Acute Phase Immune Response Research Articles

Brief Pain Inventory (BPI) Pain Survey Versus Cysteine Protease Caspase-1 (Casp1) Blood Levels Following Midline Laparotomy: A Prospective Randomized Study of Patients With Benign Disease and Patients With Cancer.

There is lack of studies assessing the correlation between pain scales and acute phase immune response (APR) following surgery. The purpose of this work was to assess the correlation between cysteine protease caspase-1 (Casp1) blood levels and two pain scales in a cohort of 56 midline laparotomy (MLa) patients and to assess their link with other cytokines (CYTs). Blood levels of Casp1 and other CYTs (IL-18, IL-18BP, IL-1ra, IL-6, IL-8, IL-10, IL-1β) were measured before operation and following surgery in patients with MLa. Pain levels were assessed using the Numerical Rating Scale (NRS) and Brief Pain Inventory (BPI) scale, both preoperatively and postoperatively. Casp1 blood levels showed an increasing trend at postoperative day 1 (POP1) and this increase was almost significant in a linear mixed effect model (LME) analysis (p=0.06). Additionally, Casp1 blood levels were higher in patients with cancer than those with benign disease and correlated with IL-18 blood levels (r=0.24, p=0.007). Furthermore, Casp1 blood levels correlated with BPIsev (severity) score values in MLa patients (r=-0.49, p=0.048). A significant correlation was also observed between Casp1 blood levels and NRS scores in patients with MLa. This is the first report to evaluate two pain surveys (NRS and BPI) in MLa patients in relation to blood levels of Casp1 and eight CYTs. This analysis is important in confirming the significant correlation between NRS and BPI pain scales and Casp1 blood levels. Our study is also the first to demonstrate that adequate postoperative analgesia in patients with MLa provides better functional ability and improved patient satisfaction.

Correlation Between Blood Levels of Cysteine Protease Caspase-1 (Casp1) and Pain Scores (NRS) Post-surgery: A Prospective Randomized Study of Patients With Cholelithiasis.

Cysteine protease caspase-1 (Casp1) plays a crucial role in the conversion of pro-cytokines to active cytokines (CYTs). The purpose of this work was to determine Casp1 blood levels in a cohort of 114 cholecystectomy patients and assess their association with other CYTs and numeric rating scale (NRS) pain scores, postoperatively. Blood levels of Casp1 and seven CYTs (IL-18, IL-18BP, IL-1ra, IL-6, IL-10, IL-1β, and IL-8) were measured at three time points; before operation, immediately after operation, and six hours after operation in 114 patients with cholelithiasis (Chole). Casp1 blood levels correlated with NRS pain scores at 24 h following surgery (p=0.016). In addition, Casp1 blood levels correlated significantly to IL-18 blood levels (p<0.001). This is the first report to evaluate Casp1 blood levels in Chole patients in correlation with other CYTs. The findings confirm a significant correlation between Casp1 blood levels and NRS pain scores. Moreover, this study provides initial evidence suggesting that inhibition of the activity of Casp1 may reduce postsurgical acute phase immune response possibly through the Casp1/pro-Il-18 pathway.

Combined transcriptomics and proteomics unveil the impact of vitamin C in modulating specific protein abundance in the mouse liver

BackgroundVitamin C (ascorbate) is a water-soluble antioxidant and an important cofactor for various biosynthetic and regulatory enzymes. Mice can synthesize vitamin C thanks to the key enzyme gulonolactone oxidase (Gulo) unlike humans. In the current investigation, we used Gulo−/− mice, which cannot synthesize their own ascorbate to determine the impact of this vitamin on both the transcriptomics and proteomics profiles in the whole liver. The study included Gulo−/− mouse groups treated with either sub-optimal or optimal ascorbate concentrations in drinking water. Liver tissues of females and males were collected at the age of four months and divided for transcriptomics and proteomics analysis. Immunoblotting, quantitative RT-PCR, and polysome profiling experiments were also conducted to complement our combined omics studies.ResultsPrincipal component analyses revealed distinctive differences in the mRNA and protein profiles as a function of sex between all the mouse cohorts. Despite such sexual dimorphism, Spearman analyses of transcriptomics data from females and males revealed correlations of hepatic ascorbate levels with transcripts encoding a wide array of biological processes involved in glucose and lipid metabolisms as well as in the acute-phase immune response. Moreover, integration of the proteomics data showed that ascorbate modulates the abundance of various enzymes involved in lipid, xenobiotic, organic acid, acetyl-CoA, and steroid metabolism mainly at the transcriptional level, especially in females. However, several proteins of the mitochondrial complex III significantly correlated with ascorbate concentrations in both males and females unlike their corresponding transcripts. Finally, poly(ribo)some profiling did not reveal significant enrichment difference for these mitochondrial complex III mRNAs between Gulo−/− mice treated with sub-optimal and optimal ascorbate levels.ConclusionsThus, the abundance of several subunits of the mitochondrial complex III are regulated by ascorbate at the post-transcriptional levels. Our extensive omics analyses provide a novel resource of altered gene expression patterns at the transcriptional and post-transcriptional levels under ascorbate deficiency.

