulfated glycan, and this binding affinity is lost during chronic inflammation. The fecal pH strongly impacts the prognosis for severe bowel disease. We developed a strip test to evaluate HGF as a local acute phase response marker in the bowel. This test assessed the binding affinity of HGF to sulfated glycans in fecal samples and determined fecal pH as an indicator of illness severity. METHODS: Fresh feces from patients with diarrhea (n=513) were collected and tested blindly, and information about patient illness course and outcome was collected. Patients were classified based on the focus of inflammation and the cause of the symptoms. Objectively verified diagnoses of infectious gastroenteritis (n=131) and IBD onset/exacerbation and bowel cancer (n=44) were used to estimate the performance of the test strip. ELISA was performed on 101 freeze-thawed feces samples to determine the fecal HGF levels. RESULTS: The test rapidly distinguished infectious gastroenteritis from non-infectious inflammatory causes of diarrhea (sensitivity, 87.96%; specificity, 90.9%; positive predictive value, 96.6%; negative predictive value, 71.4%; accuracy, 89.1%). Fecal pH (p<0.0001) and mortality within 28days of sampling (p<0.04) was higher in patients with sepsis/SIRS and diarrhea. The concentration of HGF was higher in strip test-positive stool samples (p<0.01). CONCLUSIONS: HGF is a good local acute phase response marker of acute bowel inflammation. Test-strip determination of the binding affinity of fecal HGF to sulfated glycan was a rapid, equipment-free way to assess patients with diarrhea and to guide the diagnostic and therapeutic approaches on admission.

Development and comparative evaluation of SYBR Green I-based one-step real-time RT-PCR assay for detection and quantification of West Nile virus in human patients.

The recent outbreaks of West Nile Virus (WNV) in the Northeastern American continents and other regions of the world have made it essential to develop an efficient protocol for surveillance of WN virus. Nucleic acid based techniques like, RT-PCR have the advantage of sensitivity, specificity and rapidity. A one step single tube Env gene specific real-time RT-PCR was developed for early and reliable clinical diagnosis of WNV infection in clinical samples. The applicability of this assay for clinical diagnosis was validated with 105 suspected acute-phase serum and plasma samples from the recent epidemic of mysterious fever in Tamil Nadu, India in 2009-10. The comparative evaluation revealed the higher sensitivity of real-time RT-PCR assay by picking up 4 additional samples with low copy number of template in comparison to conventional RT-PCR. All the real-time positive samples further confirmed by CDC reported TaqMan real-time RT-PCR and quantitative real-time RT-PCR assays for the simultaneous detection of WNV lineage 1 and 2 strains. The quantitation of the viral load samples was done using a standard curve. These findings demonstrated that the assay has the potential usefulness for clinical diagnosis due to detection and quantification of WNV in acute-phase patient serum samples.