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Neurotrophins are signalling molecules involved in the formation and maintenance of synapses in the brain. They can cross the blood-brain barrier and be detected in peripheral blood, suggesting they may be a potential biomarker for brain health and function. In this review, the available literature was systematically searched for studies comparing peripheral neurotrophins levels with MRI and cognitive measures in healthy adults. Twenty-four studies were identified, six of which included a neuroimaging outcome. Fifteen studies measuring cognition were eligible for meta-analysis. The majority of studies measured levels of brain-derived neurotrophic factor (BDNF), with few assessing other neurotrophins. Results revealed BDNF is related to some neuroimaging outcomes, with some studies suggesting older age may be an important factor. A higher proportion of studies who had older samples observed significant effects between cognition and neurotrophin levels. When cognitive studies were pooled together in a meta-analysis, there was a weak non-significant effect between BDNF and cognitive outcomes. There was also a high level of heterogeneity between cognitive studies. Results indicated that gender was a notable source of the heterogeneity, but additional studies employing relevant covariates are necessary to better characterise the inter-relationship between circulating neurotrophins and cognition., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Systemic sclerosis is a connective tissue disease characterized by tissue fibrosis leading to interstitial lung disease. Transforming growth factor-β (TGF-β) has been of interest as a potential diagnostic marker and also as a drug target in systemic sclerosis. The aim of this study was to assess the serum content of TGF-β1 in patients with systemic sclerosis and to assess its potential role in tissue fibrosis. The study included 30 patients, 5 men and 25 women, of the mean age of 46.9 ± 12.8 years, diagnosed with systemic sclerosis. The control group consisted of 19 women of the mean age of 28.4 ± 7.8 years, diagnosed with primary Raynaud's disease. TGF-β1 serum levels were measured, chest imaging examinations were performed, and fibrotic tissue changes were assessed using the modified Rodnan Skin Score. We found that the mean serum TGF-β1 content in patients with systemic sclerosis was 598.7 ± 242.6 pg/mL, whereas it was 568.4 ± 322.2 pg/mL in the control group (p = 0.378). We also failed to substantiate any significant relationship between TGF-β1 serum levels and the severity of pulmonary and skin fibrosis in systemic sclerosis. In conclusion, systemic sclerosis does not seem a disease that would be accompanied by a specific enhancement of serum TGF-β1. Thus, this cytokine is rather unlikely to play an essential role in the development and course of the disease, nor can it be considered diagnostic or prognostic marker.

Congenital pseudarthrosis of tibia is a genetic, systemic pathology with impaired bone remodeling and unknown pathogenetic mechanisms. Orthopaedic treatment of the disease can fail in some cases. The process of bone remodeling is known to occur under control of local and systemic growth factors, and we sought to explore several osteotropic growth factors, markers of osteogenesis and biologically active molecules in the blood serum of patients with congenital pseudarthrosis of tibia. The study included 12 patients with congenital pseudarthrosis of tibia and anatomical shortening of 2.5±1.1 cm. The' age of patients ranged from 7 years to 18 years. Blood serum was used for enzyme immunoassay analysis. The own blood serum levels of 103 conditionally healthy individuals (of mean age of 13.0±0.27 years) were considered as the norm. Greater changes in the concentration were detected among vascular endothelial and transforming growth factors. The patients showed imbalance in serum TGF, low reparative potential of bone tissue due to osteoclast activation prevailing over differentiation of osteoblasts, progenitor and mesenchymal cells. Dynamics in serum concentration of IGF at the time of frame removal indicated to terminating osteoblast activation and collagen synthesis and concomitant active bone restructuring.

This study examined resting levels of catabolic and anabolic osteokines related to Wnt signaling and their responses to a single bout of plyometric exercise in child and adolescent females. Fourteen premenarcheal girls [10.5 (1.8) y old] and 12 postmenarcheal adolescent girls [15.0 (1.0) y old] performed a plyometric exercise trial. One resting and 3 postexercise blood samples (5 min, 1 h, and 24 h postexercise) were analyzed for sclerostin, dickkopf-1 (DKK-1), osteoprotegerin (OPG), receptor activator of nuclear factor kappa-β ligand (RANKL), and transforming growth factors (TGF-β1, TGF-β2, and TGF-β3). Premenarcheal girls had significantly higher resting sclerostin, TGF-β1, TGF-β2, and TGF-β3 than the postmenarcheal girls, with no significant time effect or group-by-time interaction. DKK-1 was higher in premenarcheal compared with postmenarcheal girls. There was an overall significant DKK-1 decrease from baseline to 1 h postexercise, which remained lower than baseline 24 h postexercise in both groups. There was neither a significant group effect nor group-by-time interaction in OPG, RANKL, and their ratio. RANKL decreased 5 min postexercise compared with baseline and remained significantly lower from baseline 24 h following the exercise. No changes were observed in OPG. OPG/RANKL ratio was significantly elevated compared with resting values 1 h postexercise. In young females, high-impact exercise induces an overall osteogenic effect through a transitory suppression of catabolic osteokines up to 24 h following exercise.