Blood Interleukin-18 (IL-18) and IL-18 Binding Protein (IL-18BP) Levels Following Midline Laparotomy: A Prospective Randomized Study of Patients With Benign Disease and Patients With Cancer.

The acute phase immune response (APR) in midline laparotomy (MLa) patients following surgery has been rarely studied, with no studies assessing the association of blood IL-18 (interleukin-18) and IL-18BP (IL-18 binding protein) values with the numeric rating scale (NRS) pain score following MLa. Blood levels of seven cytokines (CYT) (IL-18, IL-18BP, IL-1ra, IL-6, IL-8, IL-10, IL-1β) and high-sensitivity C-reactive protein (hs-CRP) were measured at three time points; before operation (PRE), immediately after operation (POP1), and 24 h after operation (POP2) in 56 patients with MLa. The satisfaction of the patients at 24 h following MLa (SFS24; 0=fully unsatisfied; 10=fully satisfied) was recorded on a 11-point numeric rating scale. In all patients, the IL-18 and IL-18BP blood levels decreased at POP1 and the drop between the preoperative and POP1 levels in the IL-18 and IL-18BP was highly significant (p<0.001). However, the median IL-18 and IL-18BP blood levels increased significantly at POP2 (p<0.001) with the linear mixed-effect model (LME) showing a statistically significant time effect (p<0.001). The hs-CRP blood levels increased significantly at POP2 with the LME model showing a statistically significant time effect. The preoperative and POP2 IL-18 values were clearly higher in patients with cancer versus benign disease (177/182 vs. 135/126, p=0.039/p=0.013, respectively). Interestingly, in all patients of the study, the median IL-18 versus IL-18BP blood levels correlated at POP1 (r=0.315, p=0.036). A noteworthy discovery of this study is the correlation of IL-18BP with SFS24 (r=0.361, p=0.05), proposing that APR and quality of life are associated in MLa patients.

Rising to the Challenge: Mounting an Acute Phase Immune Response Has No Long-Term Negative Effects on Captive Sparrow Migratory Body Composition or Migratory Restlessness.

Migratory animals may trade-off between investing energy in immune defense versus investing in energy reserves needed for seasonal migration. However, these trade-offs are often masked by other sources of variation and may not be detected through observational field studies of free-living animals. Moreover, observational studies can rarely distinguish the costs of pathogenic infection from those of mounting an immune response. To disentangle such effects, we conducted an immune challenge experiment. We captured song sparrows (Melospiza melodia) and white-throated sparrows (Zonotrichia albicollis) in autumn migratory condition, challenged the sparrows with non-infectious antigens that induce an acute-phase immune response, then monitored body composition and migratory restlessness behavior. For both species, body mass was higher the day after exposure to keyhole limpet hemocyanin (KLH) compared to controls. White-throated sparrows, but not song sparrows, increased lean mass 1 week after exposure to lipopolysaccharide (LPS), suggesting that effects of immune upregulation on body composition may be long-lasting and specific to certain combinations of hosts and antigens. White-throated sparrows exposed to KLH increased nocturnal migratory restlessness (Zugunruhe) for the week following exposure. These findings suggest that short-term activation of the acute immune response does not constrain migratory physiology in these songbirds.

Thermoregulatory costs of the innate immune response are modulated by winter food availability in a small passerine.

