Production Of Acute Phase Reactants Research Articles

MODERN VIEWS ON THE PATHOGENESIS OF IMMUNE DYSFUNCTION AGAINST THE BACKGROUND OF THE METABOLIC SYNDROME IN ISCHEMIC HEART DISEASE

Introduction. Today, the pathology of the cardiovascular system is one of the most common and fatal diseases. Cardiovascular diseases are the cause of disability among the younger and younger population. Taking into account the frequency of cardiovascular diseases, the severity of the course and their lethality, the study of this topic remains one of the most urgent problems of medicine, in particular cardiology.
 The aim of the study. Consider modern views on the pathogenesis of coronary heart disease against the background of metabolic syndrome and the role of the immune system.
 Conclusions. Ischemic heart disease is the leading cause of mortality in Ukraine and the world. In recent years, there has been convincing evidence of a significant prevalence of cardiovascular disease in patients with metabolic syndrome. The presence of concomitant metabolic syndrome in patients with coronary heart disease worsens the course of the underlying disease and has an unfavorable prognosis, and even fatal cases.
 Therefore, the detection of an increase in the level of body mass index, dyslipidemia, hyperglycemia, arterial hypertension in a patient strengthens the effects of each other, that is, they have a synergistic effect, and in general, the risk of developing CHD becomes quite high.
 IL-6 is one of the cytokines released by both macrophages and adipocytes and its levels have been shown to be increased in insulin resistance and obesity. In fact, IL-6 is known to regulate fat and glucose metabolism, mediating insulin resistance through various complex mechanisms. This cytokine acts on various tissues, leading to the metabolic effects of obesity. In the liver, IL-6 increases the production of acute phase reactants, including CRP. Several studies have demonstrated that high CRP levels have the strongest correlation with cardiac events, T2DM, and MS. IL-6 also contributes to a prothrombotic state by increasing the level of fibrinogen, another acute phase reactant. In addition, IL-6 targets other tissues, such as endothelial cells, to promote the expression of vascular cell adhesion molecules, leading to vascular wall atherosclerosis, inflammation, and dysfunction.
 These data support the role of IL-6 in the development of insulin resistance, but do not support the hypothesis that IL-6 is involved in β-cell failure.
 IL-18 is a pro-inflammatory cytokine associated with insulin resistance and T2DM risk. IL-18 stimulates the production of gamma interferon (IFN-γ), which, in turn, is probably involved in the pathogenesis of atherosclerosis. IL-18 is a cytokine that is a predictor of metabolic syndrome.
 TNFα is another cytokine produced in adipose tissue, mainly from local macrophages, and its production also varies with adipose tissue mass and correlates with insulin resistance, both hallmarks of MS. TNFα exerts its pathogenic effects by disrupting insulin signaling in adipocytes and hepatocytes through serine phosphorylation and inactivation of insulin receptors and downstream signaling molecules, leading to decreased metabolic effects of insulin. TNFα also contributes to insulin resistance by inducing hepatic lipolysis.

"Usefulness of the Acute Phase Reactants (APR) Score: Early Detection of Delayed Onset of Sepsis in Extremely Low Birth Weight Infants by APR Score"

The production of acute phase reactants (APRs) in the liver is stimulated by increased inflammatory cytokines. Therefore, inflammatory cytokines are more advantageous than APRs for early diagnosis of neonatal sepsis. There is a machine Latessier TM that can produce results after about 3 minutes with a small amount of sample of 10 μL each at the same time of C-reactive protein (CRP), α1 acid glycoprotein (AGP), and haptoglobin (Hp).

Plasma proteome responses in zebrafish following λ-carrageenan-Induced inflammation are mediated by PMN leukocytes and correlate highly with their human counterparts.