Background: The dynamics of the extracellular matrix (ECM) fibrosis process in dilated cardiomyopathy (DCM) may be assessed non-invasively by means of serum markers of fibrosis., Aim: To explore the kinetics of serum markers of fibrosis during a 12-month follow-up in DCM., Methods: We included 70 consecutive DCM patients (pts) (48±12.1years, EF 24.4±7.4%) with new-onset (n=35, duration <6months) and chronic DCM (n=35, >6months). Markers of collagen type I and III synthesis - procollagens type I and III carboxy- and amino-terminal peptides (PICP, PINP, PIIICP, PIIINP), and ECM metabolism controlling factors - tumor growth factor beta-1 (TGF1-β), and connective tissue growth factor (CTGF) - were measured in serum at baseline, and at 3- and 12-month follow-up. All pts underwent endomyocardial biopsy to determine the presence and extent of ECM fibrosis., Results: Markers of collagen type I synthesis (PICP and PINP) were almost homogenously increased over the 3- and 12-month period, whereas PIIINP values decreased and PIIICP levels were unchanged in new-onset and chronic DCM, and in pts with and without ECM fibrosis. Both TGF-β and CTGF levels decreased over the observation period. Kinetics of serum markers of collagen synthesis and fibrosis controlling factors did not differ between DCM pts categorized according to disease duration and fibrosis status., Conclusions: The kinetics of collagen type I and III synthesis in DCM move in opposite directions, with production of collagen type I consistently increasing, and the synthesis of collagen type III decreasing. Levels of TGF and CTGF, which are proven fibrosis-stimulating factors, had a tendency to decrease. Regardless of disease duration or fibrosis status, the kinetics of serum markers of collagen synthesis, TGF and CTGF were similar in DCM. A better understanding of the kinetics of serum markers of fibrosis in DCM may help to develop more tailored therapeutic approaches to fibrosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Emerging evidence suggests that inflammation and neurodegeneration underlies bipolar disorder. To investigate biological markers of cytokines and brain-derived neurotrophic factor between bipolar I, bipolar II, and other specified bipolar disorder with short duration hypomania may support the association with inflammatory dysregulation and bipolar disorder and, more specifically, provide evidence for other specified bipolar disorder with short duration hypomania patients were similar to bipolar II disorder patients from a biological marker perspective., Methods: We enrolled patients with bipolar I disorder (n=234), bipolar II disorder (n=260), other specified bipolar disorder with short duration hypomania (n=243), and healthy controls (n=140). Their clinical symptoms were rated using the Hamilton Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokine (tumor necrosis factor-α, C-reactive protein, transforming growth factor-β1, and interleukin-8) and brain-derived neurotrophic factor levels were measured in each group. Multivariate analysis of covariance and linear regression controlled for possible confounders were used to compare cytokine and brain-derived neurotrophic factor levels among the groups., Results: Multivariate analysis of covariance adjusted for age and sex and a main effect of diagnosis was significant (P<.001). Three of the 5 measured biomarkers (tumor necrosis factor-α, transforming growth factor-β1, and interleukin-8) were significantly (P=.006, .01, and <.001) higher in all bipolar disorder patients than in controls. Moreover, covarying for multiple associated confounders showed that bipolar I disorder patients had significantly higher IL-8 levels than did bipolar II disorder and other specified bipolar disorder with short duration hypomania patients in multivariate analysis of covariance (P=.03) and linear regression (P=.02) analyses. Biomarkers differences between bipolar II disorder and other specified bipolar disorder with short duration hypomania patients were nonsignificant., Conclusion: The immunological disturbance along the bipolar spectrum was most severe in bipolar I disorder patients. Other specified bipolar disorder with short duration hypomania patients and bipolar II disorder patients did not differ in these biological markers., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Background: Variations in formulations used to prepare platelet-rich plasmas (PRPs) result in differences in the cellular composition and biomolecular characteristics., Purpose: To evaluate the cellular composition and the cytokine-release kinetics of PRP according to differences in the preparation protocols., Study Design: Controlled laboratory study., Methods: Five preparation procedures were performed for 14 healthy subjects, including 2 manual procedures (single-spin [SS] at 900 g for 5 minutes; double-spin [DS] at 900 g for 5 minutes and then 1500 g for 15 minutes) and 3 methods with commercial kits (Arthrex ACP, Biomet GPS, and Prodizen Prosys). After evaluation of cellular composition, each preparation was divided into 4 aliquots and incubated for 1 hour, 24 hours, 72 hours, and 7 days for the assessment of cytokine release over time. The cytokine-release kinetics were evaluated by assessing platelet-derived growth factor (PDGF), transforming growth factor (TGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), interleukin-1 (IL-1), and matrix metalloproteinase-9 (MMP-9) concentrations of each aliquot with bead-based sandwich immunoassay., Results: The DS PRP had a higher concentration of platelets and leukocytes than did the SS PRP. Every PRP preparation exhibited an increase in PDGF, TGF, VEGF, and FGF release when compared with whole blood samples. The FGF and TGF release occurred quickly and decreased over time, while the PDGF and VEGF release was constant and sustained over 7 days. The PDGF and VEGF concentrations were higher in the DS PRP than in the SS PRP, whereas the TGF and FGF concentrations were higher in the SS PRP than in the DS PRP. Biomet GPS had the highest VEGF and MMP-9 concentrations but the lowest TGF concentration. Arthrex ACP had the highest FGF concentration but the lowest PDGF concentration. Prodizen Prosys had the highest IL-1 concentration and higher PDGF concentration than Arthrex ACP., Conclusion: The DS method generally led to a higher concentration of platelet relative to the SS method. However, the cytokine content was not necessarily proportional to the cellular composition of the PRPs, as the greater content could be different between the SS or DS method depending on the type of cytokine., Clinical Relevance: Physicians should select proper PRP preparations after considering their biomolecular characteristics and patient indications., (© 2015 The Author(s).)