In winter, a challenge to the immune system could pose a major energetic trade-off for small endotherms, whereby increasing body temperature (Tb ; i.e. eliciting fever) may be beneficial to fight off invading pathogens yet incur a cost for vital energy-saving mechanisms. Having previously shown that the availability and acquisition of energy, through manipulation of food predictability, influences the depth of rest-phase hypothermia in a wild bird in winter, we expected that the nocturnal thermoregulatory component of the acute-phase immune response would also be modulated by food availability. By manipulating winter food availability in the wild for great tits Parus major, we created an area offering a "predictable" and constant supply of food at feeding stations, while an unmanipulated area was subject to naturally "unpredictable" food. Birds were subject to an immune challenge shortly after dusk, and the thermoregulatory response was quantified via continuous recording of nocturnal Tb , using subcutaneous thermo-sensitive transponders. In response to immune challenge, all birds increased Tb above the level maintained prior to immune challenge (i.e. baseline). However, birds experiencing a naturally unpredictable food supply elevated Tb more than birds subject to predictable food resources, during the period of expected peak response and for the duration of the night. Furthermore, "unpredictable-food" females took longer to return to their baseline Tb . Assuming baseline nocturnal Tb reflects an individual's optimum, based on their available energy budget, the metabolic cost of eliciting an acute-phase response for "unpredictable-food" birds was more than double that of "predictable-food" birds. The absence of differences in absolute Tb during the peak response could support the idea of an optimal Tb for immune system activation. Alternatively, "predictable-food" birds could have acquired tolerance to endotoxin as a result of using feeding stations, thus affording them reduced costs associated with a smaller Tb increase. These findings shed new light on the trade-offs associated with food acquisition, thermoregulation and immune function in small-bodied endotherms. This knowledge is of increasing importance, given the predicted elevated pathogen risks associated with changes in climate and anthropogenic activities.

Effect of oestrus synchronisation through ovulation delay by vaccination against foot-and-mouth disease in Hanwoo (Bos taurus coreanae) cows.

In Korean cattle, after foot-and-mouth disease (FMD) vaccination, anovulation increases, acute immune response is stimulated. Here, we aimed to improve the fertility rate by ovulation delay caused by the foot-and-mouth disease vaccine. 160 cows (control, FMD, FMD+Gn250 and FMD+Gn500 groups, with 40 cows each) were used. We analysed the ovulation delay, ovulation rate, conception rate and acute-phase immune responses. In the group vaccinated only with FMD, the average follicle size was maintained at 12mm and ovulation was delayed. The ovulation rate of the FMD+Gn500 group (500μg gonadotropin-releasing hormone (GnRH) injections 3 days after the FMD vaccination) was the highest at 81.8%. The ovulation rate of the FMD+Gn250 group (250μg GnRH injections 3 days after FMD vaccination) was 54.5%, and that of the control group (not FMD vaccinated) was 53.3%. The conception rate was 52.5% (19/40) in the control group, 37.5% (15/40) in the FMD+Gn250 group, and 67.5% (27/40) in the FMD+Gn500 group. Analysis of acute-phase immune response revealed that the plasma contents of haptoglobin and serum amyloid A increased up to 7 days after vaccination against FMD in all the experimental groups, except the control group. We concluded that ovulation delay can be employed to improve conception rate after FMD vaccination through a modified ovulation synchronisation method with GnRH.

Integrative analyses of mRNA and microRNA expression profiles reveal the innate immune mechanism for the resistance to Vibrio parahaemolyticus infection in Epinephelus coioides

Vibrio parahaemolyticus, as one of the main pathogens of marine vibriosis, has brought huge losses to aquaculture. However, the interaction mechanism between V. parahaemolyticus and Epinephelus coioides remains unclear. Moreover, there is a lack of comprehensive multi-omics analysis of the immune response of grouper spleen to V. parahaemolyticus. Herein, E. coioides was artificially injected with V. parahaemolyticus, and it was found that the mortality was 16.7% in the early stage of infection, and accompanied by obvious histopathological lesions in the spleen. Furthermore, 1586 differentially expressed genes were screened by mRNA-seq. KEGG analysis showed that genes were significantly enriched in immune-related pathways, Acute-phase immune response, Apoptosis, Complement system and Cytokine-cytokine receptor interaction. As for miRNA-seq analysis, a total of 55 significantly different miRNAs were identified. Further functional annotation analysis indicated that the target genes of differentially expressed miRNAs were enriched in three important pathways (Phosphatidylinositol signaling system, Lysosome and Focal adhesions). Through mRNA-miRNA integrated analysis, 1427 significant miRNA–mRNA pairs were obtained and “p53 signaling pathway”, “Intestinal immune network for IgA production” were considered as two crucial pathways. Finally, miR-144-y, miR-497-x, novel-m0459-5p, miR-7133-y, miR-378-y, novel-m0440-5p and novel-m0084-3p may be as key miRNAs to regulate immune signaling pathways via the miRNA-mRNA interaction network. The above results suggest that the mRNA-miRNA integrated analysis not only sheds new light on the molecular mechanisms underlying the interaction between host and V. parahaemolyticus but also provides valuable and new insights into resistance to vibrio infection.

