Acute Phase Response

The parameters of pentylenetetrazol (PTZ)-induced seizures have been evaluated at various time intervals after lipopolysaccharide (LPS; Escherichia coli O111:B4, 100 g/kg, i.p.) administration in mice. A proconvulsant effect occurred 4 h after LPS injection with decreased seizure latency and enhanced seizure intensity. In contrast, the incidence of seizures was reduced 18 h after LPS injection. There were no significant alterations on seizure parameters 2, 8, 12, and 24 h after LPS treatment. SC-58236, a selective cyclooxygenase (COX)-2 inhibitor (20 or 40 mg/kg, s.c.) treatment alone had no effect on PTZ-induced seizures, but reversed the antiseizure activity observed 18 h after LPS injection. However, SC-58236 treatment partially restored the proconvulsant changes that were observed 4 h after LPS administration. On the other hand, COX-1-selective inhibitor valeryl salicylate (20 or 40 mg/kg, s.c.) itself facilitated PTZ-induced seizures. Thus, it was not possible to evaluate the effects of valeryl salicylate on the excitability changes after LPS injection. These results indicate that the parameters of PTZ-induced seizures change time-dependently after LPS treatment, in which proconvulsant and anticonvulsant states could be seen in a sequence. It seems that COX-2 isoenzyme may be involved in the neuronal excitability changes due to LPS.

Background-Plasminogen activator inhibitor (PAI)-1, a key regulator of fibrinolysis, is associated with increased risk of coronary heart disease (CHD) and is a potential therapeutic target for CHD. However, the relationship between PAI-1 and the most common diabetic microvascular complication, retinopathy, is unclear. The purpose of this study was to assess the relationship between PAI-1 activity and both retinopathy and CHD in type 2 diabetes. Methods and Results-We determined PAI-1 activity and both retinopathy (assessed by masked grading of 3-field retinal photographs) and CHD status (assessed by ECG and standard questionnaires) in 147 men and women with type 2 diabetes, mean age (SD) 64 ( ) years, in a cross-sectional setting. Plasma PAI-1 activity was inversely associated with prevalent retinopathy (Pϭ0.006) and severity of retinopathy (Pϭ0.022), and was associated with lower risk of diabetic retinopathy, independent of major retinopathy risk factors (duration of diabetes and HbA1c) and determinants of PAI-1 (obesity and triglyceride level) (OR 0.74 [0.60 to 0.92], Pϭ0.006). Conversely, higher plasma PAI-1 activity was independently associated with greater risk of CHD, after adjusting for the major CHD risk factors and determinants of PAI-1 (OR 1.31 [1.06 to 1.62], Pϭ0.001). Conclusion-These data support mounting evidence that a higher PAI-1 plasma level is independently associated with a lower risk of retinopathy but a higher risk of CHD in type 2 diabetes.

The serum level of six acute phase proteins (APP) has been evaluated preoperatively and for a few days in the postoperative period. Thirty patients undergoing total gastrectomy for gastric cancer have been studied in two subgroups according to their nutritional status. Those with gastric cancer had significantly higher baseline serum levels of alpha 1 acid glycoprotein (cllAGP) and C-reactive protein (CRP) than a control group. Malnourished The participation of inflammatory connective tissue in synthesis of acute serum glucoproteins. Journal of Laboratory and Clinical Medicine.

STATEMENT OF FINDINGS: Acute-phase serum amyloid A (A-SAA) is a major component of the acute-phase response. A sustained acute-phase response in rheumatoid arthritis (RA) is associated with increased joint damage. A-SAA mRNA expression was confirmed in all samples obtained from patients with RA, but not in normal synovium. A-SAA mRNA expression was also demonstrated in cultured RA synoviocytes. A-SAA protein

Replication of human cytomegalovirus is controlled by a vigorous CD8 T cell response. The persistent nature of infection is believed to periodically stimulate T cell responses resulting in considerable expansions of virus-specific CD8 T cells over time. In this study, we describe the magnitude and breadth of CD8 T cell responses against the immunodominant viral Ags, IE-1 and pp65, in acute and long-term infection using the IFN-γ ELISPOT assay. Simultaneously, we have identified several novel MHC class I restricted CD8 T cell epitopes. Acute phase responses in immunocompetent donors appear to be extremely focused as early as 1 week post diagnosis with dominant peptide-specific responses observed against both proteins. These dominant responses remain detectable at all later time points over a 4-year follow-up. Interestingly the IE-1 responses show an increase over time whereas the pp65 responses do not, which contrasts with data showing that responses against both Ags are elevated in ...

Physiologic stress depresses plasma zinc and elevates plasma copper, but effects on other zinc and copper related parameters are largely unknown. Therefore, several such parameters were investigated in 19 young, adult male trauma patients. Patients were studied 1 and 7 days after admission and compared to 21 aged matched male controls. At day 1, plasma zinc and zinc R-values (low molecular weight zinc) were low. Zinc activation of a-D-mannosidase in vitro was high at days 1 and 7. Each of these results can indicate impaired zinc function, but activities of the zinc enzyme 5 '-nucleotidase were high at both sampling days. Plasma activity and protein levels for ceruloplasmin, a copper-containing acute phase protein, were high after trauma. In contrast, ratios of ceruloplasmin activity to protein were normal. Activities of the copper enzymes plasma diamine oxidase and erythrocyte superoxide dismutase were low after trauma, with the latter accompanied by low immunoreactive protein values. In summary, trauma produced abnormal values for some zinc and copper related blood parameters. However, not all observations supported the idea that zinc or copper deficiency existed. b 1998Elsevlersci~Llc.