Background: Acute kidney injury (AKI) is a condition that leads to a rapid deterioration of renal function associated with impairment to maintain electrolyte and acid balance, and, if left untreated, ultimately irreversible kidney damage and renal necrosis. There are a number of causes that can trigger AKI, ranging from underlying conditions as well as trauma and surgery. Specifically, the global rise in surgical procedures led to a substantial increase of AKI incidence rates, which in turn impacts on mortality rates, quality of life and economic costs to the healthcare system. However, no effective therapy for AKI exists. Current approaches, such as pharmacological intervention, help in alleviating symptoms in slowing down the progression, but do not prevent or reverse AKI-induced organ damage., Methods: An in-depth understanding of the molecular machinery involved in and modulated by AKI induction and progression is necessary to specifically pharmacologically target key molecules. A major hurdle to devise a successful strategy is the multifactorial and complex nature of the disorder itself, whereby the activation of a number of seemingly independent molecular pathways in the kidney leads to apoptotic and necrotic events., Results: The renin-angiotensin-aldosterone-system (RAAS) axis appears to be a common element, leading to downstream events such as triggers of immune responses via the NFB pathway. Other pathways intricately linked with AKI-induction and progression are the tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGF) signaling cascades, as well as a number of other modulators. Surprisingly, it has been shown that the involvement of the glutamatergic axis, believed to be mainly a component of the neurological system, is also a major contributor., Conclusions: Here we address the current understanding of the molecular pathways evoked in AKI, their interplay, and the potential to pharmacologically intervene in the effective prevention and/or progression of AKI., (© 2015 KUMS, All rights reserved.)

Objectives: Noninvasive biomarkers would be valuable for diagnosis and monitoring of eosinophilic esophagitis (EoE). The aim of this study was to determine the utility of a panel of serum biomarkers for the diagnosis and management of EoE., Methods: We conducted a prospective cohort study of consecutive adults undergoing outpatient esophagogastroduodenoscopy. Incident cases of EoE were diagnosed per consensus guidelines; controls had gastroesophageal reflux disease (GERD) or dysphagia and did not meet the EoE criteria. EoE cases were treated with topical steroids and had repeat endoscopy. Pre- and post-treatment serum samples were analyzed in a blinded manner for interleukin (IL)-4, IL-5, IL-6, IL-9, IL-13, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor-α, eotaxin-1, -2, and -3, thymic stromal lymphopoietin (TSLP), major basic protein, and eosinophil-derived neurotoxin. Cases and controls were compared at baseline, and pre- and post-treatment assays were compared in cases., Results: A total of 61 incident EoE cases and 87 controls were enrolled; 51 EoE cases had post-treatment serum analyzed. There were no significant differences in any of the biomarkers between EoE cases and controls at baseline. IL-13 and eotaxin-3 for cases and controls were 85 ± 160 vs. 43 ± 161 pg/ml (P=0.12) and 41 ± 159 vs. 21 ± 73 (P=0.30). There were no significant differences in assay values among cases before and after treatment. There were also no differences after stratification by atopic status or treatment response., Conclusions: A panel of inflammatory factors known to be associated with EoE pathogenesis were not increased in the serum, nor were they responsive to therapy. None of these biomarkers are likely candidates for a serum test for EoE. Histologic analysis for diagnosis and management of EoE continues to be necessary, and novel, less invasive, biomarkers are needed.