Acute-Phase Immune Response Involves Fever, Sickness Behavior, and an Elevated Metabolic Rate in the Subterranean Rodent Ctenomys talarum.

AbstractThe acute-phase response (APR) is an induced innate response and may involve pronounced physiological and behavioral changes. One of the most common assays to study the APR involves the use of a lypopolysaccharide (LPS) from the cell wall of gram-negative bacteria. In this study, we determined the energetic costs of the APR in the subterranean rodent Ctenomys talarum, as well as the effects of the exposure to LPS on body temperature, body mass loss, and behavior in this species. Furthermore, we monitored levels of circulating endotoxin after LPS exposure. Our results suggest that in C. talarum, the APR is energetically costly, resulting in a 14% increase in metabolic rate. Animals exposed to LPS experienced a short-term thermal response, weight loss, and changes in their behavior that included more time spent resting and with their eyes totally or partially closed. However, the magnitude of the effects of LPS exposure varied between sexes and among animals. Also, there was a clear peak in circulating endotoxin levels in plasma 3 h postinjection (hpi) and a significant decrease of these levels 24 hpi, but peak endotoxin concentration values recorded were highly variable among animals. In light of these results, ecological determinants of immune function variation in tuco-tucos are discussed considering the roles of pace of life, habitat, and degree of pathogen exposure in these subterranean rodents.

Acute-Phase Levels of CXCL8 as Risk Factor for Chronic Arthralgia Following Chikungunya Virus Infection.

The immunopathogenesis of chikungunya virus (CHIKV) infection and the role of acute-phase immune response on joint pain persistence is not fully understood. We investigated the profile of serum chemokine and cytokine in CHIKV-infected patients with acute disease, compared the levels of these biomarkers to those of patients with other acute febrile diseases (OAFD) and healthy controls (HC), and evaluated their role as predictors of chronic arthralgia development. Chemokines and cytokines were measured by flow Cytometric Bead Array. Patients with CHIKV infection were further categorized according to duration of arthralgia (≤ 3 months vs >3 months), presence of anti-CHIKV IgM at acute-phase sample, and number of days of symptoms at sample collection (1 vs 2-3 vs ≥4). Patients with acute CHIKV infection had significantly higher levels of CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, IL-12, and IL-10 as compared to HC. CCL2, CCL5, and CXCL10 levels were also significantly higher in patients with CHIKV infection compared to patients with OAFD. Patients whose arthralgia lasted > 3 months had increased CXCL8 levels compared to patients whose arthralgia did not (p<0.05). Multivariable analyses further indicated that high levels of CXCL8 and female sex were associated with arthralgia lasting >3 months. Patients with chikungunya and OAFD had similar cytokine kinetics for IL-1β, IL-12, TNF, IFN-γ, IL-2, and IL-4, although the levels were lower for CHIKV patients. This study suggests that chemokines may have an important role in the immunopathogenesis of chronic chikungunya-related arthralgia.

Health monitoring in birds using bio-loggers and whole blood transcriptomics

Monitoring and early detection of emerging infectious diseases in wild animals is of crucial global importance, yet reliable ways to measure immune status and responses are lacking for animals in the wild. Here we assess the usefulness of bio-loggers for detecting disease outbreaks in free-living birds and confirm detailed responses using leukocyte composition and large-scale transcriptomics. We simulated natural infections by viral and bacterial pathogens in captive mallards (Anas platyrhynchos), an important natural vector for avian influenza virus. We show that body temperature, heart rate and leukocyte composition change reliably during an acute phase immune response. Using genome-wide gene expression profiling of whole blood across time points we confirm that immunostimulants activate pathogen-specific gene regulatory networks. By reporting immune response related changes in physiological and behavioural traits that can be studied in free-ranging populations, we provide baseline information with importance to the global monitoring of zoonotic diseases.

Effect of Foot-and-Mouth Disease Vaccination on Acute Phase Immune Response and Anovulation in Hanwoo (Bos taurus coreanae).