Regulation of inflammation is a critical process for maintaining physiological homeostasis. The λ-carrageenan (λ-CGN) is a mucopolysaccharide extracted from the cell wall of red algae (Chondrus crispus) capable of inducing acute intestinal inflammation, which is translated into the production of acute phase reactants secreted into the blood circulation. However, the associated mechanisms in vertebrates are not well understood. Here, we investigated the crucial factors behind the inflammatory milieu of λ-CGN-mediated inflammation administered at 0, 1.75, and 3.5% (v/w) by i.p. injection into the peritoneal cavity of adult zebrafish (ZF) (Danio rerio). We found that polymorphonuclear leukocytes (neutrophils) and lymphocytes infiltrating the ZF peritoneal cavity had short-term persistence. Nevertheless, they generate a strong pattern of inflammation that affects systemically and is enough to produce edema in the cavity. Consistent with these findings, cell infiltration, which causes notable tissue changes, resulted in the overexpression of several acute inflammatory markers at the protein level. Using reversed-phase high-performance liquid chromatography followed by a hybrid linear ion-trap mass spectrometry shotgun proteomic approach, we identified 2938 plasma proteins among the animals injected with PBS and 3.5% λ-CGN. First, the bioinformatic analysis revealed the composition of the plasma proteome. Interestingly, 72 commonly expressed proteins were recorded among the treated and control groups, but, surprisingly, 2830 novel proteins were differentially expressed exclusively in the λ-CGN-induced group. Furthermore, from the commonly expressed proteins, compared to the control group 62 proteins got a significant (p < 0.05) upregulation in the λ-CGN-treated group, while the remaining ten proteins were downregulated. Next, we obtained the major protein-protein interaction networks between hub protein clusters in the blood plasma of the λ-CGN induced group. Moreover, to understand the molecular underpinnings of these effects based on the unveiled protein sets, we performed a bioinformatic structural similarity analysis and generated overlapping 3D reconstructions between ZF and humans during acute inflammation. Biological pathway analysis pointed to the activation and abundance of diverse classical immune and acute phase reactants, several catalytic enzymes, and varied proteins supporting the immune response. Together, this information can be used for testing and finding novel pharmacological targets to treat human intestinal inflammatory diseases.

A CROSS SECTIONAL STUDY AMONG BODY MASS INDEX AND SERUM FERRITIN LEVEL IN A TERTIARY CARE HOSPITAL, KOLKATA.

Introduction: The rising prevalence of overweight and obesity in India has resulted in an increased prevalence of obesity-related comorbidities. Obesity predisposes affected people to subclinical inammation. Adipose tissue is an active endocrine organ that increases the released of inammatory mediators in obesity. Serum ferritin is well known acute phase reactant and also marker of acute and chronic inammation. In this study we tried to evaluate whether obesity correlate with change in serum ferritin level or not in Indian population. Materials and Methods: This cross sectional observational study was conducted in department of biochemistry of NRS Medical College and Hospital from January 2021 to October 2021. 105 otherwise healthy participants were selected for this study, among them 60 are female and 45 are male. The participants were assessed for BMI and serum ferritin. Result: Correlation test was performed between BMI and serum ferritin of both group (male and female). Statistically signicant positive correlation was found between serum ferritin and BMI among the female participants (P Value-0.018, r-0.304). Correlation is signicant at the 0.05 level (2-tailed). Conclusion: In this study BMI was positively correlated with serum ferritin among female participants. Adipose tissue may play a vital role in the production of acute phase reactants like ferritin.

Marked Increased Production of Acute Phase Reactants by Skeletal Muscle during Cancer Cachexia.