Purpose: Prediction of radiation pneumonitis (RP) has been shown to be challenging due to the involvement of a variety of factors including dose-volume metrics and radiosensitivity biomarkers. Some of these factors are highly correlated and might affect prediction results when combined. Bayesian network (BN) provides a probabilistic framework to represent variable dependencies in a directed acyclic graph. The aim of this study is to integrate the BN framework and a systems' biology approach to detect possible interactions among RP risk factors and exploit these relationships to enhance both the understanding and prediction of RP., Methods: The authors studied 54 nonsmall-cell lung cancer patients who received curative 3D-conformal radiotherapy. Nineteen RP events were observed (common toxicity criteria for adverse events grade 2 or higher). Serum concentration of the following four candidate biomarkers were measured at baseline and midtreatment: alpha-2-macroglobulin, angiotensin converting enzyme (ACE), transforming growth factor, interleukin-6. Dose-volumetric and clinical parameters were also included as covariates. Feature selection was performed using a Markov blanket approach based on the Koller-Sahami filter. The Markov chain Monte Carlo technique estimated the posterior distribution of BN graphs built from the observed data of the selected variables and causality constraints. RP probability was estimated using a limited number of high posterior graphs (ensemble) and was averaged for the final RP estimate using Bayes' rule. A resampling method based on bootstrapping was applied to model training and validation in order to control under- and overfit pitfalls., Results: RP prediction power of the BN ensemble approach reached its optimum at a size of 200. The optimized performance of the BN model recorded an area under the receiver operating characteristic curve (AUC) of 0.83, which was significantly higher than multivariate logistic regression (0.77), mean heart dose (0.69), and a pre-to-midtreatment change in ACE (0.66). When RP prediction was made only with pretreatment information, the AUC ranged from 0.76 to 0.81 depending on the ensemble size. Bootstrap validation of graph features in the ensemble quantified confidence of association between variables in the graphs where ten interactions were statistically significant., Conclusions: The presented BN methodology provides the flexibility to model hierarchical interactions between RP covariates, which is applied to probabilistic inference on RP. The authors' preliminary results demonstrate that such framework combined with an ensemble method can possibly improve prediction of RP under real-life clinical circumstances such as missing data or treatment plan adaptation.

Aim: To determine the serum level of cytokines in women with coronary heart disease (CHD) concurrent with osteoporosis (OP) and in those with isolated CHD; to assess a relationship of the levels of cytokines, osteoprotegerin (OPG), and transforming growth factor-β (TGF-β) to the ten-year absolute risk of osteoporotic fractures, the presence of fractures in the history, and that of CHD; and to establish the role of elevated cytokine levels in the development of future fractures., Subjects and Methods: A cross-sectional cohort study included 98 women (mean age, 71.2?8.6 years) with CHD. Forty-eight patients had CHD concurrent with severe OP. The Fracture Risk Assessment Tool (FRAX) was applied to estimate a ten-year absolute risk for fractures in all the patients. The serum levels of OPG, TGF-β, interleukin (IL)-1β, IL-4, IL-6, IL-8, and IL-10, and tumor necrosis factor-a (TNF-α) were measured by enzyme immunoassay., Results: The women with comorbidity were found to have higher levels of OPG, TGF-β, IL-6, IL-8, IL-10, and TNF-α than those with isolated CHID. There was a direct correlation between fractures, CHID, and IL-10 and TNF-α levels and an inverse relationship between fractures, CHD, and IL-8; between CHD and OPG levels. Conclusion. The women with comorbidity were noted to have elevated levels of proinflammatory cytokines and OPG; a correlation was between cytokine levels and fractures and CHD. Increased OPG and IL-6 levels are independent predictors of fractures.

