Serum Concentrations Of Tumor Necrosis Factor Research Articles

Molecular and imaging biomarkers of local inflammation at 2 years after anterior cruciate ligament injury do not associate with patient reported outcomes at 5 years

To estimate the association between molecular or imaging inflammatory biomarkers at 2 years after anterior cruciate ligament (ACL) injury and patient-reported outcomes at 5 years. For 116 ACL-injured patients, molecular biomarkers of inflammation (synovial fluid and serum cytokines) and Hoffa- and effusion-synovitis as visualized on magnetic resonance imaging (MRI) were assessed 2 years post-injury. Knee injury and Osteoarthritis Outcome Score (KOOS) and SF-36 were assessed at 2 and 5 years. We used multiple imputation to handle biomarker values that were below the level of detection or missing, and linear regression for statistical analyses. None of the synovial fluid cytokines or imaging biomarkers of inflammation at 2 years were associated with any of the patient-reported outcomes at 5 years. With each log10 unit higher of serum tumor necrosis factor concentration the knee-related quality of life of KOOS was increased (i.e., better outcome) by 35 (95% confidence interval 7 to 63) points. No other serum biomarker measured at 2 years was associated with patient-reported outcome at 5 years. Local joint inflammation assessed by biomarkers in synovial fluid and Hoffa- and effusion-synovitis on MRI at 2 years after an ACL injury did not associate with patient-reported outcomes at 5 years. Thus, chronic inflammation in the ACL-injured knee, as reflected by the biomarkers studied here, seems not to be a key determinant for the long-term patient-reported outcomes.

Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients

Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg−1) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration–time profiles of infliximab. Typical clearance of infliximab was 0.404 L day−1 and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (Bmax was 19.8 pg mL−1 and the dissociation constant (Kss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.

Reprint of Milk fever in dairy cows is preceded by activation of innate immunity and alterations in carbohydrate metabolism prior to disease occurrence

The objective of this study was to search for potential alterations in innate immunity reactants and carbohydrate and lipid metabolism in the blood of transition dairy cows before, during, and after clinical occurrence of milk fever (MF) and identify potential predictive biomarkers of disease. One hundred pregnant multiparous Holstein dairy cows were involved in the study starting from −8wks before the expected day of parturition until +8wks postpartum as part of a large retrospective longitudinal study. Health status, DMI, milk yield, and milk composition were monitored during the whole experimental period. Six healthy cows (CON) and 6 cows that showed clinical signs of MF were selected for blood analyses. Serum concentrations of lactate, non-esterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA) were determined. Results indicated that concentrations of serum lactate, IL-6, TNF, SAA, and Hp were greater in cows with MF than those in the CON group at different time points. Moreover, serum lactate, TNF, SAA, and Hp were greater in cows with MF starting at −8 and −4wks prior to parturition. Both principal component analysis (PCA) and partial least squares - discriminant analysis (PLS-DA) showed separated clusters between MF and CON cows at −8, −4, and disease diagnosis weeks. Overall DMI and milk production were lower in MF-affected cows. Additionally milk fat and fat:protein ratio were greater in MF. In conclusion, cows affected by MF showed alterations in some of the innate immunity reactants and metabolites related to carbohydrate metabolism several weeks prior to appearance of clinical signs of MF. Variable importance in projection plots demonstrated that TNF and SAA in the serum were the strongest discriminators between MF cows and CON ones, which might be useful as predictive biomarkers of the disease.

