A preoptic neuronal population controls fever and appetite during sickness.

During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue1,2. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPOLPS) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPOLPS neurons. Finally, we show that VMPOLPS neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPOLPS neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.

Specific patterns of vital sign fluctuations predict infection and enable sepsis diagnosis in pediatric burn patients.

Early recognition of the clinical signs of bloodstream infection in pediatric burn patients is key to improving survival rates in the burn unit. The objective of this study was to propose a simple scoring criteria that used readily available temperature, heart rate (HR) and mean arterial pressure (MAP) data to accurately predict bloodstream infection in pediatric burn patients. A retrospective chart review included 100 patients admitted to the pediatric burn unit for >20% total body surface area (TBSA) burn injuries. Each patient had multiple blood culture tests, and each test was treated as a separate and independent "infection event" for analysis. The time at each blood culture draw was time 0 for that event, and temperature, HR and MAP data was collected for 24 hours after the blood culture was drawn. "Infection events" included in this study had at least six complete sets of temperature, HR and MAP data entries. Median temperature, HR and MAP, as well as mean fever spikes, HR spikes and MAP dips, were compared between infection group (positive blood cultures) and control group (negative blood cultures). These vital sign fluctuations were evaluated individually and as a combination of all three as timely predictors of bloodstream infection. In addition, we tested the prediction of Gram-negative bacteria versus Gram-positive or fungi present in blood cultures. Patients in the infection group had significantly higher median temperatures (p<0.001), mean fever spikes (p<0.001) and mean HR spikes (p<0.001), compared to the control group. Using the combination scoring criteria to predict bloodstream infection, the strongest predictive values in the 24-hour timeframe had high sensitivity (93%) and specificity (81%). The predictive test metric based on vital sign spikes predicted Gram-negative bacteria, but with limited sensitivity (57%) and specificity (44%). A simple scoring criteria using a combination of fever spikes, HR spikes and MAP dips predicted bloodstream infection in pediatric burn patients, and can be feasibly implemented in routine clinical care. There is also potential to use the predictive metric to detect a few select organisms based on vital signs, however further work is necessary to enhance accuracy to levels that would allow consideration for clinical use.

Changes of Migration, Immunoregulation and Osteogenic Differentiation of Mesenchymal Stem Cells in Different Stages of Inflammation.

Bone infection has always been the focus of orthopedic research. Mesenchymal stem cells (MSCs) are the natural progenitors of osteoblasts, and the process of osteogenesis is triggered in response to different signals from the extracellular matrix. MSCs exert important functions including secretion and immune regulation and also play a key role in bone regeneration. The biological behavior of MSCs in acute and chronic inflammation, especially the transformation between acute inflammation and chronic inflammation, has aroused great interest among researchers. This paper reviews the recent literature and summarizes the behavior and biological characteristics of MSCs in acute and chronic inflammation to stimulate further research on MSCs and treatment of bone diseases.

Insights into the role of paraoxonase 2 in human pathophysiology.

Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular enzyme that is known to have a protective role from oxidative stress. Clinical studies have also demonstrated the significance of PON2 in the manifestation of cardiovascular and several other diseases, and hence, it is considered an important biomarker. Recent findings of its expression in brain tissue suggest its potential protective effect on oxidative stress and neuroinflammation. Polymorphisms of PON2 in humans are a risk factor in many pathological conditions, suggesting a possible mechanism of its anti-oxidative property probably through lactonase activity. However, exogenous factors may also modulate the expression and activity of PON2. Hence, this review aims to report the mechanism by which PON2 expression is regulated and its role in oxidative stress disorders such as neurodegeneration and tumor formation. The role of PON2 owing to its lactonase activity in bacterial infectious diseases and association of PON2 polymorphism with pathological conditions are also highlighted.

Glomerular filtration rate in children and young adults with haemato-oncological disease and infection is best described by three-compartment iohexol model.