Despite the widespread clinical use of distraction osteogenesis for limb lengthening, the cellular and molecular mechanisms by which this surgical treatment promotes new bone formation in humans are not well understood. The aim of the research was to study the levels of growth factors (GFs) in the serum of patients that were undergoing tibial lengthening with the Ilizarov method of distraction osteogenesis. Those were patients with unilateral congenital discrepancy of the tibia (n = 12), unilateral posttraumatic tibial shortening (n = 7), and healthy patients that underwent cosmetic bilateral tibial lengthening (n = 10). The study established that unlike the congenital group, the posttraumatic group and healthy subjects showed a significantly evident increase in the levels of angiogenic GFs in their serum on day 10 of distraction. In the congenital group, the changes were not significant at this time point. The levels of TGF-α, TGF-β1, and TGF-β2 tended to decrease on day 10 of distraction and on day 30 of the post-distraction period in the cosmetic and posttraumatic groups while they grew in the congenital group. Most dynamic changes in the GFs levels during tibial lengthening were noted in the subjects undergoing cosmetic lengthening, and the least ones were in the congenital group., (© 2013 Orthopaedic Research Society.)

Background: Syndecan-4 is a transmembrane heparan sulfate-carrying glycoprotein that mediates signal transduction pathways activated by growth factors and cell surface receptors, thereby modulating tissue regeneration, angiogenesis, and focal adhesion. The aim of the present study was to determine the clinical use of serum syndecan-4 concentration for diagnosis of heart failure., Methods: Concentration of serum syndecan-4 and other biomarkers of heart failure was measured in 45 patients with heart failure and 21 healthy subjects. Clinical and echocardiographic parameters of cardiac function were recorded., Results: Serum syndecan-4 concentration significantly increased in proportion to the decrease in ejection fraction (r=-0.599, p<0.001) and increase in the left ventricular (LV) mass index (r=0.315, p<0.05). Serum syndecan-4 concentration was significantly correlated with LV geometrical parameters (i.e. LV mass index, LV end-diastolic volume, and LV dimension), while B-type natriuretic peptide (BNP) was significantly correlated with pressure-related parameters [i.e. early transmitral flow velocity/early diastolic velocity of the mitral valve annulus (E/e'), right ventricular systolic pressure, and left atrial volume index]. Syndecan-4 concentration did not significantly correlate with plasma BNP, transforming growth factor-1, matrix metalloproteinase-2, and tenascin-C concentrations. Serum syndecan-4 concentration could predict cardiac death and re-hospitalization due to heart failure (area under curve, 0.706, p<0.05)., Conclusion: Serum syndecan-4 concentration shows promise as a novel diagnostic and prognostic biomarker for heart failure. Since syndecan-4 correlated with LV geometrical rather than hemodynamic parameters, serum syndecan-4 may represent a biomarker of LV remodeling in the failing heart., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Surgery is the primary therapeutic strategy for most solid tumours; however, modern oncology has established that neoplasms are frequently systemic diseases. Being however a local treatment, the mechanisms through which surgery plays its systemic role remain unknown. We have investigated the influence of cytoreduction on the immune system of primary and recurrent ovarian cancer. All ovarian cancer patients show an increase in CD4+ CD25+ FOXP3+ circulating cells (CD4 T(reg) ). CD4/CD8 ratio is increased in primary tumours, but not in recurrent neoplasms. Primary cytoreduction is able to increase circulating CD4 and CD8 effector cells and decrease CD4 naïve T cells. CD4+ T(reg) cells rapidly decreased after primary tumour debulking, while CD8+ CD25+ FOXP3+ (CD8 T(reg) ) cells are not detectable in peripheral blood. Similar results on CD4 T(reg) were observed with chemical debulking in women subjected to neoadjuvant chemotherapy. CD4 and CD8 T(reg) cells are both present in neoplastic tissue. Interleukin (IL)-10 serum levels decrease after surgery, while no changes are observed in transforming growth factor-β₁ and IL-6 levels. Surgically induced reduction of the immunosuppressive environment results in an increased capacity of CD8+ T cells to respond to the recall antigens. None of these changes was observed in patients previously subjected to chemotherapy or affected by recurrent disease. In conclusion, we demonstrate in ovarian cancer that primary debulking is associated with a reduction of circulating T(reg) and an increase in CD8 T-cell function. Debulking plays a beneficial systemic effect by reverting immunosuppression and restoring immunological fitness., (© 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Objective: To investigate the prevalence of clinical and subclinical atherosclerosis in systemic sclerosis (SSc) patients and its associated features., Methods: Fifty unselected SSc patients and 41 controls, matched for sex and age, were investigated for previous cardiovascular events, cardiovascular risk factors, and ultrasonographic features of subclinical atherosclerosis in the carotid arteries, that is intima-media thickness (IMT) > 0.9 mm or plaques. SSc patients were also investigated for disease features and previous treatment. Finally, blood samples were randomly selected from 27 patients and 18 controls to evaluate concentrations of amino-terminal propeptide of type III procollagen (PIIINP), transforming growth factor (TGF)-β, hepatocyte growth factor (HGF), soluble interleukin-2 receptor (sIL-2R), IL-13, E-selectin, intercellular adhesion molecule (ICAM)-1, plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (t-PA), D-dimer, and prothrombin fragments (F1+2)., Results: Previous cardiovascular events were recorded in three SSc patients and no controls (p > 0.05). Mean IMT (0.613 ± 0.240 vs. 0.654 ± 0.173 mm) did not differ between patients and controls (p > 0.05), but subclinical atherosclerosis was detected in 14/50 SSc patients and 4/41 controls (p = 0.036). At multiple logistic regression analysis, mean IMT was correlated with older age [p = 0.006; odds ratio (OR) 1.276, 95% confidence interval (CI) 1.043-1.516] and a higher cumulative corticosteroid intake (p = 0.017; OR 1.155, 95% CI 1.027-1.300). No correlation was found with any soluble marker of disease activity and of coagulation/fibrinolysis system activation., Conclusion: Our study confirms an increased prevalence of subclinical atherosclerosis in SSc patients and demonstrates a hitherto unknown association with corticosteroid cumulative dosage.