Milk fever in dairy cows is preceded by activation of innate immunity and alterations in carbohydrate metabolism prior to disease occurrence

The objective of this study was to search for potential alterations in innate immunity reactants and carbohydrate and lipid metabolism in the blood of transition dairy cows before, during, and after clinical occurrence of milk fever (MF) and identify potential predictive biomarkers of disease. One hundred pregnant multiparous Holstein dairy cows were involved in the study starting from −8wks before the expected day of parturition until +8wks postpartum as part of a large retrospective longitudinal study. Health status, DMI, milk yield, and milk composition were monitored during the whole experimental period. Six healthy cows (CON) and 6 cows that showed clinical signs of MF were selected for blood analyses. Serum concentrations of lactate, non-esterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA) were determined. Results indicated that concentrations of serum lactate, IL-6, TNF, SAA, and Hp were greater in cows with MF than those in the CON group at different time points. Moreover, serum lactate, TNF, SAA, and Hp were greater in cows with MF starting at −8 and −4wks prior to parturition. Both principal component analysis (PCA) and partial least squares - discriminant analysis (PLS-DA) showed separated clusters between MF and CON cows at −8, −4, and disease diagnosis weeks. Overall DMI and milk production were lower in MF-affected cows. Additionally milk fat and fat:protein ratio were greater in MF. In conclusion, cows affected by MF showed alterations in some of the innate immunity reactants and metabolites related to carbohydrate metabolism several weeks prior to appearance of clinical signs of MF. Variable importance in projection plots demonstrated that TNF and SAA in the serum were the strongest discriminators between MF cows and CON ones, which might be useful as predictive biomarkers of the disease.

Occurrence of retained placenta is preceded by an inflammatory state and alterations of energy metabolism in transition dairy cows.

BackgroundFailure to expel fetal membranes within 24 h of calving is a pathological condition defined as retained placenta (RP). The objective of this investigation was to evaluate whether there are alterations in several selected serum variables related to innate immunity and carbohydrate and lipid metabolism that precede occurrence of RP in transition Holstein dairy cows.MethodsOne hundred multiparous Holstein dairy cows were involved in the study. Blood samples were collected from the coccygeal vein during the −8 to +4 wks around parturition, once per week before the morning feeding. Six healthy control cows (CON) and 6 cows with RP were selected and serum samples at −8, −4, time of diagnosis of disease, and +4 wks relative to parturition were used for analyses. All samples were analyzed for lactate, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHBA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA).ResultsCows with RP had greater concentrations of serum lactate, IL-1, IL-6, TNF, and SAA in comparison with CON cows. Intriguingly, elevated concentrations of all five variables were observed at −8 and −4 wks before the occurrence of RP compared to healthy cows. Cows with RP also had lower DMI and milk production vs CON animals; however milk composition was not affected by RP.ConclusionsCows with RP showed an activated innate immunity 8 wks prior to diagnosis of disease. Overall results suggest that serum IL-1, IL- 6, and TNF, and lactate can be used as screening biomarkers to indicate cows that might have health issues during the transition period.

Brain Death–Induced Inflammatory Activity in Human Pancreatic Tissue

Long-term insulin independence after islet transplantation depends on engraftment of a large number of islets. However, the yield of pancreatic islets from brain-dead donors is negatively affected by the up-regulation of inflammatory mediators. Brain death is also believed to increase tissue factor (TF) expression, contributing to a low rate of engraftment. We conducted a case-control study to assess brain death-induced inflammatory effects in human pancreas. Seventeen brain-dead patients and 20 control patients undergoing pancreatectomy were studied. Serum tumor necrosis factor (TNF), interleukin (IL) 6, IL-1β, interferon (IFN) γ, and TF were measured using enzyme-linked immunosorbent assay kits. Gene expressions of these cytokines and TF were evaluated by reverse transcriptase quantitative polymerase chain reaction. Protein quantification was performed by immunohistochemistry in paraffin-embedded pancreas sections. Brain-dead patients had higher serum concentrations of TNF and IL-6 and increased TNF protein levels compared to controls. The groups had similar TNF, IL-6, IL-1β, and IFN-γ messenger RNA levels in pancreatic tissue. Reverse transcriptase quantitative polymerase chain reaction revealed TF messenger RNA up-regulation in controls. Immunohistochemical analyses showed that brain-dead patients had increased TNF protein levels compared to controls. Brain death induces inflammation evidenced by the up-regulation of TNF in serum and pancreatic tissue. Blocking the expression of key inflammatory mediators in brain-dead donors should be evaluated as a new approach to improve the outcomes of islet transplantation.