BACKGROUND: Children with cancer and infection may develop glomerular hyperfiltration. With the aim to determine the prevalence of glomerular hyperfiltration in children and young adults with haemato-oncological disease and infection, we developed population pharmacokinetic model of iohexol. We further aimed to assess the accuracy of estimated glomerular filtration rate (eGFR) equations and single- or two-point measured GFR (mGFR) formulas compared with GFR based on iohexol clearance from our population pharmacokinetic model (iGFR). PROCEDURE: Hospitalised patients (0.5-25 years) with haemato-oncological disease and infection were included if their eGFR was ≥80 ml/min/1.73 m2 at the screening visit. Iohexol plasma concentrations were described by population pharmacokinetic model. Bias, precision and accuracy of 23 eGFR equations and 18 mGFR formulas were calculated. RESULTS: Total of 32 iohexol administrations were performed in 28 patients. Median (range) eGFR was 136 ml/min/1.73 m2 (74-234) and age 15.1 years (0.8-26.0). Three-compartment model with allometric scaling of central, one peripheral compartment and clearance (with power 0.75) to weight fitted the best. Median (range) iGFR was 103 ml/min/1.73 m2 (68-140). All except one eGFR equation overestimated GFR. Lund-Malmö revised eGFR equation performed the best, followed by Gao equation. Of single- or two-point mGFR formulas, 15 overestimated iGFR. Modified Jacobsson formula at 5.5 hours performed the best, followed by Fleming formula at 3 hours. CONCLUSIONS: In children and young adults with haemato-oncological disease and infection, renal function is best described by iohexol clearance from three-compartment pharmacokinetic model, while eGFR equations and single- and two-point mGFR formulas overestimate iGFR.

Toxoplasma bradyzoites exhibit physiological plasticity of calcium and energy stores controlling motility and egress.

Toxoplasma gondii has evolved different developmental stages for disseminating during acute infection (i.e., tachyzoites) and establishing chronic infection (i.e., bradyzoites). Calcium ion (Ca2+) signaling tightly regulates the lytic cycle of tachyzoites by controlling microneme secretion and motility to drive egress and cell invasion. However, the roles of Ca2+ signaling pathways in bradyzoites remain largely unexplored. Here, we show that Ca2+ responses are highly restricted in bradyzoites and that they fail to egress in response to agonists. Development of dual-reporter parasites revealed dampened Ca2+ responses and minimal microneme secretion by bradyzoites induced in vitro or harvested from infected mice and tested ex vivo. Ratiometric Ca2+ imaging demonstrated lower Ca2+ basal levels, reduced magnitude, and slower Ca2+ kinetics in bradyzoites compared with tachyzoites stimulated with agonists. Diminished responses in bradyzoites were associated with downregulation of Ca2+-ATPases involved in intracellular Ca2+ storage in the endoplasmic reticulum (ER) and acidocalcisomes. Once liberated from cysts by trypsin digestion, bradyzoites incubated in glucose plus Ca2+ rapidly restored their intracellular Ca2+ and ATP stores, leading to enhanced gliding. Collectively, our findings indicate that intracellular bradyzoites exhibit dampened Ca2+ signaling and lower energy levels that restrict egress, and yet upon release they rapidly respond to changes in the environment to regain motility.

The spectrum of inflammatory responses.

Inflammation is an integral part of animal biology. It provides critical protection from adverse environmental factors by enforcing the defense of homeostasis and the functional and structural integrity of tissues and organs. Recent advances have uncovered a broad range of biological processes that involve inflammatory control, calling for a renewed framework of inflammation beyond its classical roles in defense from infection and injury. In this Review, new perspectives on inflammation biology are discussed and new research directions are suggested to address the fundamental gaps in our current understanding.

Clinical phenotypes from fatal cases of acute respiratory distress syndrome caused by pneumonia.

There have been no report of objective clinical characteristics or prognostic factors that predict fatal outcome of acute respiratory distress syndrome (ARDS) since the Berlin definition was published. The aim of this study is to identify clinically available predictors that distinguish between two phenotypes of fatal ARDS due to pneumonia. In total, 104 cases of Japanese patients with pneumonia-induced ARDS were extracted from our prospectively collected database. Fatal cases were divided into early (< 7 days after diagnosis) and late (≥ 7 days) death groups, and clinical variables and prognostic factors were statistically evaluated. Of the 50 patients who died within 180 days, 18 (36%) and 32 (64%) were in the early (median 2 days, IQR [1, 5]) and late (median 16 days, IQR [13, 29]) death groups, respectively. According to multivariate regression analyses, the APACHE II score (HR 1.25, 95%CI 1.12-1.39, p < 0.001) and the disseminated intravascular coagulation score (HR 1.54, 95%CI 1.15-2.04, p = 0.003) were independent prognostic factors for early death. In contrast, late death was associated with high-resolution computed tomography (HRCT) score indicating early fibroproliferation (HR 1.28, 95%CI 1.13-1.42, p < 0.001) as well as the disseminated intravascular coagulation score (HR 1.24, 95%CI 1.01-1.52, p = 0.039). The extent of fibroproliferation on HRCT, and the APACHE II scores along with coagulation abnormalities, should be considered for use in predictive enrichment and personalized medicine for patients with ARDS due to pneumonia.