Pathogens have the well-known advantage of rapid evolution due to short generation times and large populations. However, pathogens have the rarely noted disadvantage of the vulnerability to stress involved in proliferation as well as being localized. Presented here are numerous new paradigms in immunology, and especially immunometabolism, which are derived from examining how hosts capitalize on pathogen vulnerabilities to stress. Universally, proliferation requires both resources and synthesis, which are vulnerable to resource-limiting stress and damaging/noxious stress, respectively. Pathogens are particularly vulnerable to stress at the time when they are most threatening-when they are proliferating. Since immune cells actively controlling pathogens (effector cells) typically do not proliferate at infected sites, there is a "stress vulnerability gap" wherein proliferating pathogens are more vulnerable to any type of stress than are the attacking effector cells. Hosts actively stress vulnerable proliferating pathogens by restricting resources (resource-limiting stress) and generating noxious waste products (damaging/disruptive stress) in a fundamental defense herein termed "immune-stressing." While nutritional immunity emphasizes denying pathogens micronutrients, immune-stressing extends the concept to restricting all resources, especially glucose and oxygen, coupled with the generation of noxious metabolic products such as lactic acid, reactive oxygen species (ROS), and heat to further harm or stress the pathogens. At present much of the field of immunometabolism centers on how nutrition and metabolism regulate immune function, a central feature being the inefficient use of glucose via aerobic glycolysis (with much lactate/ lactic acid production) by effector immune cells. In contrast, immune-stressing emphasizes how the immune system uses nutrition and metabolism to control infections. Immune-stressing addresses effector cell glycolysis at the infected site by noting that the high uptake of glucose linked with high output of lactic acid is an ideal double-pronged stressor targeting proliferating pathogens. Once the basic vulnerability of pathogen proliferation is recognized, numerous other paradigms of immunometabolism, and immunology as a whole, are challenged.

Tuberculosis (TB) represents a global health problem, affecting millions of individuals worldwide. A TB-related inflammatory response can occur, resulting in anorexia and increased catabolism, which may lead to malnutrition. Conversely, malnutrition is the most prevalent cause of secondary immunodeficiency and may contribute to both the incidence and prognosis of tuberculosis. In this context, there is a bidirectional relationship between malnutrition and TB. Nutritional interventions have the potential to significantly impact the prognosis of TB disease. This review aims to elucidate the relationship between malnutrition and TB and to highlight the efficacy of nutritional interventions in managing malnutrition in TB patients.

The investigation of serum amyloid A (SAA), IL-6, and IL-8 concentrations in serum during episodes of clinical and subclinical mastitis is of significant value. The objective of this study was to assess the diagnostic value of Serum Amyloid A (SAA), IL-6, and IL-8 in the early detection of subclinical mastitis in cows infected with Escherichia coli (E. coli) and staphylococcus infections. This cross-sectional analytical study, conducted in 2023 at the Veterinary Laboratory in Urmia, Iran, evaluated inflammatory markers in 79 dairy cows with clinical and subclinical mastitis. The cows were divided into three groups: healthy cows, cows with subclinical mastitis, and cows with clinical mastitis. Each of these groups was then evaluated for Serum Amyloid A (SAA), IL-6, and IL-8. The diagnostic value of the inflammatory markers was determined by calculating the areas under the curves (AUCs) of the receiver operating characteristic (ROC) curves. In general, among patients with a positive culture test result (57%), 19% were found to be infected with E. coli, 22.8% with Streptococcus uberis, and 15.2% (12 cases) with Staphylococcus aureus. A strong correlation was observed between the mean SCC and the values of IL-6 (P<0.005), IL-8 (P<0.005), and SAA (P<0.005). Furthermore, a strong correlation was observed between SAA and IL-8 (P<0.005). The value of IL-6 exhibited a moderate correlation with both IL-8 (P<0.005) and SAA (P<0.005). The sensitivity and specificity of SCC (0.98), SAA (0.90), IL-6 (0.95), and IL-8 (0.87) were high for the diagnosis of mastitis in cows. The present study demonstrated that mastitis in dairy cows is associated with an increase in inflammatory cytokines, including amyloid A, IL-6, and IL-8. The findings of this study indicate that fluctuations in these biomarkers may serve as a potential indicator for disease diagnosis.

Toxicogenomics using a reference database can provide a better understanding and prediction of toxicity, largely by creating biomarkers that tie gene expression to actual pathology events. During the course of building a toxicogenomic database, an observation was made that a number of non-steroidal anti-inflammatory compounds (NSAIDs) at supra-pharmacologic doses induced an acute phase response (APR) and displayed hepatic gene expression patterns similar to that of intravenous lipopolysaccharide (LPS). Since NSAIDs are known to cause injury along the gastrointestinal tract, it has been suggested that NSAIDs increase intestinal permeability, allowing LPS and/or bacteria into the systemic circulation and stimulating an APR detectable in the liver. A short term study was subsequently conducted examining the effects of aspirin, indomethacin, ibuprofen, and rofecoxib to rats and a variety of endpoints were examined that included serum levels of inflammatory cytokines, histologic evaluati...

Although AAV vectors show promise for hepatic gene therapy, the optimal transcriptional regulatory elements have not yet been identified. In this study, we show that an AAV vector with the CMV enhancer/chicken b -actin promoter results in 9.5-fold higher expression after portal vein injection than an AAV vector with the EF1a promoter, and 137-fold higher expression than an AAV vector with the CMV promoter/enhancer. Although induction of the acute-phase response with the administration of lipopolysaccharide (LPS) activated the CMV promoter/enhancer from the context of an adenoviral vector in a previous study, LPS resulted in only a modest induction of this promoter from an AAV vector in vivo. An AAV vector with the CMV-b -actin promoter upstream of the coagulation protein human factor X (hFX) was injected intravenously into neonatal mice. This resulted in expression of hFX at 548 ng/ml (6.8% of normal) for up to 1.2 years, and 0.6 copies of AAV vector per diploid genome in the liver at the time of sacrifice. Neonatal intramuscular injection resulted in expression of hFX at 248 ng/ml (3.1% of normal), which derived from both liver and muscle. We conclude that neonatal gene therapy with an AAV vector with the CMV-b -actin promoter might correct hemophilia due to hFX deficiency.