Influence of polymorphisms and TNF and IL1β serum concentration on the infliximab response in Crohn’s disease and ulcerative colitis

Inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), are partially attributable to an increased secretion of proinflamatory cytokines, such as tumour necrosis factor (TNF) and interleukin-1β (IL1β), which play essential roles in the disease pathogenesis and are target molecules for specific therapy. Given the inter-individual variability in the response to the anti-TNF monoclonal antibody infliximab, the aim of our study was to explore the predictive value of TNF and/or IL1β as surrogate markers of infliximab response. Serial serum concentrations of TNF and IL1β and TNF promoter region and IL1B polymorphisms were determined in 47 patients (29 CD and 18 UC) receiving infliximab and correlated with treatment response. Baseline serum concentrations of TNF and IL1β were higher in UC patients than in CD patients (p = 0.0097 and 0.0024, respectively). CD patients showing <0.64 pg/ml IL1β at baseline were more frequently responders than non-responders (p = 0.036), and the C allele of the IL1B polymorphism was associated with higher IL1β serum concentrations (p = 0.026) and with poorer clinical remission after 14 weeks of infliximab treatment. No significant association was found between serum TNF concentration or TNF polymorphism and patient response to infliximab. This is the first study evaluating the pharmacogenetic role of the rs1143634 polymorphism of IL1B and TNF polymorphisms in infliximab-treated IBD patients. We found an association between the rs1143634 C allele and higher serum IL1β concentrations and a lower response to infliximab treatment in CD patients that warrants the interest of future studies in larger and independent series.

Cardiotrophin-1 Induces Tumor Necrosis Factor Synthesis in Human Peripheral Blood Mononuclear Cells

Chronic heart failure (CHF) is associated with elevated concentrations of tumor necrosis factor (TNF) α and cardiotrophin-1 (CT-1) and altered peripheral blood mononuclear cell (PBMC) function. Therefore, we tested whether CT-1 induces TNFα in PBMC of healthy volunteers. CT-1 induced in PBMC TNFα protein in the supernatant and TNFα mRNA in a concentration- and time-dependent manner determined by ELISA and real-time PCR, respectively. Maximal TNFα protein was achieved with 100 ng/mL CT-1 after 3–6 hours and maximal TNFα mRNA induction after 1 hour. ELISA data were confirmed using immunofluorescent flow cytometry. Inhibitor studies with actinomycin D and brefeldin A showed that both protein synthesis and intracellular transport are essential for CT-1 induced TNFα expression. CT-1 caused a dose dependent nuclear factor (NF) κB translocation. Parthenolide inhibited both NFκB translocation and TNFα protein expression indicating that NFκB seems to be necessary. We revealed a new mechanism for elevated serum TNFα concentrations and PBMC activation in CHF besides the hypothesis of PBMC activation by bacterial translocation from the gut.

The anti-oxidant defence response in individuals with the indeterminate form of Chagas disease (American trypanosomiasis)

In previous studies in animal models, Trypanosoma cruzi-induced oxidative stress and damage have sometimes been controlled by the host's anti-oxidant defence responses. The role of the anti-oxidant defence responses, such as the activities of the anti-oxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD), in protection against inflammation and damage have now been investigated in humans infected with T. cruzi. The subjects were 32 asymptomatic but seropositive individuals with the indeterminate form of Chagas disease, 18 symptomatic and seropositive patients with the chronic disease, and 50 seronegative and apparently healthy controls. The inflammatory process was explored using serum concentrations of tumour necrosis factor (TNF) and NO. The serum concentrations of GPx in the patients in the indeterminate phase of infection were similar to those in the controls but much higher than those in the chronic cases (P=0.001). The serum concentrations of SOD in the patients in the indeterminate phase of infection were not only significantly higher than those in the cases of chronic Chagas disease (P=0.0004) but also significantly higher than those in the controls (P<0.001). The seropositive subjects had significantly higher serum concentrations of TNF and NO than the controls (P<0.01 for each) and the cases of chronic Chagas disease had significantly higher serum concentrations of TNF and NO than the subjects with the indeterminate form of the disease (P<0.01 for each). It therefore appears that the host's anti-oxidant defence responses (at least in terms of elevated concentrations of SOD) may inhibit inflammation during the indeterminate phase of Chagas disease.