Evaluation of pain susceptibility by taking blood pressure in patients with infections: A prospective comparative study.

ABSTRACT: Pain sensitization leading to polyalgia can be observed during infectious diseases. The blood pressure cuff-evoked pain threshold (BPCEPT) has been used in previous studies as a screening tool for fibromyalgia.We aimed to use the BPCEPT as a screening test for detecting pain sensitization in patients suffering from infectious diseases. We also investigated whether specific factors were associated with pain sensitization.We performed a prospective comparative study including all patients of our infectious diseases center in a 1-year period. We created a positive control group of patients suffering from fibromyalgia and a negative control group of "apparently healthy" patients consulting for vaccination.The blood pressure (BP) cuff was inflated until the patient signaled that they experienced pain, and this pressure value was noted.A total of 2355 patients were included. The positive control group had significantly lower values of the BPCEPT than all other groups. Among hospitalized patients with infectious diseases, a low BPCEPT was significantly associated with high temperature (P < .0001), older age (P = .002), being a woman (P = .004), high serum glutamic-oxaloacetic transaminase (P = .007), and high C reactive protein levels (P = .02). Moreover, in multivariate analysis, respiratory infection, meningitis, urinary tract infection, febrile neutropenia, and Q fever were independently associated with a low BPCEPT. A significant negative dynamic correlation between the BPCEPT and temperature was also observed (P < .001).We demonstrated for the first time in a large sample of patients that the BPCEPT method can be used to detect pain susceptibility. We observed a significant dynamic correlation between pain sensitization and temperature. Additionally, pain sensitization was associated with some diseases, suggesting that they trigger pain sensitivity.

New obstetric systemic inflammatory response syndrome criteria for early identification of high-risk of sepsis in obstetric patients.

OBJECTIVES: We aimed to establish new cut-off values for SIRS (Systemic Inflammatory Response Syndrome) variables in the obstetric population. METHODS: A prospective cohort study in pregnant and postpartum women admitted with systemic infections between December 2017 and January 2019. Patients were divided into three cohorts: Group A, patients with infection but without severe maternal outcomes (SMO); Group B, patients with infection and SMO or admission to the intensive care unit (ICU); and Group C, a control group. Outcome measures were ICU admission and SMO. The relationship between SIRS criteria and SMO was expressed as the area under the receiver operating characteristics curve (AUROC), selecting the best cut-off for each SIRS criterion. RESULTS: A total of 541 obstetric patients were enrolled, including 341 with infections and 200 enrolled as the reference group (Group C). The patients with infections included 313 (91.7%) in Group A and 28 (8.2%) in Group B. There were significant differences for all SIRS variables in Group B, compared with Groups A and C, but there were no significant differences between Groups A and C. The best cut-off values were the following: temperature 38.2 °C, OR 4.1 (1.8-9.0); heart rate 120 bpm, OR 2.9 (1.2-7.4); respiratory rate 22 bpm, OR 4.1 (1.6-10.1); and leukocyte count 16,100 per mcl, OR 3.5 (1.6-7.6). CONCLUSIONS: The cut-off values for SIRS variables did not differ between healthy and infected obstetric patients. However, a higher cut-off may help predict the population with a higher risk of severe maternal outcomes.

Accuracy of pancreatic stone protein for the diagnosis of infection in hospitalized adults: a systematic review and individual patient level meta-analysis.