Objective: To determine resting energy expenditure (REE) by indirect calorimetry and to compare measured resting energy expenditure (mREE) by indirect calorimetry with prediction equations (pREE). Material and method: Infants and young children with chronic lung diseases from King Chulalongkorn Memorial Hospital were enrolled and assessed for nutritional status and severity of chronic lung diseases. For mREE, indirect calorimetry was performed by custom-made airtight canopy with O2 and CO2 sensors, with the patients were in a resting state. Prediction equations were Food and Agriculture/World Health Organization/United Nations University (FAO/WHO/UNU), Schofield-Weight, Schofield-Weight/Height, Harris Benedict, and Harris Benedict-Infant equations. Agreement between mREE and pREE was assessed by Bland-Altman method. Results: Eighteen patients (median age 6 months, range 1 to 26 months) were recruited. Sixteen children had weight for age Z-score below -2 SD. Median weight for age Z-score, length for age Z-score and weight for length Z-score were -3.0, -3.1, and -1.9, respectively. Median mREE was 53.8 kcal/kg/day (interquartile range 47.5 to 72.6 kcal/kg/day). The Schofield-Weight/Height equation showed the lowest mean of difference at 0.94 kcal/kg/day with 95% confidence interval for the bias -44.4 to 46.3 kcal/kg/day. Conclusion: To ensure optimal nutritional support, REE should be measured by indirect calorimetry in pediatric patients with chronic lung diseases. Based on our finding, the Schofield-Weight/Height equation was the most accurate equation for predicting REE in this group of patients.

C-reactive protein (CRP) is a positive major acute-phase protein in dogs and can be used as a predictive marker for risk of disease and to monitor the response to treatment. Increased concentrations in certain diseases are associated with poor outcome. This cross-sectional, observational study of 75 dogs naturally infected with Babesia rossi was designed to examine the relationship between outcome and CRP concentration at admission and the magnitude of CRP change 24 hours after admission. Diagnosis was confirmed by polymerase chain reaction (PCR) and reverse line blot. CRP concentrations were determined by an automated human CRP Turbidometric Immunoassay, previously validated for use in dogs. There was no significant difference in mean CRP concentration between survivors (n=57), 107.5 ± 49.5 mg/ℓ and non-survivors (n=11), 122.1 ± 64.6 mg/ℓ at admission and using the exact logistic regression, adjusting for age and sex, there was no association with outcome (P = 0.53). Multiple regre...

Major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFNgamma), may play a crucial role in the immune and acute phase response in depression. Lower serum zinc and changes in the erythron are indirect indicators of IRS activation in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain led us to hypothesize that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression. The IRS activation model of depression provides an explanation for the psycho-social (external stress) as well as or...

Background. Among older people, distraction while walking may increase the risk of falls. Factors underlying individual differences in dual tasking are not fully understood. Our aim was to study the effect of a second task on maximal walking speed and to examine whether individual differences in walking speed measured with and without a second task are accounted for by genetic and environmental influences shared across tasks or specific to each task. Methods. The data were collected from the 101 monozygotic and 116 dizygotic twin pairs aged 63-76 years recruited from the Finnish Twin Cohort. Maximal walking speed (MWS) over 10 m was measured on a laboratory corridor and timed with photocells. The test was repeated while subjects performed, first, a manual task (MWSmanual) and, second, a verbal task (MWSverbal). Results. Mean walking speed without a simultaneous task was 1.72 m/s (standard deviation [SD] 0.33), with a manual task it was 1.52 m/s (SD 0.26), and with a verbal task it was 1.36 m/s (SD 0.27). Multivariate genetic analysis showed that an additive genetic factor in common accounted for 17% of individual differences in MWS, 19% in MWSmanual, and 12% in MWSverbal. In addition, MWSverbal had a genetic factor specific to it accounting for 10% of the variance. Shared environmental influences, common to all three traits, accounted for 39%, 27%, and 21% of the individual differences, respectively. Approximately half of the individual differences in walking with or without another task were accounted for by genetic and nongenetic familial effects in common, and the rest of the variation was accounted for by unique environmental factors in common and factors specific to walking tests.

Background -Because surgery involving cardiopulmonary bypass induces a sys- temic inflammatory response, the effect of cardiopulmonary bypass on nitric oxide (NO) generation was investigated in human lung tissue. Methods -Nitric oxide synthase (NOS) activity was measured by the conversion of '4C-L-arginiine to "4C-L-citrulline in tissue biopsy samples obtained before and after cardiopulmonary bypass. Results -The Ca2"-independent pro- duction of NO found before cardiopulmonary bypass was extremely low (1 5 (0.5) pmol citrulline/mg/min), but was in- creased after the bypass operation (23.6 (11) pmollmg/min). Conclusions -Ca2"-independent NOS ac- tivity was detected in human lung after cardiopulmonary bypass. This finding may provide an important insight into the pathogenesis of the tissue damage and acute phase response observed after such surgery.

Amyloidosis remains currently a severe potential complication of many chronic inflammatory disorders. It is not exactly know why some patients develop a progressive amyloidosis, whereas others do not although latent deposits may be present. A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis. Genetic factors have however been recently emphasized. Among persistent or emerging causes of AA amyloidosis, hereditary periodic fever syndromes also known as auto-inflammatory syndromes are a group of diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases. Amyloid was first described in the nineteenth century as an extracellular material found in tissues of patients affected with chronic infectious diseases [1]. Amyloid has then been observed in various clinical settings leading to a first clinical classification of amyloidoses, which are the diseases associated with amyloid deposits. Four main entities were thus recognized: primary amyloidosis (i.e. amyloidosis without any detectable infectious cause, secondary amyloidosis (to an infectious disease), hereditary and localized types. A dramatic change in our knowledge of amyloid occurred in 1971, when Glenner showed that the main protein constituent of amyloid in primary amyloidosis was derived from a light

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BACKGROUND: The acute phase response is beneficial to theanimal in restoring homeostasis, and measuring the circulatingacute phase proteins, cytokines, and enzymes can be used toevaluate the innate immune system&#39;s responses to invader agentssuch as bacterial lipopolysaccharide. Measurement of theseparameters has shown to be useful as diagnostic and prognosticmarkers in animal endotoxemia. OBJECTIVES: The aim of thepresent experimental study was expression of the acute phaseresponse following the induction of endotoxemia by Escherichiacoli serotype O55:B5 in sheep and the relationships among the acutephase response parameters during endotoxemia and their changingpatterns. METHODS: Five clinically healthy 1-year-old Iranian fattailedewes (25±1.5 kg, bodyweight) were randomly selected andlipopolysaccharide from Escherichia coli serotype O55:B5 wasinfused at 20 μg/kg intravenously to each animal. Fluid therapy wasperformed in all ewes over 120 minutes after lipopolysaccharideinjecti...