Simple SummaryMuscle wasting during cancer is recognized as an independent predictor of mortality. The aim of this study was to characterize the changes in the muscle secretome associated with cancer cachexia to gain a better understanding of the mechanisms involved and to identify secreted proteins which may reflect this wasting process. Our study demonstrated that skeletal muscle is a source of several acute phase reactants during cancer cachexia that may hold the key to a cachexia-specific signature. Future work will have to determine whether some of these acute phase reactants contribute to and/or reflect the muscle atrophy caused by cancer, therefore representing potential therapeutic targets and/or biomarkers of cancer cachexia.Loss of skeletal muscle mass in cancer cachexia is recognized as a predictor of mortality. This study aimed to characterize the changes in the muscle secretome associated with cancer cachexia to gain a better understanding of the mechanisms involved and to identify secreted proteins which may reflect this wasting process. The changes in the muscle proteome of the C26 model were investigated by label-free proteomic analysis followed by a bioinformatic analysis in order to identify potentially secreted proteins. Multiple reaction monitoring and Western blotting were used to verify the presence of candidate proteins in the circulation. Our results revealed a marked increased muscular production of several acute phase reactants (APR: Haptoglobin, Serine protease inhibitor A3N, Complement C3, Serum amyloid A-1 protein) which are released in the circulation during C26 cancer cachexia. This was confirmed in other models of cancer cachexia as well as in cancer patients. Glucocorticoids and proinflammatory cytokines are responsible for an increased production of APR by muscle cells. Finally, their muscular expressions are strongly positively correlated with body weight loss as well as the muscular induction of atrogens. Our study demonstrates therefore a marked increased production of APR by the muscle in cancer cachexia.

Prognostic Significance of Inflammatory Markers IL-6, sP-Selectin, TNF-α, BNP-32, and Procalcitonin Levels in Thoracic Surgery

Following surgical trauma, alterations of the immune response increased synthesis of proinflammatory cytokines, and lymphocytic proliferation occurs together with increased production of acute-phase reactants. We aimed to identify associations of such parameters regarding complications following major thoracic surgical interventions. Fifty-four cases aged over 18 years, who were planned to undergo surgery for lung cancer (34 cases) or causes other than lung cancer (20 cases), were included. Blood samples were collected preoperatively and postoperatively in the first and sixth hours, and on the first, fourth, and seventh days. Pleural fluid samples were obtained postoperatively in the first hour and on the first and fourth days. High trend of TNF-α both in serum and pleural fluid during the early postoperative period and low trend of serum sP-Selectin were associated with incomplete expansion. Regarding atelectasis, most consistent trends belonged to IL-6 and TNF-α pleural fluid measurements, both being high. High trend of serum BNP-32 involving preoperative and early postoperative periods and high trend of IL-6 in the pleural fluid were associated with postoperative pneumonia. Regression analysis revealed significant associations of PCT with all complications. TNF-α was associated with atelectasis and empyema, and IL-6 with postoperative fever. Our study provided results both consistent and inconsistent with the literature. BNP-32 was not indicative of atrial fibrillation. Among inflammatory markers, serum PCT and TNF-α values obtained in the preoperative or early postoperative period might serve as predictors for thoracic surgical complications.

Pulmonary impairment, not muscle injury, is associated with elevated ESR in the idiopathic inflammatory myopathies

Pulmonary impairment, not muscle injury, is associated with elevated ESR in the idiopathic inflammatory myopathies

Abstract 1932: Association of genetic variants with prostate cancer risk.

Abstract Background: Genetic alterations can contribute to the malignant transformation and progression of prostate cancer. We have previously shown a strong association between specific leptin gene alleles, elevated serum leptin level, and body mass index in subjects with prostate and breast cancer. These studies showing association with leptin suggest a strong link with obesity as an increased risk factor. Studies have shown that adipose tissue TNFa and leptin, which are both overexpressed in obesity, induces the production of acute phase reactants through their autocrine or endocrine role. When GSTP1 is inactivated, prostate cells appear to become more vulnerable to somatic alterations upon chronic exposure to genome-damaging stresses such as oxidants and electrophiles that are contributed by environment and lifestyle. Studies also show that the methylation status of glutathione S-transferase p1 (GSTP1) could individually distinguish prostate cancer from benign prostatic hyperplasia. Based on prior studies, it is possible that multi gene analysis can provide better diagnostic or prognostic values for prostate cancer. Methods: In this study, we screened leptin gene markers, TNFa, GSTP1 and BCCIP(TOK-1A) in 126 prostate cancer and normal healthy age &amp; sex matched controls (Prostate cases: Age range 45-94, Mean age 73.3 Control males: Age range 65-98, Mean age 73.5). Polymerase chain reaction was used to amplify Leptin, TNF-308 and GSTP1 genes and the products are analyzed using 3130 Genetic analyzer and PCR-RFLP methods. Statistical analysis was performed using the SPSS/PC statistical program (version 10.0 for Windows; SPSS, Inc.,Chicago, IL). Relationships between two groups and genotype variables were assessed by Pearson's correlation coefficient. Conclusions: Prostate cancer is a complex, heterogeneous disease and there a variety of gene-based biomarkers that have been associated with prostate cancer. Our results show strong association of leptin (p&amp;lt;0.006), GSTP1 (p&amp;lt;0.023) with prostate cancer. Individually TNF and BCCIP showed a modest association but TNF/BCCIP gene interaction had a significant effect on prostate cancer risk and disease progression suggesting a multigene model for prostate cancer screening. Citation Format: Radhika G. Andavolu, Jean-Luc Cardenas, Ross Shore, Zach Rubin, James MacMurray, Krishna Kanth Chiravuri, Murthy VS Andavolu, Svetlana Rubakovic. Association of genetic variants with prostate cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1932. doi:10.1158/1538-7445.AM2013-1932