Numerous studies have provided support for genetic susceptibility to tuberculosis (TB); however, heterogeneity in disease expression has hampered previous genetic studies. The purpose of this work was to investigate possible intermediate phenotypes for TB. A set of cytokine profiles, including antigen-stimulated whole-blood assays for interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and the ratio of IFN to TNF, were analyzed in 177 pedigrees from a community in Uganda with a high prevalence of TB. The heritability of these variables was estimated after adjustment for covariates, and TNF-alpha, in particular, had an estimated heritability of 68%. A principal component analysis of IFN-gamma, TNF-alpha, and TGF-beta reflected the immunologic model of TB. In this analysis, the first component explained >38% of the variation in the data. This analysis illustrates the value of such intermediate phenotypes in mapping susceptibility loci for TB and demonstrates that this area deserves further research.

Changes of concentration of proinflammatory cytokines--tumor necrosis factor (TNF), interleukin-1, growth transforming factor, granulocyte--macrophage colony stimulating factor in the blood serum of patients with probable diagnosis of an acute pancreatitis (AP) were examined. Seven days before the disease occurrence the TNF concentration rise was observed, what proved, by the authors opinion, its significance as an early diagnostic criterion for AP. Other diagnostic methods did not prove their information value in determination of the disease occurrence during the 7 day premorbid period.

The ability of an emergency oil adjuvanted foot-and-mouth disease (FMD) vaccine to elicit early protective immunity in pigs against direct contact homologous challenge was examined. All vaccinates showed reduced viraemia and shedding of FMDV, and certain animals were protected, showing no clinical signs. IL-6, IL-8 and IL-12 were consistently detected in challenged animals that had been vaccinated. Other cytokines--IL-1, IL-2, TNF, TGF and interferons--were not detected. This demonstrates that the vaccine did not induce a systemic inflammatory response, nor a systemic elevation of T lymphocyte activity. Although the IL-6 and IL-8 did not relate to protection, IL-12 production was highest in the protected vaccinated pigs. Thus, the induction of monocytic cell activity, demonstrable by the production of IL-6, IL-8 and IL-12, appears to play a critical role in FMDV emergency vaccine induction of the innate immune defences which relate to early protection against FMD. The possible modes of defence in which such cytokine activity would be involved are discussed., (Copyright 2002 Elsevier Science Ltd.)

The aim of this review was to assess the role of white cells and neoplastic cells in haemostasis.