BACKGROUND: Accurate biomarkers to diagnose infection are lacking. Studies reported good performance of pancreatic stone protein (PSP) to detect infection. The objective of the study was to determine the performance of PSP in diagnosing infection across hospitalized patients and calculate a threshold value for that purpose. METHODS: A systematic search across Cochrane Central Register of Controlled Trials and MEDLINE databases (1966-March 2019) for studies on PSP published in English using 'pancreatic stone protein', 'PSP', 'regenerative protein', 'lithostatin' combined with 'infection' and 'sepsis' found 44 records. The search was restricted to the five trials that evaluated PSP for the initial detection of infection in hospitalized adults. Individual patient data were obtained from the investigators of all eligible trials. Data quality and validity was assessed according to PRISMA guidelines. We choose a fixed-effect model to calculate the PSP cut-off value that best discriminates infected from non-infected patients. RESULTS: Infection was confirmed in 371 of 631 patients. The median (IQR) PSP value of infected versus uninfected patients was 81.5 (30.0-237.5) versus 19.2 (12.6-33.57) ng/ml, compared to 150 (82.70-229.55) versus 58.25 (15.85-120) mg/l for C-reactive protein (CRP) and 0.9 (0.29-4.4) versus 0.15 (0.08-0.5) ng/ml for procalcitonin (PCT). Using a PSP cut-off of 44.18 ng/ml, the ROC AUC to detect infection was 0.81 (0.78-0.85) with a sensitivity of 0.66 (0.61-0.71), specificity of 0.83 (0.78-0.88), PPV of 0.85 (0.81-0.89) and NPV of 0.63 (0.58-0.68). When a model combining PSP and CRP was used, the ROC AUC improved to 0.90 (0.87-0.92) with higher sensitivity 0.81 (0.77-0.85) and specificity 0.84 (0.79-0.90) for discriminating infection from non-infection. Adding PCT did not improve the performance further. CONCLUSIONS: PSP is a promising biomarker to diagnose infections in hospitalized patients. Using a cut-off value of 44.18 ng/ml, PSP performs better than CRP or PCT across the considered studies. The combination of PSP with CRP further enhances its accuracy.

Glyphosate inhibits melanization and increases susceptibility to infection in insects.

Melanin, a black-brown pigment found throughout all kingdoms of life, has diverse biological functions including UV protection, thermoregulation, oxidant scavenging, arthropod immunity, and microbial virulence. Given melanin's broad roles in the biosphere, particularly in insect immune defenses, it is important to understand how exposure to ubiquitous environmental contaminants affects melanization. Glyphosate-the most widely used herbicide globally-inhibits melanin production, which could have wide-ranging implications in the health of many organisms, including insects. Here, we demonstrate that glyphosate has deleterious effects on insect health in 2 evolutionary distant species, Galleria mellonella (Lepidoptera: Pyralidae) and Anopheles gambiae (Diptera: Culicidae), suggesting a broad effect in insects. Glyphosate reduced survival of G. mellonella caterpillars following infection with the fungus Cryptococcus neoformans and decreased the size of melanized nodules formed in hemolymph, which normally help eliminate infection. Glyphosate also increased the burden of the malaria-causing parasite Plasmodium falciparum in A. gambiae mosquitoes, altered uninfected mosquito survival, and perturbed the microbial composition of adult mosquito midguts. Our results show that glyphosate's mechanism of melanin inhibition involves antioxidant synergy and disruption of the reaction oxidation-reduction balance. Overall, these findings suggest that glyphosate's environmental accumulation could render insects more susceptible to microbial pathogens due to melanin inhibition, immune impairment, and perturbations in microbiota composition, potentially contributing to declines in insect populations.

Tight Junctions as a Key for Pathogens Invasion in Intestinal Epithelial Cells.

Tight junctions play a major role in maintaining the integrity and impermeability of the intestinal barrier. As such, they act as an ideal target for pathogens to promote their translocation through the intestinal mucosa and invade their host. Different strategies are used by pathogens, aimed at directly destabilizing the junctional network or modulating the different signaling pathways involved in the modulation of these junctions. After a brief presentation of the organization and modulation of tight junctions, we provide the state of the art of the molecular mechanisms leading to permeability breakdown of the gut barrier as a consequence of tight junctions' attack by pathogens, including bacteria, viruses, fungi, and parasites.

Chronic and End-Stage Kidney Disease in the Neurological Intensive Care Unit.

Patients with renal disease have increased rates of admission to the neurological intensive care unit related to overlapping risk factors for renal and cerebrovascular disease as well as unique risks associated with renal dysfunction alone. Management of acute neurological injury in these patients requires individualized attention to diagnostic and management factors as they relate to coagulopathy, disorders of immune function, encephalopathy and renal replacement modalities. Careful consideration of these brain-kidney interactions is necessary to optimize care for this special patient population and improve neurological and renal outcomes.

Infection, Infectious Agents and Vascular Disease.