Correlation of the serum concentrations of tumour necrosis factor and nitric oxide with disease severity in chronic Chagas disease (American trypanosomiasis)

Pro-inflammatory cytokines such as tumour necrosis factor (TNF) and nitric oxide (NO) are believed to play an important role in the severity of chronic disease. When evaluated in 71 patients who were seropositive for Trypanosoma cruzi and 50 apparently healthy controls, the mean (S.D.) serum concentrations of both TNF [7.65 (1.32) nu. 4.24 (1.53) ng/ml; P<0.001] and NO [114 (40) nu. 74 (21) microM; P<0.0001] were found to be significantly higher in the patients than in the controls. In addition, patients with chronic, symptomatic disease affecting their hearts--eight with dilated cardiomyopathy [8.82 (1.47) ng TNF/ml; 142 (45) microM NO] and 17 others with electrocardiographic alterations [8.37 (1.26) ng TNF/ml; 134 (53) microM NO]--had significantly higher serum concentrations of these cytokines than 34 patients who were in the asymptomatic, indeterminate phase of the disease [6.38 (1.35) ng TNF/ml; 99 (28) microM NO]. In those infected with T. cruzi, it therefore appears that serum concentrations of TNF and NO correlate with disease severity, indicating that these cytokines play some role in the pathogenesis of chronic Chagas disease.

Serum concentrations of inflammatory mediators related to organ failure in patients with acute pancreatitis.

Leucocyte activation and proinflammatory cytokine release (tumour necrosis factor (TNF) and interleukin 6 (IL-6)) are thought to contribute to the induction of a systemic inflammatory response, an acute-phase response and multiple organ failure in patients with acute pancreatitis. The serum concentration of TNF, soluble TNF receptors (sTNFR55 and sTNFR75), IL-6 and C-reative protein (CRP) in 58 patients with acute pancreatitis was assessed during the first 2 days of admission. Thirty patients had mild disease and 28 severe disease, of whom 18 developed local pancreatic complications alone (Atlanta classification) and ten developed organ failure (a Goris score of 1 or more). TNF was detected in only 17 patients on the first day of admission, while soluble TNF receptors were detected in all patients and IL-6 in 34. On the first and second days of admission there was a progressive and significant (P < 0.03) increase in the median concentration of sTNFR55, sTNFR75 and IL-6 in patients eventually classified into those with mild disease, a local pancreatic complication alone, or organ failure. This pattern was also evident in CRP levels from the second but not the first day of admission. These findings suggest that proinflammatory cytokines or their soluble receptors may be more accurate early predictors of outcome than CRP, Moreover, markers of inflammation in the sera of patients with acute pancreatitis are highest in those who subsequently develop organ failure.