1. Interleukin-6 as a biomarker in major depressive disorder

Interleukin-6 is a pro-inflammatory cytokine that stimulates the HPA-axis, sympathetic nervous system, and production of acute-phase reactants. Elevations of IL-6 have been reported in patients with major depressive disorder (MDD). Further studies have suggested that IL-6 is an indicator of the severity of symptoms, especially suicidality. Forty-eight MDD patients and 23 healthy subjects were analyzed from two consecutive studies of identical design. Subjects met DSM-IV criteria for primary MDD. Severity of depression was assessed using the HAMD-17 scale. Anxiety was assessed with the HAMA scale. Patients in the first study were treated for 12 weeks with escitalopram. In the second study, patients received quetiapine XR for 12 weeks with flexible dosing. The data for IL-6 were not normally distributed, so non-parametric tests were used for statistical analyses. Patients with MDD (n = 48) had significantly higher baseline serum IL-6 than healthy controls (n = 20) (p = 0.05). Serum IL-6 failed to normalize with either escitalopram or quetiapine after treatment. Treatment response (⩽50% reduction or ⩽7 in HAM-D17 score) did not correlate with baseline level of IL-6. There was a significant correlation between baseline IL-6 and depression severity as measured by HAMD-7 (p = 0.05). This significance was lost with the HAMD-17 scale. There were no correlations between baseline IL-6 and severity of anxiety. Age was the only confound as younger MDD patients (<39 yrs) had higher IL-6 than healthy controls (p = 0.01).

Healthy centenarians show high levels of circulating interleukin-22 (IL-22)

Aging is characterized by a progressive alteration of homeostatic mechanisms modulated by environmental and genetic factors. It is associated with a pro-inflammatory status. In centenarians, an increase of pro-inflammatory cytokine production balanced by anti-inflammatory immune response that would promote longevity is observed. Cytokine dysregulation is believed to play a key role in the proposed remodeling of the immune-inflammatory responses accompanying old age. IL-22 is a pro-inflammatory cytokine belonging to the IL-10 family and represents an important effector molecule of activated T helper (Th)-22, Th-1, and Th-17 cells. We recruited 17 healthy centenarians (4 males, 13 females, range 100–105 years). All ultralongeval subjects were living at home or in a nursing home. Sixteen healthy, sex-matched individuals (4 males, 12 females, range 60–95 years) were also recruited as controls. Centenarians displayed significantly higher circulating IL-22 levels compared to control population (45.7±66.9pg/ml versus 11.1±6.5pg/ml; p=0.031). It's well known that IL-22 is a pro-inflammatory cytokine produced by activated T lymphocytes and NK cells. IL-22 stimulates the production of acute phase reactants and promotes the antimicrobial defense. The results of the present study show, for the first time, that there is an increase of IL-22 in healthy centenarians. This pro-inflammatory condition probably is protective against infection, promoting the longevity of these subjects.