Immune neuroendocrine interactions are vital for the individual’s survival in certain physiopathological conditions, such as sepsis and tissular injury. It is known that several animal venoms, such as those from different snakes, are potent neurotoxic compounds and that their main component is a specific phospholipase A type 2 (PLA2). It has been described recently that the venom from Crotalus durissus terrificus [snake venom (SV), in the present study] possesses some cytotoxic effect in different in vitro and in vivo animal models. In the present study, we investigated whether SV and its main component, PLA2 (obtained from the same source), are able to stimulate both immune and neuroendocrine functions in mice, thus characterizing this type of neurotoxic shock. For this purpose, several in vivo and in vitro designs were used to further determine the sites of action of SV-PLA2 on the hypothalamo-pituitary-adrenal (HPA) axis function and on the release of the pathognomonic cytokine, ...

This study investigated whether lipoprotein(a) [Lp(a)] is an acute-phase reactant that can cause important bias in risk factor analysis for coronary heart disease among patients with an acute-phase response (APR patients). To determine whether serum Lp(a) concentrations increase among APR patients, we compared the Lp(a) concentrations and apolipoprotein(a) [apo(a)] phenotypes of 100 controls with those of a random sampling of 100 APR patients. Serum Lp(a) concentration was measured by ELISA; Lp(a) phenotyping was performed by electrophoresis on sodium dodecyl sulfate–polyacrylamide gel. Lp(a) was significantly (P &lt;0.0001) higher among APR patients (mean ± SD 0.300 ± 0.284 g/L) than among controls (0.118 ± 0.193 g/L) even though the distribution of apo(a) phenotypes did not differ significantly. The 100 APR patients were grouped into 4 categories: 48 patients with infections, 25 postoperative patients, 17 patients with tumors, and 10 patients with other diseases, all of whom showe...

Introduction: Low Carbohydrate High Protein diet represents a popular strategy to achieve weight loss. Objective: The aim of this study was to characterize effects of low carbohydrate, high protein diet (LCHP) on atherosclerotic plaque development in brachiocephalic artery (BCA) in apoE/LDLR-/mice and to elucidate mechanisms of proatherogenic effects of LCHP diet. Materials and Methods: Atherosclerosis plaques in brachiocephalic artery (BCA) as well as in aortic roots, lipoprotein profile, inflammation biomarkers, expression of SREBP-1 in the liver as well as mortality were analyzed in Control diet (AIN-93G) or LCHP (Low Carbohydrate High Protein) diet fed mice. Results: Area of atherosclerotic plaques in aortic roots or BCA from LCHP diet fed mice was substantially increased as compared to mice fed control diet and was characterized by increased lipids and cholesterol contents (ORO staining, FT-IR analysis), increased macrophage infiltration (MOMA-2) and activity of MMPs (zymography). Pro-atherogenic phenotype of LCHP fed apoE/ LDLR-/mice was associated with increased plasma total cholesterol concentration, and in LDL and VLDL fractions, increased TG contents in VLDL, and a modest increase in plasma urea. LCHP diet increased SCD-1 index, activated SREBP-1 transcription factor in the liver and triggered acute phase response as evidence by an increased plasma concentration of haptoglobin, CRP or AGP. Finally, in long-term experiment survival of apoE/LDLR-/mice fed LCHP diet was substantially reduced as compared to their counterparts fed control diet suggesting overall detrimental effects of LCHP diet on health. Conclusions: The pro-atherogenic effect of LCHP diet in apoE/LDLR-/mice is associated with profound increase in LDL and VLDL cholesterol, VLDL triglicerides, liver SREBP-1 upregulation, and systemic inflammation.

Background: In previous comparisons of inflammatory and stress responses to open (OR) and laparoscopic (LR) hernia repair, all operations were performed under general anesthesia. Since local anesthesia is widely used for OR, a comparison of this approach with LR seemed relevant. Methods: Patients with recurrent inguinal hernia were randomized to OR under local anesthesia (n = 30) or LR under general anesthesia (n = 31). The magnitude of the surgical trauma was assessed by measuring markers of coagulation (prothrombin fragment 1 + 2), endothelial activation (von Willebrand factor), inflammation [leukocytes, interleukin-6,-8 and-10, granulocyte macrophage colony-stimulating factor, and C-reactive protein (CRP)], and endocrine stress (cortisol) in blood collected before operation, 4 h postincision, and on postoperative day 2. Results: Leukocyte counts and interleukin-6 and CRP levels increased in both groups, with the CRP increase being significantly greater in the OR group. The other markers did not increase significantly. Conclusion: The acute phase response was more pronounced after OR, even when this was done under local anesthesia. Both techniques seemed rather atraumatic.

ABSTRACTThe acute‐phase response is associated with profound effects on oxidative drug metabolism. However, the effects on glucuronidation are poorly characterized. The aim of the present study was to determine the role of mediators of the acute‐phase response in the regulation of hepatic uridine diphosphate glucuronosyltransferase (UGT) expression. Family 1 and family 2 UGT isoforms were studied in turpentine‐injected rats and in primary hepatocyte cultures exposed to cytokines and/or dexamethasone. In the in vivo model, glucuronidation of p‐nitrophenol was unaffected, while testosterone glucuronidation was reduced to 65% of control (P &lt; 0.01). In contrast, the mRNA level of UGT1*1 (which metabolizes bilirubin, not phenols) was depressed to 16% of control (P &lt; 0.002), while the mRNA level of UGT2B3 (which metabolizes testosterone) was reduced to 53% (P &lt; 0.05). In primary hepatocyte culture, dexamethasone treatment resulted in a 3.4‐fold induction of UGT1*1 mRNA levels (P ...