Purpose: Angiogenesis, that is new blood vessel formation, is a prerequisite for growth and metastasis of solid tumors. This study was undertaken to quantify tumor capillaries, investigate immunohistochemical expression and measure serum concentrations of angiogenic growth factors in patients with Wilms tumor., Materials and Methods: The hospital records of 33 patients were reviewed and new slides were stained for the endothelial cell marker CD31. Capillaries were quantified in the most vascularized part of the tumor (hot spot) and in the whole slide. New slides were stained immunohistochemically for the angiogenic growth factors angiogenin, basic fibroblast growth factor (bFGF), transforming growth factor alpha, transforming growth factor beta1-3, tumor necrosis factor alpha and vascular endothelial growth factor (VEGF), and their immunoreactivity was quantified. Pretreatment serum samples from 14 patients and 56 healthy control children were analyzed using enzyme-linked immunosorbent assay kits for angiogenin, basic fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, tumor necrosis factor alpha and VEGF., Results: Logistic regression analysis and Kaplan-Meier estimates showed that quantifications based on the tumor hot spot had a significant impact on survival probability (p <0.05). The tumor hot spot counts were highest in the blastemal compartment. Levels of hepatocyte growth factor and VEGF in serum were 3 times higher than those in controls (p <0.01)., Conclusions: Although the sample size is small in this study, the results imply that angiogenesis in Wilms tumor is driven by angiogenic growth factors, and that intratumoral capillary quantification and determinations of serum levels of angiogenic growth factors may be of clinical value.

The cachexia of disease may be promoted by proinflammatory cytokines, eg, interleukin (IL) 1 beta, tumor necrosis factor alpha (TNF-alpha), and IL-6. These, as well as some antiinflammatory cytokines, eg, IL-1 receptor antagonist (IL-1ra), IL-10, and transforming growth factor beta 1 (TGF-beta 1), were analyzed in serum (IL-6, IL-1ra, IL-10, TGF-beta 1) and stimulated blood monocytes (IL-1 beta, TNF alpha, IL-6) obtained from elderly patients with protein-energy malnutrition (PEM). Twenty-one uninfected malnourished patients aged 75 +/- 1 y (mean +/- SD), with a body mass index (BMI; in kg/m2) of 17.2 +/- 0.5 and various noncancer disorders, and 22 healthy matched control subjects aged 72 +/- 1 y, with a BMI of 25.4 +/- 0.7 (significantly different from patients, P < 0.001), were included. Fifteen patients and their corresponding control subjects were reexamined 3 mo later. Isolated monocytes were stimulated with lipopolysaccharide (LPS) and concentrations of IL-1 beta, TNF-alpha, and IL-6 were determined. Serum concentrations of IL-6, IL-1ra, IL-10, TGF-beta 1, and acute-phase reactants were analyzed. Serum concentrations of orosomucoid and IL-6 were higher in the malnourished subjects than in the control subjects (1.14 +/- 0.1 compared with 0.8 +/- 0.3 g/L, P < 0.001; and 5 ng/L compared with undetectable concentrations, P < 0.01, respectively). Higher generation of IL-1 beta (2.7-fold; P < 0.05) and IL-6 (3.7-fold; P < 0.05) was found in monocytes from patients with PEM relative to the control subjects when monocytes were stimulated with 0.1 microgram LPS/L. Monocyte TNF generation and serum concentrations of IL-10, IL-1ra, and TGF-beta 1 did not differ. Similar results were obtained at follow-up. IL-1ra was negatively correlated with delayed cutaneous hypersensitivity (r = -0.34, P < 0.05). We conclude that enhanced generation of proinflammatory cytokines such as IL-6 and IL-1 beta in malnourished patients may contribute to the PEM often encountered in chronic nonmalignant disorders.

The process of angiogenesis plays a critical role in tumor growth and metastasis. Recently, there has been much interest in the possible use of angiogenic growth factors as tumor markers. This paper will review the results thus far of attempts at measuring various angiogenic factors in bodily fluids. In the future, angiogenic factors will most likely be useful as a monitor of therapy and/or a predictor of outcome after cancer has been diagnosed.

Pancreatic cancer is one of the most frequent carcinomas of the human gastrointestinal tract. despite considerable progress in diagnosis, its prognosis has remained unchanged during the last years. Up to now, there is no possibility to screen patients for pancreatic carcinomas, and the symptoms of the disease are uncharacteristic and often misleading. Surgical treatment, with resection of the tumor is the only chance for cure, but for experienced pancreatic surgeons, an advanced tumor stage at the time of operation is a common finding. Large studies reveal the poor prognosis of the disease. Only 20-30% of all patients suffering from pancreatic cancer can be operated with curative intention. In 80-85% of all cases, the tumor has spread into peripancreatic lymph nodes. Thus, mean 5-years survival rates of 3 to 5% are commonly reported, and the median survival time after establishment of diagnosis is 4-6 months. Improvements in surgical technique and postoperative patient's care have led to an impressive decrease in the formerly considerable morbidity and mortality after pancreatic resection. If the tumor can be resected at an early stage and the regional lymph nodes are not involved, median 5-years survival rates of 20-40% are commonly reported. Further approaches include more radical surgical procedures with dissection of the entire peripancreatic region and resection of the upper abdominal blood vessels. Whether this new technique or a combination of operation, radiation and chemotherapy will improve the prognosis of the disease remains unclear. Large clinical trials are necessary to prove these assumptions.