BACKGROUND: Infectious agents may be involved in the pathogenesis of vascular disease and related complications. The aim of this review is to analyze the most relevant information on the common infections related to vascular disease, discussing the main pathophysiological mechanisms. METHODS: In the current review, the most important evidence on the issue of infections and vascular disease is searched on Medline, Scopus, and ScienceDirect database. RESULTS: Among infectious agents, herpesviruses, parvovirus B19, hepatitis viruses, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, treponema pallidum, mycobacterium tuberculosis, pseudomonas aeruginosa, staphylococcus aureus, and candida albicans seem to particularly related to vascular disease. CONCLUSION: Infectious agents may affect vessel's homeostasis and functionality, both on the arterial and venous side, by means of several pathophysiological mechanisms such as dysregulation in vasomotor function, thromboembolic complications, initiation and progression of atherosclerosis, alteration of perivascular adipose tissue, recruiting inflammatory cells and molecules.

Evolution of pathogen-specific improved survivorship post-infection in populations of Drosophila melanogaster adapted to larval crowding.

The environment experienced by individuals during their juvenile stages has an impact on their adult stages. In holometabolous insects like Drosophila melanogaster, most of the resource acquisition for adult stages happens during the larval stages. Larval-crowding is a stressful environment, which exposes the larvae to scarcity of food and accumulation of toxic waste. Since adult traits are contingent upon larval stages, in larval-crowding like conditions, adult traits are prone to get affected. While the effect of resource limited, poor-developmental environment on adult immune response has been widely studied, the effect of adaptation to resource-limited developmental environment has not been studied, therefore in this study we assayed the evolution of ability to survive infection in adult stages as a correlated response to adaptation to larval crowding environments. Using four populations of Drosophila melanogaster adapted to larval crowding for 240 generations and their respective control populations, we show that populations adapted to larval crowding show an improved and evolved post-infection survivorship against a gram-negative bacteria Pseudomonas entomophila. Whereas, against a gram-positive bacteria Enterococcus faecalis, no difference in post-infection survivorship was observed across control and selected populations. In this study, we report the co-related evolution of pathogen-specific increased survivorship post-infection in populations of Drosophila melanogaster as a result of adaptation to larval crowding environment.

The potential role of necroptosis in clinical diseases (Review).

As an important type of programmed cell death in addition to apoptosis, necroptosis occurs in a variety of pathophysiological processes, including infections, liver diseases, kidney injury, neurodegenerative diseases, cardiovascular diseases, and human tumors. It can be triggered by a variety of factors, such as tumor necrosis factor receptor and Toll­like receptor families, intracellular DNA and RNA sensors, and interferon, and is mainly mediated by receptor­interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain­like protein. A better understanding of the mechanism of necroptosis may be useful in the development of novel drugs for necroptosis­related diseases. In this review, the focus is on the molecular mechanisms of necroptosis, exploring the role of necroptosis in different pathologies, discussing their potential as a novel therapeutic target for disease therapy, and providing suggestions for further study in this area.

Plasminogen: an enigmatic zymogen.

Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.

Does UV Light as an Adjunct to Conventional Treatment Improve Healing and Reduce Infection in Wounds? A Systematic Review.

OBJECTIVE: To examine the effect of UV light on wound healing and infection in patients with skin ulcers or surgical incisions. Outcomes of interest included healing time, wound size and appearance, bacterial burden, and infection. DATA SOURCES: Ovid MEDLINE, Embase, Cochrane, PubMed, CINAHL, and Web of Science. STUDY SELECTION: Comparative and noncomparative clinical studies were considered, including observational cohort, retrospective, and randomized controlled studies. They addressed the research question: "Does the use of UV light as an adjunct to conventional treatment help improve healing and reduce infection in wounds?" Selection criteria included any English language study in adults who used UV light to improve wound healing and prevent or treat wound infection. DATA EXTRACTION: Authors extracted information pertaining to patient demographics, treatment protocols, and the following wound outcomes: appearance, healing time, infection, and bacterial burden. DATA SYNTHESIS: The search yielded 30,986 articles, and screening resulted in 11 studies that underwent final analysis. Of these (N = 27,833), seven (64%) demonstrated an improvement in healing outcomes with adjunctive UV therapy, and the results of four (36%) achieved statistical significance. CONCLUSIONS: There is limited research on the utility of adjunctive UV therapy to improve wound healing outcomes in humans. The majority of literature included in this review supported improved wound healing outcomes with adjuvant UV therapy. Future well-designed randomized controlled trials will be essential in further determining the benefit and utility of UV therapy in wound healing.