Source-Dependent Functions for TNF

Grivennikov et al. created transgenic mice with tumor necrosis factor (TNF) selectively deleted in specific leukocyte types to investigate differences in TNF function that depend on the cellular source. TNF, a cytokine that has been implicated in cell trafficking, inflammatory responses, and defense against pathogens, has both beneficial and deleterious effects. Thus, whereas inhibition of TNF activity may be beneficial in various inflammatory disorders, such inhibition may increase susceptibility to certain pathogens. Grivennikov et al. found that mice that did not express TNF in macrophages or neutrophils (MN-TNF KO mice) had reduced serum concentrations of TNF compared with those of wild-type mice after injection of lipopolysaccharide (LPS, which elicits TNF production through Toll-like receptor signaling). However, mice lacking T cell (T-TNF KO) or B cell (B-TNF KO) TNF did not. MN-TNF KO mice were resistant to septic shock produced by injection of LPS plus D-galactosamine, whereas T-TNF KO and B-TNF KO mice were not. When toxic shock was induced by superantigen from Staphylococcus aureus , however, T-TNF KO and MN-TNF KO mice were both resistant, whereas B-TNF KO mice were not. Macrophage- and neutrophil-derived TNF was required for resistance to infection with the intracellular bacterium Listeria monocytogenes , whereas B cell-derived TNF was dispensable and T cell-derived TNF was protective only under conditions of high bacterial load. Loss of either T cell-derived TNF or of macrophage- and neutrophil-derived TNF was protective in a mouse model of autoimmune hepatitis. Thus, the authors conclude that TNF derived from different sources plays distinct biological roles and suggest that selective inhibition of T cell-derived TNF production may be therapeutically preferable to systemic inhibition of TNF activity. S. I. Grivennikov, A. V. Tumanov, D. J. Liepinsh, A. A. Kruglov, B. I. Marakusha, A. N. Shakhov, T. Murakami, L. N. Drutskaya, I. Förster, B. E. Clausen, L. Tessarollo, B. Ryffel, D. V. Kuprash, S. A. Nedospasov, Distinct and nonredundant in vivo functions of TNF produced by T cells and macrophages/neutrophils: Protective and deleterious effects. Immunity 22 , 93-104 (2005). [PubMed]

Multiple imputation procedures allow the rescue of missing data: An application to determine serum tumor necrosis factor (TNF) concentration values during the treatment of rheumatoid arthritis patients with anti-TNF therapy

Longitudinal studies aimed at evaluating patients clinical response to specific therapeutic treatments are frequently summarized in incomplete datasets due to missing data. Multivariate statistical procedures use only complete cases, deleting any case with missing data. MI and MIANALYZE procedures of the SAS software perform multiple imputations based on the Markov Chain Monte Carlo method to replace each missing value with a plausible value and to evaluate the efficiency of such missing data treatment. The objective of this work was to compare the evaluation of differences in the increase of serum TNF concentrations depending on the -308 TNF promoter genotype of rheumatoid arthritis (RA) patients receiving anti-TNF therapy with and without multiple imputations of missing data based on mixed models for repeated measures. Our results indicate that the relative efficiency of our multiple imputation model is greater than 98% and that the related inference was significant (p-value < 0.001). We established that under both approaches serum TNF levels in RA patients bearing the G/A -308 TNF promoter genotype displayed a significantly (p-value < 0.0001) increased ability to produce TNF over time than the G/G patient group, as they received successively doses of anti-TNF therapy.

Serum Concentrations of Tumor Necrosis Factor‐a in Neonatal Calves with Presumed Septicemia

This study was performed to determine the concentrations of tumor necrosis factor (TNF) in the serum of neonatal calves with presumed sepsis and determine the correlation between serum concentrations of TNF and the severity and outcome of disease. Thirty‐five sick calves &lt;30 days old that suffered from enteritis, respiratory disease, or both were considered suitable for inclusion in this study by satisfying clinical and laboratory criteria suggestive of septicemia. At admission, blood samples were collected from all calves to determine the prevalence of high concentrations of TNF. The clinical course and outcome of disease then were recorded. Of the 35 calves with presumed sepsis, 10 had high serum TNF concentrations. Scleral injection, weak or absent suckling reflex, sternal or lateral recumbency, unresponsive or comatose state, and death rate of calves with high serum TNF concentration were greater than those values for calves without high serum TNF concentration. Calves with high serum TNF concentration had significantly lower mean IgG (P &lt; .001), globulin (P &lt; .0001), and calcium (P &lt; .0001) concentrations; greater serum creatinine concentrations (P &lt; .0001); and &gt;2+ toxic changes in neutrophils than did calves without high serum TNF concentrations. Mean values for packed cell volume, band neutrophil count, and venous PCO2 were significantly (P &lt; .007) higher in the group of calves with high serum TNF concentration. Results of this study indicate that serum TNF concentration is correlated with clinical criteria of sepsis in neonatal calves. A close association was apparent between disease severity and serum TNF concentrations in this group of calves with presumed septicemia.