Vaccination against foot-and-mouth disease is the most common method for preventing the spread of the disease; the negative effects include miscarriage, early embryo death, lower milk production, and decreased growth of fattening cattle. Therefore, in this study, we analyze the side effects of vaccination by determining the acute immune response and ovulation rate after vaccinating cows for foot-and-mouth disease. The test axis was synchronized with ovulation using 100 Hanwoo (Bos taurus coreanae) cows from the Gyeongsangbuk-do Livestock Research Institute; only individuals with estrus confirmed by ovarian ultrasound were used for the test. All test axes were artificially inseminated 21 days after the previous estrus date. The control group was administered 0.9% normal saline, the negative control was injected intramuscularly with lipopolysaccharide (LPS; 0.5 µg/kg), and the test group was administered a foot-and-mouth disease virus vaccine (FMDV vaccine; bioaftogen, O and A serotypes, inactivated vaccine) 2, 9, and 16 days before artificial insemination. White blood cells and neutrophils increased significantly 1 day after vaccination, and body temperature in the rumen increased for 16 h after vaccination. Ovulation was detected 1 day after artificial fertilization by ovarian ultrasound. The ovulation rates were as follows: control 89%, LPS 60%, FMDV vaccine (−2 d) 50%, FMDV vaccine (−9 d) 75%, and FMDV vaccine (−16 d) 75%. In particular, the FMDV vaccine (−2 d) test group confirmed that ovulation was delayed for 4 days after artificial insemination. In addition, it was confirmed that it took 9 days after inoculation for the plasma contents of haptoglobin and serum amyloid A to recover to the normal range as the main acute immune response factors. The conception rate of the FMDV vaccine (−2 d) group was 20%, which was significantly lower than that of the other test groups.

Changes in redox plasma proteome of Pon1−/− mice are exacerbated by a hyperhomocysteinemic diet

High-density lipoprotein (HDL), in addition to promoting reverse cholesterol transport, possesses anti-oxidative, anti-inflammatory, and antithrombotic activities, which are thought to be promoted by paraoxonase 1 (PON1), an HDL-associated enzyme. Reduced levels of PON1 are associated with increased oxidative stress and cardiovascular disease both in humans and Pon1−/− mice. However, molecular basis of these associations are not fully understood. We used label-free mass spectrometry and Ingenuity Pathway Analysis bioinformatics resources to examine plasma proteomes in four-month-old Pon1−/− mice (n = 32) and their Pon1+/+ siblings (n = 15) fed with a hyper-homocysteinemic (HHcy) diet. We found that inactivation of the Pon1 gene resulted in dysregulation of proteins involved in the maintenance of redox homeostasis in mice. Redox-responsive proteins affected by Pon1−/− genotype were more numerous in mice fed with HHcy diet (18 out of 89, 20%) than in mice fed with a control diet (4 out of 50, 8%). Most of the redox-related proteins affected by Pon1−/− genotype in mice fed with a control diet (3 out of 4, 75%) were also affected in HHcy mice, while the majority of Pon1−/− genotype-dependent redox proteins in HHcy mice (15 out of 18, 83%) were not affected by Pon1−/− genotype in control diet animals. In addition to redox-related proteins, we identified proteins involved in acute phase response, complement/blood coagulation, lipoprotein/lipid metabolism, immune response, purine metabolism, glucose metabolism, and other proteins that were dysregulated by Pon1−/− genotype in HHcy mice. Taken together, our findings suggest that Pon1 interacts with proteins involved in antioxidant defenses and other processes linked to cardiovascular disease. Dysregulation of these processes provides an explanation for the pro-oxidant and pro-atherogenic phenotypes observed in Pon1−/− mice and humans with attenuated PON1 levels.

Anthelmintic drugs modulate the acute phase immune response but not the microbiota in wild Song Sparrows

Abstract Co-infection with microparasites (e.g., bacteria) and macroparasites (e.g., helminths) is often the natural state for wild animals. Despite evidence that gut helminths can bias immune responses away from inflammatory processes, few field studies have examined the role that helminths, or their potential interactions with internal microbial communities, play in modulating immunity in free-living, wild birds. Here, we used anthelmintic drugs to treat wild Song Sparrows (Melospiza melodia) for helminth infections and measured markers of systemic inflammation (heterothermia and locomotor activity) in response to an immune challenge with lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria. Using birds from a population that previously showed high helminth prevalence, we monitored skin temperature and activity remotely using automated radio telemetry. We also collected cloacal swabs to determine whether drug treatment was associated with changes in the cloacal microbiota, and whether cloacal microbial community structure was associated with the severity of birds’ immune responses. Because helminths can reduce the severity of inflammatory immune responses in other species, we predicted that in comparison with untreated control birds, anthelmintic-treated birds would be more lethargic and display higher fevers when challenged with LPS. Consistent with these predictions, anthelmintic-treated birds expressed higher fevers in response to immune challenge. However, all LPS-challenged birds decreased locomotor activity to a similar degree, regardless of anthelmintic treatment. Although several individual indicator bacterial taxa were strongly associated with anthelmintic treatment, this treatment did not alter overall bacterial alpha- and beta- diversity. Similarly, we did not find evidence that bacterial community diversity influenced the severity of immune responses to LPS. These results suggest that under field conditions, natural helminth infection can reduce the severity of songbirds’ thermoregulatory responses (fever) during an immune challenge, without major impacts on internal microbial communities or behavioral responses to infection.