Fibrinogen-β (FBG-β), an important acute phase protein (APP), is generated by the liver as a target for inflammatory mediators. Here, we have identified FBG-β as a hepatitis C virus (HCV) core interacting protein by screening a human liver cDNA library using mammalian two-hybrid analysis. An association between FBG-β and HCV core protein was verified by confocal microscopy and coimmunoprecipitation from transfected human hepatocyte (Huh-7) cell line. HCV core or genomic RNA transfected Huh-7 cells modestly increased FBG-β protein expression when compared to the basal level in control hepatocytes. Transfection of HCV core or full-length (FL) gene into Huh-7 cells upegulated basal FBG-β promoter activity. Exogenous addition of IL-6 stimulates FBG-β promoter activity in hepatocytes. However, ectopic expression of HCV core or FL in hepatocytes inhibited IL-6 stimulated FBG-β promoter activation. Inhibition of endogenous FBG-β expression following introduction of siRNA into cells displayed a gain of function of promoter regulation by HCV core protein. Further studies suggested that HCV core gene expression in stable transfectants of Huh-7 cells resulted in a basal upregulation of FBG-β, and other APPs. However, treatment with cytokines, IL-6 or TNF-α, repressed FBG-β and other acute phase response (APR) genes. Conclusion: Our results reveal that the core/FBG-β interaction may act as a regulatory feedback, allowing repression of IL-6 stimulated APR genes. Together, these data suggested a network of interactions between HCV core and the hepatic APR genes, and may contribute to impaired innate immunity for viral persistence.

Fibrinogen-β (FBG-β), an important acute phase protein (APP), is generated by the liver as a target for inflammatory mediators. Here, we have identified FBG-β as a hepatitis C virus (HCV) core interacting protein by screening a human liver cDNA library using mammalian two-hybrid analysis. An association between FBG-β and HCV core protein was verified by confocal microscopy and coimmunoprecipitation from transfected human hepatocyte (Huh-7) cell line. HCV core or genomic RNA transfected Huh-7 cells modestly increased FBG-β protein expression when compared to the basal level in control hepatocytes. Transfection of HCV core or full-length (FL) gene into Huh-7 cells upegulated basal FBG-β promoter activity. Exogenous addition of IL-6 stimulates FBG-β promoter activity in hepatocytes. However, ectopic expression of HCV core or FL in hepatocytes inhibited IL-6 stimulated FBG-β promoter activation. Inhibition of endogenous FBG-β expression following introduction of siRNA into cells displayed a gain of function of promoter regulation by HCV core protein. Further studies suggested that HCV core gene expression in stable transfectants of Huh-7 cells resulted in a basal upregulation of FBG-β, and other APPs. However, treatment with cytokines, IL-6 or TNF-α, repressed FBG-β and other acute phase response (APR) genes. Conclusion: Our results reveal that the core/FBG-β interaction may act as a regulatory feedback, allowing repression of IL-6 stimulated APR genes. Together, these data suggested a network of interactions between HCV core and the hepatic APR genes, and may contribute to impaired innate immunity for viral persistence.

In order to gain a better understanding of the molecular processes that underlie apoptosis and tissue regression in mammary gland, we undertook a large-scale analysis of transcriptional changes during the mouse mammary pregnancy cycle, with emphasis on the transition from lactation to involution. Affymetrix microarrays, representing 8618 genes, were used to compare mammary tissue from 12 time points (one virgin, three gestation, three lactation and five involution stages). Six animals were used for each time point. Common patterns of gene expression across all time points were identified and related to biological function. The majority of significantly induced genes in involution were also differentially regulated at earlier stages in the pregnancy cycle. This included a marked increase in inflammatory mediators during involution and at parturition, which correlated with leukaemia inhibitory factor-Stat3 (signal transducer and activator of signalling-3) signalling. Before involution...

I In nt tr ro od du uc ct ti io on n: : This study investigates the course of blood cytokine levels and CRP in patients with rheumatoid arthritis (RA) undergoing total knee replacement (TKR). Additionally, we set out to examine the relationship between cytokines IL-6, TGF-β1 and CRP and parameters such as body temperature, tourniquet time and blood loss. M Ma at te er ri ia al l a an nd d m me et th ho od ds s: : The study concerns 40 patients with RA undergoing total knee replacement (TKR). Operative and postoperative details were recorded, including circulation, ventilation, body temperature, tourniquet time under operation and postoperative blood loss. Peripheral vein blood was serially sampled; the first was obtained before anaesthesia and next at 6, 12, 24, 36 h after the end of surgery. IL-6, TGF-β1 and CRP were evaluated in blood and at the same time body temperature (°C) was measured. R Re es su ul lt ts s: : In patients with RA undergoing TKR under regional anaesthesia, the levels of IL-6 and TGF-β1 in the peripheral blood were not significantly changed compared with the levels before operation. The rise of CRP protein concentration was achieved at first 36 h postoperatively. No significant changes in serum IL-6, TGF-β1 and CRP levels with regard to tourniquet time were found. The volume of blood loss was not associated with changes in cytokine and CRP blood concentrations either. A correlation between postoperative CPR levels and temperature was found. The body temperature remained elevated up to 36 h postoperatively. C Co on nc cl lu us si io on ns s: : Our data indicate that high production of cytokines (IL-6, TGF-β1) present in chronic inflammation prevents further enhancement of cytokine synthesis triggered by surgery. The rise of CRP concentrations postoperatively and the significant correlation between CRP and temperature were addressed. The postoperative rise of temperature in the first 3 days following TKR may be a normal physiological response. K Ke ey y w wo or rd ds s: : inflammatory response, orthopaedic surgery, rheumatoid arthritis.