Osteoporosis and cardiovascular disease--two sides of the same coin?

Osteoporosis and cardiovascular disease have numerous epidemiologic changes, health economic consequences, and molecular mechanisms in common, which are highlighted in this short review. The incidence of osteoporosis and cardiovascular disease is increasing in western societies, and genetic background, nutrition and psychologic factors play important roles in the pathogenesis of both diseases. The presence of a decreased bone mass or osteoporotic vertebral fractures are associated with an increased cardiovascular mortality. Calcaneal bone loss of 1 SD (standard deviation) as measured by osteodensitometry is associated with a 1.31 times increased risk for the occurrence of stroke. The observed increase in interleukin-6 and tumor necrosis factor serum concentrations during the menopause contributes to osteoporotic bone loss and is associated with arteriosclerosis. Furthermore, the presence of hydroxyapatite in arteriosclerotic plaques supports the notion of common pathogenetic mechanisms for both, osteoporosis and arteriosclerosis. Osteopontin, bone GLA protein and bone morphogenetic protein-2, which have first been isolated from the organic bone matrix, are also present in arteriosclerotic plaques. 1,25-dihydroxycholecalciferol potently stimulates bone matrix mineralization and is also a negative regulator of the renin-angiotensin system; therefore vitamin D(3) deficiency in addition to bone metabolism also affects blood pressure. Osteoporosis and arteriosclerosis develop in mice lacking the osteoprotegerin gene and also in klotho gene knockout mice. Diagnosis of osteopenia, osteoporosis and osteoporotic vertebral or hip fractures indicates the presence of an increased cardiovascular risk which needs to be addressed by the physician who cares for patients with osteoporosis. The experimental finding of an osteoanabolic effect of statins supports the possibility of common pathogenetic disturbances which may be responsible for the simultaneous and frequent manifestation of osteoporosis and arteriosclerosis in elderly patients.

Tumor necrosis factor as a mediator of cardiac toxicity following snake envenomation.

To investigate the possible role of tumor necrosis factor in mediating cardiotoxicity following venom injection in a rat. A randomized controlled experimental study using a Langendorff isolated heart model. Animal laboratory. Adult male Wistar rats. The control group (n = 10) was injected with saline only. Each animal in the experimental groups 1-3 (n = 10 each) was injected with Vipera aspis venom 500 microg/kg intramuscularly. Group 1 animals received no additional substance beforehand, group 2 animals were injected intramuscularly with 250 microg of soluble tumor necrosis factor receptor (sTNF-R p55) 15 mins before the venom injection, and group 3 animals were injected intraperitoneally with 40 microg of anti-tumor necrosis factor 60 mins before the venom injection. Cardiac performances were investigated following envenomation. Cardiac histology and myocardial tumor necrosis factor-RNA concentrations were assessed. Serum tumor necrosis factor concentrations rose and peaked 2 hrs following envenomation. A reduction in peak systolic pressures, maximum and minimum change in pressure over time, time-pressure integral, and coronary flow occurred in the venom-only-injected rats compared with controls, whereas blocking tumor necrosis factor activity prevented the deleterious cardiac effects of the envenomation. No histologic changes or increases in myocardial tumor necrosis factor-RNA concentrations were detected. These results strongly suggest that systemic release of tumor necrosis factor mediates cardiac toxicity following Vipera aspis envenomation.

Small bowel segment reversal induces intestinal hyperplasia but reduces whole-body growth in massive bowel resected rats.