Lack of Interleukin-6 Affects IFN-γ and TNF-α Production and Early In Vivo Control of Brucella abortus Infection.

Interleukin-6 (IL-6) is a pleiotropic cytokine promptly produced in response to infections, which contributes to host defense through the stimulation of acute phase immune responses. Brucella abortus is an intracellular bacterium that causes chronic disease in humans and domestic animals and triggers a robust immune response, characterized by the production of inflammatory cytokines. However, the mechanisms of IL-6-related immune responses in the context of Brucella infections are not completely understood. In this report, we describe an increased susceptibility of IL-6 knockout (KO) mice in the early phase of Brucella infection. Furthermore, we demonstrate that IL-6 is required for interferon (IFN)-γ and tumor necrosis factor (TNF)-α induction by infected splenocytes, indicating a protective role for IL-6 against B. abortus that parallels with Th1 type of immune response. Additionally, IL-6 KO mice exhibited reduced splenomegaly during the early phase of the infection. Corroborating this result, IL-6 KO mice displayed reduced numbers of macrophages, dendritic cells, and neutrophils in the spleen and reduced myeloperoxidase activity in the liver compared to wild-type infected mice. However, we demonstrate that IL-6 is not involved in B. abortus intracellular restriction in mouse macrophages. Taken together, our findings demonstrate that IL-6 contributes to host resistance during the early phase of B. abortus infection in vivo, and suggest that its protective role maybe partially mediated by proinflammatory immune responses and immune cell recruitment.

233 NaturSafe® supplementation mitigates some aspects of the acute phase immune response to a lipopolysaccharide (LPS) challenge in weaned beef calves

Abstract This study was conducted to determine if feeding calves NaturSafe would reduce the acute phase response (APR) to lipopolysaccharide (LPS) challenge. Crossbred steers (n=32; 274±2 kg) were randomly allotted to two treatment diets: 1) Control, fed a standard receiving ration, and 2) NaturSafe, fed the Control ration supplemented with NaturSafe at 12 g/hd/d (NaturSafe®, Diamond V). On d22, steers were fitted with indwelling jugular catheters and rectal temperature monitoring devices and placed in individual stalls. On d23, steers were challenged i.v. with 0.25 µg/kg BW LPS. Serum samples were collected and sickness behavior scores (SBS) recorded at 0.5-h intervals from -2 to 8h and at 24h relative to LPS challenge. Rectal temperatures were greater (P=0.01) in NaturSafe compared to Control steers for the following time intervals following LPS challenge: 6 to 11h, 13h, 15 to 20h, and 22 to 24h. Additionally, SBS were reduced (P&amp;lt; 0.01) in NaturSafe compared to Control steers. White blood cell concentrations were greater (P=0.05) in NaturSafe compared to Control steers prior to the LPS challenge, yet the response to LPS did not differ between treatments (P &amp;gt;0.05). A treatment × time interaction for serum cortisol concentrations (P&amp;lt; 0.01) showed an increase at 0.5 and 2h post-challenge but a reduction at 3h in NaturSafe compared to Control steers. Additionally, fibrinogen was greater (P&amp;lt; 0.01) in NaturSafe compared to Control steers. There was a treatment × time interaction (P&amp;lt; 0.01) for TNF-α where concentrations were reduced from 1 to 2h post-challenge in NaturSafe compared to Control steers. Serum IL-6 tended (P=0.09) to show a reduction in serum concentrations in NaturSafe compared to Control steers. There was a tendency (P=0.07) for a treatment × time interaction for IFN-γ. Overall these data suggest a priming effect of NaturSafe on the innate immune system of steers, resulting in an attenuated APR to the LPS challenge.