We have isolated from calf serum a protein with an apparent M r of 120,000. The protein was detected by using antibodies against major acute-phase protein in pigs with acute inflammation. The amino acid sequence of an internal fragment revealed that this protein is the bovine counterpart of ITIH4, the heavy chain 4 of the inter-alpha-trypsin inhibitor family. The response of this protein in the sera was determined for animals during experimental bacterial and viral infections. In the bacterial model, animals were inoculated with a mixture of Actinomyces pyogenes , Fusobacterium necrophorum , and Peptostreptococcus indolicus to induce an acute-phase reaction. All animals developed moderate to severe clinical mastitis and exhibited remarkable increases in ITIH4 concentration in serum (from 3 to 12 times the initial values, peaking at 48 to 72 h after infection) that correlated with the severity of the disease. Animals with experimental infections with bovine respiratory syncytial viru...

Preeclampsia is an inflammatory-mediated hypertensive disorder of pregnancy and seems to be an early indicator of increased cardiovascular risk, but mechanisms underlying this association are unclear. In this study, we identified levels of circulating inflammatory markers and dynamic changes in the systemic acute-phase response in 44 women with a history of severe early-onset preeclampsia, compared with 29 controls with only uneventful pregnancies at 1.5 to 3.5 years postpartum. Models used were in vivo seasonal influenza vaccination and in vitro whole-blood culture with T-cell stimulants and the toll-like receptor-4 ligand lipopolysaccharide. Outcome measures were C-reactive protein, interleukin-6 (IL-6), IL-18, fibrinogen, myeloperoxidase, and a panel of 13 cytokines representative of the innate and adaptive inflammatory response, in addition to established cardiovascular markers. The in vivo acute-phase response was higher for women with previous preeclampsia than that for contro...

Background: Accurate outcome prediction in gastroesophageal malignancies is challenging. Acute-phase response proteins (APRPs) have been claimed to be independent prognosticators, although the basis for their association with prognosis remains unexplained. We hypothesized that, similarly to pancreatic and lung cancers, changes in APRPs in gastroesophageal malignancies are associated with cachexia and accelerated angiogenesis. Methods: C-reactive protein (CRP), albumin and transferrin serum levels were evaluated and the Glasgow Prognostic Score (GPS) calculated. These data were compared with concentrations of circulating interleukin (IL)-1, IL-6 and IL-8, tumor necrosis factor-a (TNF-a), vascular endothelial growth factor (VEGF)-A, VEGF-C and midkine in 96 gastroesophageal cancer patients (49 with cachexia) and 42 healthy subjects. Results: Albumin and CRP levels were altered in the cancer patients, with further CRP elevation in those with cachexia. Transferrin was decreased only in the cachectic patients. The interrelationships between the APRPs were strengthened in cachexia and only then were APRPs correlated with the cytokines elevated in gastroesophageal cancer-related cachexia: IL-6, IL-8, VEGF-A and midkine. GPS corresponded well to transferrin, IL-1, IL-6, IL-8, TNF-a, VEGF-A and midkine concentrations. Conclusions: Cachexia in gastroesophageal cancers is associated with changes in APRP concentrations. This, together with a direct relationship of APRPs with accelerated angiogenesis, may constitute a founda

Background. Among older people, distraction while walking may increase the risk of falls. Factors underlying individual differences in dual tasking are not fully understood. Our aim was to study the effect of a second task on maximal walking speed and to examine whether individual differences in walking speed measured with and without a second task are accounted for by genetic and environmental influences shared across tasks or specific to each task. Methods. The data were collected from the 101 monozygotic and 116 dizygotic twin pairs aged 63-76 years recruited from the Finnish Twin Cohort. Maximal walking speed (MWS) over 10 m was measured on a laboratory corridor and timed with photocells. The test was repeated while subjects performed, first, a manual task (MWSmanual) and, second, a verbal task (MWSverbal). Results. Mean walking speed without a simultaneous task was 1.72 m/s (standard deviation [SD] 0.33), with a manual task it was 1.52 m/s (SD 0.26), and with a verbal task it was 1.36 m/s (SD 0.27). Multivariate genetic analysis showed that an additive genetic factor in common accounted for 17% of individual differences in MWS, 19% in MWSmanual, and 12% in MWSverbal. In addition, MWSverbal had a genetic factor specific to it accounting for 10% of the variance. Shared environmental influences, common to all three traits, accounted for 39%, 27%, and 21% of the individual differences, respectively. Conclusion. Approximately half of the individual differences in walking with or without another task were accounted for by genetic and nongenetic familial effects in common, and the rest of the variation was accounted for by unique environmental factors in common and factors specific to walking tests.

The objective of this study was to evaluate the acute phase response (APR) in cloned pigs derived from two different cell lines [C1 (n = 2) and C2 (n = 7)] as compared to genetically similar non-cloned pigs (CONT; n = 11) following a lipopolysaccharide (LPS; 25 g/kg BW) challenge. Pigs were weaned at 21 days of age and maintained in individual pens in the same room until sample collection approximately 1 week later. Blood samples were collected every 30 min for 2 h prior to and 4 h after the LPS challenge. Serum samples were analyzed for cortisol, tumor necrosis factor-alpha (TNF-␣) and interleukin 6 (IL-6). Average gestational length for cloned pigs, 118.8 ± 0.97 days, was longer (P < 0.005) than that of CONT pigs, 114 ± 0.41 days. For serum cortisol, there was a time by group interaction (P < 0.0001) such that the cortisol response was greater in CONT pigs as compared to C2 pigs (P < 0.0001), but not different from C1 pigs (P > 0.74). A time by group interaction (P < 0.0001) was observed for serum TNF-␣ such that the TNF-␣ response was greater in CONT pigs as compared to C2 pigs (P = 0.0002) and tended to be greater (P < 0.06) than C1 pigs. A time by group interaction (P < 0.0001) was also observed for serum IL-6 such that the serum IL-6 response was greater (P < 0.003) in CONT pigs as compared to C2 pigs and there was a trend (P = 0.10