Surgical reversal of a small bowel segment has been proposed as a means to improve nutritional status in individuals with extensive bowel resection. However, clinical experience remains controversial. The aim of this study was to determine the effects of bowel segment reversal on intestinal adaptation and whole-body anabolism. Male Wistar rats underwent a 70% small bowel resection with (REV) or without (CON) reversal of a 5-cm small bowel segment (5 cm distal to resected segment), or sham-operation (SHAM). After surgery (day 0), rats were fed with powdered diet from day 2 to day 12. Body weight, nitrogen balance, carcass compositions, and serum concentrations of albumin and insulin-like growth factor (IGF)-1 were determined to assess whole-body anabolism. The composition and architecture of the small intestine were measured to assess the intestinal growth response. Serum concentrations of tumor-necrosis factor (TNF)-alpha and interleukin (IL)-6 were measured to assess the response of postoperative cytokines. Surgical reversal significantly increased the intestinal protein and DNA contents in the proximal segment compared with surgical resection. REV rats had a significantly slower rate of weight gain and lower serum levels of albumin and IGF-1, and had significantly greater levels of circulating white blood cells, blood urea nitrogen, and IL-6 compared with CON and SHAM rats. There were no significant differences in serum concentrations of TNF-alpha and carcass percentages of water, protein, and fat among groups. Small bowel segment reversal stimulates jejunal hyperplasia but the surgical reversal induced-elevation in serum IL-6 may eliminate the whole-body anabolism in massive bowel-resected rats.

Pretreatment with tumor necrosis factor-alpha attenuates arterial hypotension and mortality induced by endotoxin in pigs.

Tumor necrosis factor (TNF)-alpha administration in large amounts can induce a state of shock similar to that seen during severe sepsis. The objective of this study was to determine whether small doses of TNF-alpha might decrease the disposition for the development of shock induced by a subsequent infusion of endotoxin and to determine whether the mechanism of this protective effect of TNF-alpha pretreatment could be associated with up-regulation of the anti-inflammatory cytokine interleukin (IL)-10. Prospective, randomized, experimental study. Investigative intensive care unit at an academic medical center. A total of 14 female Yorkshire pigs, weighing 20-25 kg. We studied two groups of animals-pigs treated with 500 ng/kg recombinant porcine TNF-alpha (n = 7) and pigs given diluent alone (n = 7). At 24 hrs after treatment, both groups of pigs were subjected to a 24-hr continuous infusion of lipopolysaccharide (LPS) at a rate of 80 ng/kg/min. The mortality rate was determined in both groups. Hemodynamic indices, oxygen transport variables, total and differential white cell counts, and serum concentrations of TNF and IL-10 were determined at frequent intervals before and after TNF-alpha administration and during the LPS infusion. Additionally, peripheral blood mononuclear cells were collected for determination of messenger ribonucleic acid expression of IL-10 by reverse transcription-polymerase chain reaction. The administration of TNF-alpha at the dose used in this study did not have any profound effect. No pig treated with TNF-alpha died in response to the LPS infusion. In contrast, three of seven control pigs died during the LPS infusion. Lipopolysaccharide-induced arterial hypotension and arterial hypoxemia were attenuated in the TNF-alpha-treated group. Both groups had significant increases in serum concentrations of TNF-alpha in response to LPS, with no significant difference in peak serum TNF-alpha between groups. Neither serum concentrations of IL-10 nor expression of IL-10 messenger ribonucleic acid in circulating mononuclear cells differed between groups. The administration of TNF-alpha attenuated the severity of hyperdynamic shock induced by a subsequent infusion of endotoxin. This effect could not be associated with increased expression or elaboration of the anti-inflammatory cytokine IL-10.