Time-course transcriptome analysis of lungs from mice exposed to ricin by intratracheal inoculation

In this study, a ricin toxin (RT)-induced pulmonary intoxication model was established in mice by intratracheal-delivered RT at a dose of 2× LD50. Based on this model, the histopathological evaluation of the lungs at 24 h and 48 h post-exposure was executed, and the genome-wide transcriptome of the lungs at 4, 12, 24 and 48 h post-exposure was analyzed. Histopathological analysis showed that a large number of neutrophils infiltrated the lungs at 24 h post-exposure, and slight pulmonary edema and perivascular-peribronchiolar edema appeared in the lungs at 48 h. Transcriptome analysis showed that the expression of a large number of genes related to leukocyte migration and chemotaxis consistently increased in the lungs upon exposure to RT, and the expression of genes that participate in acute phase immune and/or inflammatory response, also increased within 12 h of exposure to RT, which could be confirmed by the measurement of cytokines, such as IL-1β, TNF-α and IL-6, in bronchoalveolar lavage fluid. While the expression of genes related to cellular components of the extracellular matrix and cell membrane integrity consistently decreased in the lungs, and the expression of genes related to antioxidant activity also decreased within the first 12 h. There are 17 differentially expressed genes (DEGs) that participate in ribotoxic stress response, endoplasmic reticulum stress response or immune response in the lungs at 4 h post-exposure. The expression of these DEGs was upregulated, and the number of these DEGs accounted for about 59 % of all DEGs at 4 h. The 17 DEGs may play an important role in the occurrence and development of inflammation. Notably, Atf3, Egr1, Gdf15 and Osm, which are poorly studied, may be important targets for the subsequent research of RT-induced pulmonary intoxication. This study provides new information and insights for RT-induced pulmonary intoxication, and it can provide a reference for the subsequent study of the toxicological mechanism and therapeutic approaches for RT-induced pulmonary intoxication.

Some aspects of the acute phase immune response to a lipopolysaccharide (LPS) challenge are mitigated by supplementation with a Saccharomyces cerevisiae fermentation product in weaned beef calves.

This study was conducted to determine if feeding a Saccharomyces cerevisiae fermentation product (SCFP) to calves would alter the acute phase response to a lipopolysaccharide (LPS) challenge. Crossbred steer calves [n = 32; 274 ± 1.9 kg body weight (BW)] were randomly allotted to two treatment diets for 21 d: 1) control, fed RAMP (Cargill, Dalhart, TX) and 2) SCFP, fed the control ration supplemented with NaturSafe at 12 g/hd/d mixed into the TMR (NaturSafe, Diamond V, Cedar Rapids, IA). On day 22, steers were fitted with indwelling jugular catheters and rectal temperature monitoring devices and placed in individual bleeding stalls. On day 23, steers were challenged i.v. with 0.25 µg/kg BW LPS. Blood samples were collected at 0.5-h (serum) or 2-h (complete blood counts) intervals from −2 to 8 h and again at 24 h relative to the LPS challenge at 0 h. Sickness behavior scores (SBS) were recorded after the collection of each blood sample. Rectal temperatures were greater in SCFP steers from 6 to 11 h, at 13 h, from 15 to 20 h, and from 22 to 24 h following the LPS challenge compared to Control steers (treatment × time: P = 0.01). Additionally, SCFP-supplemented steers had reduced (P < 0.01) SBS compared to Control steers. Platelet concentrations remained greater in SCFP-supplemented steers compared to Control steers throughout the study (P = 0.05), while there was a tendency (P = 0.09) for SCFP steers to have greater white blood cells and eosinophils concentrations than Control steers. There was a treatment × time interaction for serum cortisol and glucose (P < 0.01). Specifically, cortisol was greater at 0.5 and 2 h postchallenge but was reduced at 3 h for SCFP steers compared to Control steers. Glucose was greater in SCFP steers at −0.5, 2, and 7.5 h compared to Control steers. Serum amyloid A was reduced in SCFP steers at 0.5 h, yet greater at 1 and 7.5 h postchallenge compared to Control steers (treatment × time: P < 0.01). Fibrinogen concentrations were greater (P < 0.01) in SCFP compared to Control steers. There was a treatment × time interaction (P < 0.01) for tumor necrosis factor-α (TNF-α) such that concentrations were reduced in SCFP steers from 1 to 2 h postchallenge compared to Control steers. Overall, these data suggest that supplementing calves with SCFP may have primed the innate immune response prior to the challenge, particularly platelets, which resulted in an attenuated sickness behavior and TNF-α response to LPS.