There are no existing treatments for the long-term degenerative effects of traumatic brain injury (TBI). This is due, in part, to our limited understanding of chronic TBI and uncertainty about which proposed mechanisms for long-term neurodegeneration are amenable to treatment with existing or novel drugs. Here, we used microarray and pathway analyses to interrogate TBI-induced gene expression in the rat hippocampus and cortex at several acute, subchronic and chronic intervals (24 hours, 2 weeks, 1, 2, 3, 6 and 12 months) after parasagittal fluid percussion injury. We used Ingenuity pathway analysis (IPA) and Gene Ontology enrichment analysis to identify significantly expressed genes and prominent cell signaling pathways that are dysregulated weeks to months after TBI and potentially amenable to therapeutic modulation. We noted long-term, coordinated changes in expression of genes belonging to canonical pathways associated with the innate immune response (i.e., NF-κB signaling, NFAT signaling, Complement System, Acute Phase Response, Toll-like receptor signaling, and Neuroinflammatory signaling). Bioinformatic analysis suggested that dysregulation of these immune mediators-many are key hub genes-would compromise multiple cell signaling pathways essential for homeostatic brain function, particularly those involved in cell survival and neuroplasticity. Importantly, the temporal profile of beneficial and maladaptive immunoregulatory genes in the weeks to months after the initial TBI suggests wider therapeutic windows than previously indicated.

The objective of the present study was to evaluate the efficacy of a J-5 Escherichia coli vaccine in a mild to moderate inflammatory challenge model using primiparous dairy cows for inoculation only. We hypothesized a clinical difference between placebo and J-5 E. coli vaccinated animals with the mild to moderate inflammatory challenge model. In case the null hypothesis could not be confirmed, the alternate hypothesis was no clinical difference between both treatment groups. Therefore, 23 primiparous cows in mo 7 of pregnancy were randomly assigned to 1 of 2 treatment groups: J-5 E. coli vaccine (n = 12) or placebo (n = 11). Animals were vaccinated 3 times at 56 (±7) and 28 (±7) d before expected calving date and within 14 d postcalving (DIM 5 ± 3). All cows were challenged by infusion with E. coli P4: O32 into 2 left mammary quarters between 14 and 28 d postparturition, at least 10 d after the 3rd vaccination, immediately after the morning milking. Clinical observations and blood and milk samples were collected at several time points from 7 d pre-challenge until 13 d post-challenge. Primiparous cows responded mild to moderately to intramammary E. coli challenge with little clinical difference between treatment groups. Rectal temperature increased earlier in the vaccinated animals, which also eliminated bacteria faster during the early hours after intramammary E. coli challenge. At post-infusion hour 9, the bacterial population was significantly lower in the infected quarters of the vaccinated animals. Blood leukocyte number was only numerically higher in the vaccinated animals, in combination with a numerically higher percentage of late immature polymorphonuclear leukocytes (band cells) in circulation. Even in the nonvaccinated animals, the E. coli challenge in the primiparous cows elicited only a mild to moderate response. The absence of a pronounced clinical difference between vaccinated and nonvaccinated animals was therefore not surprising.

Escherichia coli intramammary infection elicits localized and systemic responses, some of which have been characterized in mammary secretory tissue. Our objective was to characterize gene expression patterns that become activated in different regions of the mammary gland during the acute phase of experimentally induced E. coli mastitis. Tissues evaluated were from Fürstenburg's rosette, teat cistern (TC), gland cistern (GC), and lobulo-alveolar (LA) regions of control and infected mammary glands, 12 and 24 h after bacterial (or control) infusions. The main networks activated by E. coli infection pertained to immune and inflammatory response, with marked induction of genes encoding proteins that function in chemotaxis and leukocyte activation and signaling. Genomic response at 12 h post-infection was greatest in tissues of the TC and GC. Only at 24 h post-infection did tissue from the LA region respond, at which time the response was the greatest of all regions. Similar genetic networks were impacted in all regions during early phases of intramammary infection, although regional differences throughout the gland were noted. Data support an important sentinel function for the teat, as these tissues responded rapidly and intensely, with production of cytokines and antimicrobial peptides.

Tick bites may trigger acute phase responses. Positive and negative acute phase proteins were measured in infested cattle genetically resistant and susceptible to ticks. During heavier infestations levels of haptoglobin increased significantly in susceptible bovines; levels of serum amyloid A increased in resistant bovines; levels of alpha-1-acid glycoprotein decreased significantly in resistant bovines; levels of transferrin decreased significantly in susceptible bovines. In conclusion, tick infestations trigger acute phase responses and enhancement of specific acute phase proteins differs according to the genetic composition of hosts. Acute phase proteins may constitute useful biological signatures for monitoring the stress induced by tick infestations.

Toxic oil syndrome (TOS) was caused by the consumption of rapeseed oil contaminated with derivatives of aniline. Many persons who survived the acute phase developed a puzzling, multi-year chronic disease considered to be inflammatory or autoimmune in nature. In attempting to characterize their autoantibodies, we found that 74% of TOS patients with chronic disease had IgG antibodies to C-reactive protein (CRP). This activity was detectable only when CRP was chemically or physically denatured and behaved like a previously described antibody produced by immunization with the CRP monomer. Significant antibody reactivities to other acute phase proteins, especially 1-antitrypsin and fibrinogen (P<0•025) and ceruloplasmin (P<0•05) were also observed. IgG antibodies to cryptic epitopes in CRP and other major serum proteins that increase during the acute phase response may reflect an earlier toxin-mediated insult to the liver that included abnormal biosynthesis of and/or damage to acute phase proteins.