Treatment with Histone Deacetylase Inhibitor Attenuates MAP Kinase Mediated Liver Injury in a Lethal Model of Septic Shock

Despite global efforts to improve the treatment of sepsis, it remains a leading cause of morbidity and mortality in intensive care units. We have previously shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, markedly improves survival in a murine model of lipopolysaccharide (LPS)-induced shock. SAHA has anti-inflammatory properties that have not been fully characterized. The liver plays an important role in the production of acute phase reactants involved in the inflammatory cascade and is also one of the major organs that can become dysfunctional in septic shock. The purpose of this study was to assess the effect of SAHA treatment on MAP kinases and associated inflammatory markers in murine liver after LPS-induced injury. C57B1/6J mice were randomly divided into three groups: (A) experimental-given intraperitoneal (i.p.) SAHA (50 mg/kg) in dimethyl sulfoxide (DMSO) vehicle solution (n = 12); (B) control- given vehicle only (n = 12), and; (C) sham-given no treatment (n = 7). Two hours later, experimental and control mice were injected with LPS (20 mg/kg, i.p.) and experimental mice received a second dose of SAHA. Livers were harvested at 3, 24, and 48 h for analysis of inflammatory markers using Western Blot, Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) techniques. After 3 h, the livers of animals treated with SAHA showed significantly (P < 0.05) decreased expression of the pro-inflammatory MAP kinases phosphorylated p38, phosphorylated ERK, myeloperoxidase and interleukin-6, and increased levels of the anti-inflammatory interleukin-10 compared with controls. Phospho-p38 expression remained low in the SAHA treated groups at 24 and 48 h. Administration of SAHA is associated with attenuation of MAPK activation and alteration of inflammatory and anti-inflammatory markers in murine liver after a lethal LPS insult. The suppression of MAPK activity is rapid (within 3 h), and is sustained for up to 48 h post-treatment. These results may in part account for the improvement in survival shown in this model.

Inflammation in Atherosclerosis: Transition From Theory to Practice

Inflammation drives the formation, progression, and rupture of atherosclerotic plaques. Experimental studies have demonstrated that an inflammatory subset of monocytes/macrophages preferentially accumulate in atherosclerotic plaque and produce proinflammatory cytokines. T lymphocytes can contribute to inflammatory processes that promote thrombosis by stimulating production of collagen-degrading proteinases and the potent procoagulant tissue factor. Recent data link obesity, inflammation, and modifiers of atherosclerotic events, a nexus of growing clinical concern given the worldwide increase in the prevalence of obesity. Modulators of inflammation derived from visceral adipose tissue evoke production of acute phase reactants in the liver, implicated in thrombogenesis and clot stability. Additionally, C-reactive protein levels rise with increasing levels of visceral adipose tissue. Adipose tissue in obese mice contains increased numbers of macrophages and T lymphocytes, increased T lymphocyte activation, and increased interferon-gamma (IFN-gamma) expression. IFN-gamma deficiency in mice reduces production of inflammatory cytokines and inflammatory cell accumulation in adipose tissue. Another series of in vitro and in vivo mouse experiments affirmed that adiponectin, an adipocytokine, the plasma levels of which drop with obesity, acts as an endogenous antiinflammatory modulator of both innate and adaptive immunity in atherogenesis. Thus, accumulating experimental evidence supports a key role for inflammation as a link between risk factors for atherosclerosis and the biology that underlies the complications of this disease. The recent JUPITER trial supports the clinical utility of an assessment of inflammatory status in guiding intervention to limit cardiovascular events. Inflammation is thus moving from a theoretical concept to a tool that provides practical clinical utility in risk assessment and targeting of therapy.

Can moderate elevations of parathyroid hormone acutely increase risk for ischemic cardiac arrhythmias?