Clinical Significance of Activating Interleukin‐1 Ligands in HPV‐positive and HPV‐negative HNSCCs

Interleukin‐1 alpha (IL‐1α) and interleukin‐1 beta (IL‐1β) are cytokines involved in the acute phase immune response and their expression is upregulated in a variety of solid tumors including head and neck squamous cell carcinomas (HNSCCs). Our previous data has shown that IL‐1α in particular is associated with poor prognosis but this has yet to be studied in the context of human papilloma virus (HPV) status. This study is aimed at determining differences in tumor expression and the clinical significance of IL‐1α and IL‐1β in HPV‐positive (HPV+) and HPV‐negative (HPV‐) tumors. Differences in tumor gene expression and the prognostic value of IL‐1α and IL‐1β were determined in HPV+ and HPV− tumors from publically available gene expression datasets. Tissue microarrays (TMAs) containing HPV+ (n=31) and HPV− (n=47) primary and metastatic HNSCCs were analyzed for IL‐1α and IL‐1β expression using immunohistochemical (IHC) staining. HPV status was confirmed using p16 IHC staining and RNAish. We found that both IL‐1α and IL‐1β gene expression were significantly increased in HPV− tumors compared to HPV+ tumors. However, tumor expression (as detected by IHC) of IL‐1α (but not IL‐1β) was significantly increased in HPV− tumors compared to HPV+ tumors. Comparison of matched primary and metastatic tumors revealed a decrease in IL‐1α expression and an increase in IL‐1β in metastatic tumors compared to primary tumors. Lastly, increased IL‐1α gene expression was significantly associated with worse survival in HPV− tumors but not in HPV+ tumors. IL‐1β held no prognostic value in HPV+ or HPV− tumors. Overall IL‐1α expression may possess more prognostic significance in HPV− tumors rather than HPV+ tumors and this work warrants further investigation in larger patient cohorts.

Covid 19: Transmission, case fatality rate, protective measures, laboratory diagnosis, and possible laboratory features

Covid 19 is a coronavirus disease caused by Covid 19 virus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) formerly referred to as novel coronavirus or Wuhan coronavirus or 2019-nCoV causes a deadly respiratory infection. It is an infectious viral agent and a positive-sense (+ssRNA), single-stranded RNA virus that causes acute respiratory disease which can be mild, moderate, or severe illness including death. It is a zoonotic infection and can also be transmitted from human to human. The virus enters the cell by binding with cell that has angiotensin I converting enzyme 2 (ACE2) receptor using the spike. ACE2 receptor is found on the cell membranes of cells in the lungs, arteries, heart, kidney, and intestines. The first outbreak was reported in Wuhan, China, on December 31, 2019, hence the initial name Wuhan coronavirus. Globally, it has a fatality rate of 6.7% with a fatality rate of 3.5% in Nigeria as at April 18, 2020. The infection is air borne through droplets from infected person during coughing, spiting or sneezing. It can also be contracted by touching eyes, nose, or mouth with contaminated hands. Covid 19 may elicit both inflammatory and acute phase immune responses while the mechanical innate immune defense can be overcome to cause severe pneumonia The virus enters the lung through ACE2 receptors on the cell membrane of the lung to destroy cilia resulting into the accumulation of dead tissues, cells/dirts/wastes, and fluids thereby displacing the normal air content of the lung which will eventually bring about dry cough, and difficulties in breathing. The infection can be prevented through basic protective measures which include regular washing of hands with soap and water followed by sanitizing hands with alcohol-based sanitizer, social distancing, avoidance of gathering, quarantine measure applicable to especially those from endemic areas, self-isolation for those who are positive or manifesting related signs and symptoms, use of personal protective equipment, early diagnosis, and adequate intervention. The use of soap and alcohol are effective as soap can break through the lipid layer of the virus to become smaller particles which are washed away by water while alcohol is capable of lysing the virus. Covid 19 is diagnosed in the laboratory by real-time reverse transcription polymerase chain reaction Panel. Covid 19 may result into abnormal liver function tests due to abnormal fat retention, elevated plasma creatinine and urea which may be due to kidney damage, elevated C02, and decreased oxygen, level due to severe pneumonia, decreased and elevated anti and pro-inflammatory cytokines respectively which may be manifested as fever, acute phase response, decreased erythropoietin due to possible kidney damage, prolong prothrombin time/activated partial thromboplastin time and depleted platelet count which may manifest as disseminated intravascular coagulation. This work reviewed the transmission, case fatality rate, basic protective measures, laboratory diagnosis, and possible laboratory features of Covid 19.