Objectives: The acute phase response (APR) influences indicators of iron status. A recent WHO/CDC consultation recommended concurrent measurement of a-1-acid-glycoprotein (AGP) in surveys to control for the APR, and aid in interpreting iron status. They proposed further exploratory analyses using AGP. We examined whether the APR (measured by AGP) influences the expected relationships between iron status indicators in an HIV-infected population. Subjects: We measured hemoglobin (Hb), serum ferritin (SF), transferrin receptor (TfR), erythropoietin (EPO) and AGP in a crosssectional survey of 643 HIV-positive Zimbabwean women. Results: SF was significantly higher in APR-positive (AGP41 g/l) women (Po0.001), in whom there was no association between SF and Hb. TfR was inversely associated with Hb, in both APR-positive and APR-negative women (Po0.001). However, among anemic women (Hbo110 g/l), APR-positive women had marginally lower TfR concentrations (P ¼ 0.053). There was no difference in EPO response to decreasing Hb among APR-positive and APR-negative women. Conclusions: AGP captured the influence of the APR on iron indicators and their relationships with each other. The APR influenced SF and its relationship with Hb as expected. TfR behaved unexpectedly. Although TfR has been promoted as an iron indicator that is uninfluenced by the APR, TfR concentrations were depressed among anemic APR-positive women. Because TfR reflects iron deficiency and erythropoietic activity, pro-inflammatory cytokines associated with the APR may be inhibiting erythropoeisis, which is reflected by lower TfR concentrations. We support the WHO/CDC recommendation that AGP is a useful indicator to assess the influence of the APR on iron status indicators.

In experimental studies on the common human coxsackievirus B type 3 (CB3) infection, administered cadmium (Cd) is known to accumulate in the liver and kidneys. CB3 adapted to Balb/c mice was used to study whether infection affects the Cd-binding protein, metallothionein (MT) and if this alters the normal physiological trace element balance in the liver, kidney, spleen and brain. On day 3 of infection, degradation of liver proteins (44%, P < 0.01) occurred, whereas in the spleen, protein increased (63%, P < 0.05). The infection increased MT five-fold (P < 0.01) in liver and kidneys, and in spleen by 34% (P < 0.05). A redistribution of Cd and copper (Cu) from the liver to the kidney was associated with this increase in MT, resulting in an increased (P < 0.01) kidney/liver ratio for both elements. The infection increased the zinc (Zn) concentration more in the kidney than in the liver, but the kidney/liver ratio was not significantly affected. Results show that MT is increased in several organs during the early phase of infection and is associated with redistribution of both essential and non-essential trace elements. This may be a normal response in common infections that could adversely influence the pathogenesis when the host is concomitantly exposed to potentially toxic trace elements, even at levels in the physiological range.

In experimental studies on the common human coxsackievirus B type 3 (CB3) infection, administered cadmium (Cd) is known to accumulate in the liver and kidneys. CB3 adapted to Balb/c mice was used to study whether infection affects the Cd-binding protein, metallothionein (MT) and if this alters the normal physiological trace element balance in the liver, kidney, spleen and brain. On day 3 of infection, degradation of liver proteins (44%, P < 0.01) occurred, whereas in the spleen, protein increased (63%, P < 0.05). The infection increased MT five-fold (P < 0.01) in liver and kidneys, and in spleen by 34% (P < 0.05). A redistribution of Cd and copper (Cu) from the liver to the kidney was associated with this increase in MT, resulting in an increased (P < 0.01) kidney/liver ratio for both elements. The infection increased the zinc (Zn) concentration more in the kidney than in the liver, but the kidney/liver ratio was not significantly affected. Results show that MT is increased in several organs during the early phase of infection and is associated with redistribution of both essential and non-essential trace elements. This may be a normal response in common infections that could adversely influence the pathogenesis when the host is concomitantly exposed to potentially toxic trace elements, even at levels in the physiological range.

Transportation is an inevitable husbandry practice which animals encounter in the livestock industry and raises considerable interest both in economic and animal welfare terms. With respect to the growing interest in using acute phase proteins as health and welfare indicators, the aim of the present study was to investigate the impact of road transportation on the concentrations of fibrinogen, haptoglobin, serum amyloid A, and ceruloplasmin in Iranian dromedary camels. Ten clinically healthy Iranian dromedary camels, five males and five females, were selected and subjected to a journey of approximately 300 km in a truck by road during the late summer. Blood samples were collected immediately before loading at 8:30 A.M., after 1 h transportation, at 9:30 A.M., and at the end of the journey after unloading at 1:30 PM. A final blood sample was taken 24 h after arrival. Blood concentrations of plasma proteins, including fibrinogen, haptoglobin, serum amyloid A, ceruloplasmin, total protein, and albumin, were measured using validated methods. Mean basal pretransport concentrations of fibrinogen (3.10±0.47 g/l), haptoglobin (0.3 ± 0.04 g/l), serum amyloid A (9.77 ± 0.62 μg/ml), and ceruloplasmin (0.096±0.01 g/l) did not change significantly during and after road transportation. In addition, transportation had no significant effects on basal plasma concentrations of total protein (60.8±6.1 g/l) and albumin (38.3±2.1 g/l). No significant difference was observed in any parameter between sexes at each sampling time. We conclude that stressful conditions during the journey under hot summer environmental conditions were not severe enough to trigger an acute phase response. The value of the investigated plasma parameters as welfare indicators in dromedary camel over short transportation would be limited. Taken together, this plasma protein profile may be of value for future research on acute phase proteins as potential markers of health and welfare and to develop a baseline for practical applications in dromedary camels.

Purpose-To compare cardiac muscle cells width and cardiomyocyte lipofuscin pigment presence between malnourished and non-malnourished necropsied adults. Methods-Out of 315 necropsy protocols of adults randomly chosen, those with edema, ascitis, systemic arterial hypertension, chronic liver disease, and heart disease were excluded. Malnutrition was defined by body mass index (BMI) <17kg/m 2. Cardiomyocytes morphometry study and lipofuscin pigment counts were performed. Results-Malnourished (n=8) and controls (n=4), respectively, showed statistical differences in relation to BMI (14.86±1.13 vs 22.02±0.9kg/m 2), heart weight/body weight ratio (0.68±0.09 vs 0.54±0.07%), cardiomyocytes width (10.91±0.77 vs 12.90±1.82µm) and lipofuscin pigment presence (39.1 vs 54.4%). Conclusion-When compared with controls, necropsied malnourished adults showed decreased myocardial fibers diameters and lower lipofuscin pigment presence. These findings might reflect altered metabolism, and would be associated with harmful clinical effects in terminally ill patients.