There is suggestive evidence that chronic elevations of parathyroid hormone (PTH), associated with poor vitamin D status or low calcium intake, can increase risk for insulin resistance, weight gain, hypertension, and left ventricular hypertrophy, while stimulating production of acute phase reactants. New evidence that elevated PTH is prognostic for increased vascular mortality in very elderly subjects, prompts an examination of the possible impact of PTH on risk for arrhythmias. The cardiac effects of PTH are mediated by G protein-coupled receptors that activate phospholipase C (PLC). Catecholamines, angiotensin II, and endothelin have been shown to be arrhythmogenic for ischemic myocardium in animal studies; the receptors mediating this effect are all likewise linked to activation of PLC. Thus, it is reasonable to presume that a sufficient concentration of PTH can be arrhythmogenic in the ischemic heart. The extent to which this effect can be evoked by the high-normal PTH levels prevalent in many elderly subjects, can be assessed in epidemiological studies.

Early Systemic Inflammatory Response to Drug-Eluting Stents Implantation: The Heart of the Difference?

Percutaneous coronary intervention (PCI) is the main treatment for the revascularization of coronary arteries in patients with coronary artery disease. Intracoronary stent deployment causes arterial wall trauma which elicits a local inflammatory wound-healing response to mechanical injury leading to an increase of inflammatory mediators in the target coronary artery segment [1]. Consequently, an early systemic inflammatory response is triggered, as observed by an almost immediate rise (within minutes after PCI) in systemic inflammatory markers, such as interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). The production of acute phase reactants in the liver is stimulated, like C-reactive protein (CRP) and serum amyloid A protein (SAA), which rapidly increase in the circulation and which may directly amplify the local response to the inflammatory stimulus [2, 3]. Furthermore, coronary stenting in patients with stable angina causes an elevated systemic inflammatory response compared with patients treated with angioplasty only [4]. The relationship of the systemic inflammatory response and restenosis outcome is still unclear. The majority of the studies show a correlation between (early) post-PCI systemic inflammatory markers and restenosis outcome [4]. Nonetheless, some studies report no association [5, 6]. Several factors may contribute to this discrepancy. First, differences in baseline demographic, clinical and lesion characteristics may affect the inflammatory response and, therefore, the clinical prognosis. More complex lesions and/or lesions presenting high inflammatory infiltrates may show hypersensitivity to stent implantation leading to a higher inflammatory reaction. Second, inflammatory mediators have different half-lives (e.g., IL-6≈4 h; CRP and SAA≈19 h) and measurement in a certain time course may not correspond to their highest peak value and not detect differences in concentrations between groups. Third, the widespread use of statins, glycoprotein IIb/IIIa antagonists, and clopidogrel may attenuate the systemic inflammatory response to PCI and mask the predictive association between systemic inflammatory values and clinical outcome. On the whole, nowadays it is considered that inflammation plays an important role after PCI with regard to restenosis [7], and this is strengthened by the fact that polymorphisms in genes coding for inflammatory proteins, e.g. TNF-α, IL-10, caspase-1 and colony-stimulating factor 2 (CSF2) have been shown to be associated and causally involved in (clinical) restenosis [2, 8–10]. The introduction of drug-eluting stents (DES) in clinical practice was a milestone in the history of interventional cardiology. The two initially main worldwide available DES, i.e. Sirolimus(SES, CypherTM) and Paclitaxeleluting (PES, TAXUSTM) stents, reduce restenosis and target-vessel revascularization rate as compared to baremetal stents (BMS) [11–13]. Putative differences in terms of early systemic inflammatory response among patients treated with DES versus BMS have been put forward as a plausible explanation for the DES superiority. Literature associates DES either with a decrease [14, 15] or no effect [16, 17] in the early systemic inflammatory response compared to BMS. The reasons for these unclear results are unknown, but the same limitations as described above Cardiovasc Drugs Ther (2009) 23:103–105 DOI 10.1007/s10557-008-6158-z

The Cancer Related Thrombotic Tendency in Sepsis

The host inflammatory response is activated in both cancer and infection. This includes enhanced production of acute phase reactants, involvement of coagulation and inflammation and the potential for systemic effects. This overview will identify the prothrombotic links between cancer and sepsis and suggest antithrombotic agents as an approach in the specific treatment of sepsis in cancer patients.