Gender-dependent alterations in serum leptin in alcoholic cirrhosis

Background & Aims: Leptin is a peptide that decreases food intake and increases energy expenditure. It is produced in fat cells, is stimulated by cytokines, and its levels in serum are higher in females. Because anorexia, hypermetabolism, and elevated cytokine levels are frequently observed in cirrhosis, we hypothesized that the serum leptin level would be elevated in cirrhosis. The aim of this study was to investigate the relationship of serum leptin to gender, body composition, and tumor necrosis factor (TNF). Methods: Male (n = 18) and female (n = 10) abstinent alcoholic cirrhotic patients were studied and compared with control subjects (15 male and 8 female). Fat mass, fat-free body mass, and body cell mass were calculated by using H 2[ 18O] and bromide dilution methodology. Serum leptin and TNF concentrations were measured by immunoassays. Results: Fat mass was decreased only in male cirrhotics ( P < 0.05), whereas body cell mass was decreased in both male and female cirrhotics ( P < 0.01). Leptin levels were elevated in female ( P < 0.001) but not male cirrhotics compared with controls. When expressed per kilogram of fat mass, leptin was elevated in both male ( P < 0.01) and female ( P < 0.01) cirrhotics. Women in both cirrhotic and control groups had higher leptin levels than men. TNF was elevated in both male and female cirrhotics and did not correlate with leptin levels. Conclusions: Cirrhotics have elevated serum leptin levels, which are related to both gender- and gender-dependent alterations in body composition. GASTROENTEROLOGY 1998;115:947-953

Cytokines clearance during venovenous hemofiltration in the trauma patient

The objective of the study was to investigate whether continuous venovenous hemofiltration (CVVH) would facilitate removal of substantial amounts of tumor necrosis factor (TNF) and interleukin-6 (IL-6) from the circulation in traumatized critically ill patients with multiple organ dysfunction syndrome. The study design was a prospective, nonblind, randomized controlled trial that was set in the trauma intensive care unit of a tertiary university referral hospital. Thirty consecutive critically ill, mechanically ventilated trauma patients with multiple organ dysfunction syndrome (without renal failure) were included in the study. Patients were randomized to either CVVH or conventional treatment. Blood and ultrafiltrate samples were collected from each patient before the initiation of CVVH and after 24, 72, and 168 hours of therapy. In the control group, blood samples were collected during the same periods. In the 30 patients studied, 15 had hemofiltration and 15 did not. Both groups were similar with regard to age (36 ± 18 years v 36 ± 14 years) and severity scores (injury severity score, 32 ± 16 v 30 ± 11; APACHE II score, 22 ± 7 v 21 ± 6; Goris score, 5.2 ± 1.7 v 5.2 ± 1.8). Before CVVH, TNF and IL-6 could be detected in the serum of all patients. The mean concentration of TNF was 17 ± 22 pg/mL in patients and 22 ± 20 pg/mL in control subjects ( P = NS). The mean concentration of IL-6 was 2,153 ± 2,824 pg/mL in patients and 1,774 ± 1,637 pg/mL in control subjects ( P = NS). We found a TNF and IL-6 substantial elimination with CVVH (excretion of TNF [μg/d] at 24, 48, and 168 hours; 112.6 ± 161.2, 105.2 ± 149.4, and 143.1 ± 170.0; excretion of IL-6 [μg/d]: 1,655 ± 719, 3,091 ± 489, and 2,420 ± 366). However, no significant difference was found in serum cytokines concentration between groups during the study: mean serum TNF concentration decreased from the pretreatment level to a mean level of 12 ± 9.6 pg/mL in patients and 21 ± 27 pg/mL in control subjects. Similar results were found with IL-6 concentration that decreased from the pretreatment level to a mean of 554 ± 731 pg/mL in patients and 382 ± 568 pg/mL in control subjects. In conclusion, CVVH is associated with removal of substantial amounts of TNF and IL-6 from the circulation in traumatized critically ill patients, but the profile of these mediators is similar to that of controls, suggesting a nonclinically relevant elimination. Further prospective, randomized, clinical trials are needed to support our results.