Hyperglycemia-induced production of acute phase reactants in adipose tissue.

Chronic elevation of systemic levels of acute phase reactants and inflammatory cytokines found in patients with diabetes and the often-associated metabolic syndrome X (hypertriglyceridemia, low serum high density lipoprotein cholesterol, hypertension, and accelerated atherosclerosis) may be responsible for the increased incidence of cardiovascular problems in this population. Here we examine the contribution of adipose tissue to the systemic elevation of acute phase reactants associated with chronic hyperglycemia. We demonstrate that adipose tissue expresses a number of acute phase reactants at high levels, including serum amyloid A3 (SAA3), alphal-acid glycoprotein, the lipocalin 24p3 as well as plasminogen activator inhibitor-1 (PAI-1). Additionally, we show SAA3 is expressed at low levels under normal conditions but in the diabetic state is dramatically up-regulated in adipose tissue while down-regulated in liver. Furthermore, pro-inflammatory stimuli and high glucose can lead to the induction of SAA3 in adipose tissue in vivo as well as in the 3T3-L1 adipocyte cell line. Adipose tissue may therefore play a major role in the pathogenic sequelae of Type II diabetes, in particular the cardiovascular problems associated with prolonged hyperglycemia.

C-Reactive protein in severely malnourished children

C-reactive protein (CRP) was measured in 53 children with primary severe malnutrition at the time of their hospital admission (group A). Eight showed typical kwashiorkor, four marasmic-kwashiorkor and 41 were marasmic infants: 21 of them suffered some kind of infectious disease, mostly of bacterial origin. An equal number of eutrophic children, matched according to the origin of the infection (bacterial, viral or micotic), were choosen as controls (group B). Eight of the non-infected children of group A (25%) exhibited elevated concentrations of CRP, as opposed to one (3%) of group B. All the infected cases in both groups, showed elevated levels of CRP, with higher values in group B (average 80 mg/dL) vs. group A (av. 13.2 mg/dL). These results suggest that in children with severe malnutrition the capacity for the production of acute phase reactants is mantained, although to a lesser degree than in normal weight children.

Increased plasma and ventricular fluid interleukin-6 levels in patients with head injury.

The cytokine interleukin-6 (IL-6) plays a major role in initiating the acute phase response, especially in the production of acute phase reactants such as C-reactive protein. The objectives of this study were to determine whether plasma or ventricular fluid IL-6 levels were elevated at time of admission after head injury and whether plasma IL-6 levels related temporally to clinical improvement of levels of acute phase reactants. Thirty patients with Glasgow Coma Scale (GCS) scores of 3 through 10 were observed for 15 days after head injury. Peak elevation of plasma IL-6 occurred on admission (85 +/- 12 U/ml; normal level is less than 2 U/ml) and then decreased during the hospital course to a level of 29 +/- 4 U/ml on day 15. Plasma IL-6 levels decreased significantly faster in patients with admission peak 24-hour GCS scores of 8 through 10 compared with patients with GCS score less than 8 (p less than 0.01). Patients had markedly elevated and variable ventricular fluid IL-6 levels on admission (mean 3880 +/- 2022 U/ml; normal, less than 2 U/ml). A temporal relationship was found between plasma IL-6 levels and multiple acute phase reactants thought to be mediated by IL-6. We conclude that plasma and ventricular fluid levels of IL-6 are elevated after head injury and that plasma IL-6 level is temporally related to acute phase reactants and clinical improvement. We suggest that IL-6 may play an etiologic role in many of the metabolic or nutritional sequelae of head injury.

Effect of bacterial endotoxin on plasma concentration of haptoglobin and fibrinogen in rats treated with metopyrone

During the acute phase of the inflammatory process there is a characteristic increase in some plasma proteins called collectively acute phase reactants (APR) as well as in the levels of corticosteroids. A bacterial endotoxin (LPS) that induces a strong acute phase response, indicated by high levels of fibrinogen and haptoglobin, did not show this effect when administered to rats treated previously with metopyrone, a specific inhibitor of corticosteroid hormone synthesis. These results suggest that adequate levels of these hormones are important for the production of acute phase reactants.

The hormonal and metabolic response to stress in the neonate

It is apparent that adult patients demonstrate a catabolic response to the stresses induced by operative or accidental trauma. It seems that the degree of this catabolic response may be quantitatively related to the extent of the trauma or the magnitude of associated complications such as infection. The host response to infection, traumatic injury, or major operative stress is characterized by such events as fever, pituitary and stress hormone elaboration, mineral redistribution, and increased acute-phase protein synthesis [21]. The beneficial effects of this stress response consist in providing alternate energy sources to meet metabolic demands and essential building blocks for synthetic activities occuring in the postoperative period. It has been suggested that the hyperglycemic response is essential for supplying the increased glucose requirements of injured tissue [81]. In addition, the proteolytic component of the stress response provides the necessary amino acid elements for reparative protein synthesis and production of acute-phase reactants by the liver. The changes in metabolic patterns induced by the stress response are satisfied in part by increased lipolysis and ketogenesis to provide an alternate source of metabolic fuel for tissues such as the brain and skeletal muscle. Additionally, the observed gluconeogenesis may aid in maintaining the glucose supply for vital organs principally dependent on glucose [52, 160]. This metabolic response has also been shown to potentiate many adverse conditions in the postoperative period and to further exacerbate the stress response. Examples include a hypermetabolic state with attendant increased VO2, increased energy requirements, increased temperature, elevated cardiac output, and altered or impaired inflammatory or immune-responsiveness. Numerous investigators have demonstrated that adult patients exposed to severe degrees of traumatic stress are subjected to greatly increased rates of complications such as cardiac or pulmonary insufficiency, myocardial infarction, impaired hepatic and/or renal function, gastric stress ulcers, and sepsis. Furthermore, evidence exists to suggest that this response may be life-threatening if the induced catabolic activity remains excessive or unchecked for a prolonged period. Moyer et al. were able to identify with a great degree of certainty the patients who were likely to die based on a single analysis of a variety of plasma-borne substrates obtained up to 9 days prior to death [103]. It is apparent that modulating or blunting the catabolic response induced by the stress state may have beneficial effects. In studies of postoperative pain management, improved pain control resulted in reduction of postoperative nitrogen loss and shortened periods of convalescence following operation [28, 88]. It is evident from this review that human newborns, even those born prematurely, are capable of mounting an endocrine and metabolic response to operative stress. Unfortunately, many of the areas for which a relatively well-characterized response exists in adults are poorly documented in neonates. As is the case in adults, the response seems to be primarily catabolic in nature because the combined hormonal changes include an increased release of catabolic hormones such as catecholamines, glucagon, and corticosteroids coupled with suppression of and peripheral resistance to the effects of the primary anabolic hormone, insulin. The catecholamines may be the agents of primary importance in this response, and thus may modulate the remaining components of the hormonal response to stress as well as the metabolic changes, including inhibition of insulin release, marked hyperglycemia, and breakdown of the neonate's stores of nutrients (carbohydrate, protein, and fat). These reactions ultimately result in the release of glucose, NEFA, ketone bodies, and amino acids. Although these metabolic by-products are necessary to meet the body's altered energy needs in a time of increased metabolic demands, it is not difficult to imagine that a severe or prolonged response would be very detrimental to a previously ill neonate with limited reserves of nutrients and already high metabolic demands imposed by rapid growth, organ maturation, and adaptation to the postnatal environment. Preliminary investigations by Anand et al. outlined in this review indicate that alterations in anesthetic technique with the addition of agents such as halothane and fentanyl may be able to significantly blunt this catabolic response. In addition, it appears that modulation of the immune response may also greatly affect the postoperative catabolic response. It is hopeful that future developments and the acquisition of more detailed knowledge o the response will allow us to modify the stress response in neonates in order to further decrease their mortality and morbidity.