Transforming growth factor alpha (TGF-alpha) is a pleuripotential cytokine with diverse biological effects, including the ability to influence the proliferation of normal cells or neoplastic epithelial cells. Eosinophils are a subset of granulocytes that normally enter the peripheral tissues, particularly those beneath gastrointestinal, respiratory, and urogenital epithelium, where they reside in close proximity to the epithelial elements. In this study, we demonstrate that the great majority of eosinophils infiltrating the interstitial tissues adjacent to two colonic adenocarcinomas and two oral squamous cell carcinomas labeled specifically by in situ hybridization with a 35S-riboprobe for human TGF-alpha (hTGF-alpha). No other identifiable leukocytes in these lesions contained detectable hTGF-alpha mRNA. We also examined leukocytes purified from a patient with the idiopathic hypereosinophilic syndrome. 80% of these eosinophils, but none of the patient's neutrophils or mononuclear cells, were positive for hTGF-alpha mRNA by in situ hybridization, and 55% of these eosinophils were positive by immunohistochemistry with a monoclonal antibody directed against the COOH terminus of the mature hTGF-alpha peptide. Finally, the identification of the purified eosinophil-associated transcript as hTGF-alpha was confirmed by polymerase chain reaction product restriction enzyme analysis followed by Southern blot hybridization. In contrast to eosinophils from the patient with hypereosinophilic syndrome, the peripheral blood eosinophils from only two of seven normal donors had detectable TGF-alpha mRNA and none of these eosinophils contained immunohistochemically detectable TGF-alpha product. Taken together, these findings establish that human eosinophils can express TGF-alpha, but suggest that the expression of TGF-alpha by eosinophils may be under microenvironmental regulation. Demonstration of TGF-alpha production by tissue-infiltrating eosinophils and the eosinophils in the hypereosinophilic syndrome identifies a novel mechanism by which eosinophils might contribute to physiological, immunological, and pathological responses.

Transforming growth factor-beta (TGF-beta 1) suppresses cortisol production when added to cultured bovine adrenocortical (BAC) cells while concomitantly increasing fibronectin synthesis and assembly into extracellular fibrils. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of gelatin-Sepharose-treated media from BAC cells demonstrated a 2-fold stimulation of fibronectin production by TGF-beta 1 in both the presence and absence of serum. Indirect immunofluorescence studies revealed that TGF-beta 1 caused a striking increase in the fibronectin content of BAC extracellular matrix. TGF-beta 1 caused a 4-fold increase in deoxycholate-insoluble fibronectin after 12 h and a 7-fold increase after 24 h over that of control BAC cultures. Northern hybridization analyses indicated that TGF-beta 1 stimulated levels of fibronectin poly(A)+ RNA 2.3-fold. We found that cultured BAC cells express TGF-beta 1 mRNA, suggesting a possible autocrine role for TGF-beta 1 in the adrenal.

A sensitive enzyme-linked immunosorbent assay (ELISA) system for human transforming growth factor alpha (TGF alpha) was developed in combination with polyclonal and monoclonal antibodies. Employing this assay system, we detected TGF alpha like activity in normal human plasma as well as in cancer patients' urine and plasma. These TGF alpha were analyzed by chromatography, immunoreactivity, and EGF-TGF alpha receptor binding assay and found to be identical to authentic human TGF alpha. The presence of TGF alpha circulating in normal adult plasma suggests a new role of TGF alpha in the human body.

Transforming growth factor-beta (TGF-beta), a mediator capable of modulating a broad range of effects on the behavior of many normal cells, was found in high concentrations in the epithelial lining fluid (ELF) of the normal human lower respiratory tract. Although plasma contained small amounts of TGF-beta, the concentrations of TGF-beta in normal ELF were in the 200 to 300 pM range, more than 15-fold higher. This ELF TGF-beta had similar physical characteristics to purified human platelet TGF-beta, competed with platelet TGF-beta for its receptor on A549 carcinoma cells, and stimulated the anchorage-independent growth of NRK cells in soft agar in the presence of epidermal growth factor. Furthermore, ELF TGF-beta suppressed diploid lung fibroblast proliferation in a dose-dependent fashion similar to platelet TGF-beta. In the context of these observations and with the known biologic properties of this molecule, TGF-beta in ELF has the potential to play a role in a variety of cellular processes in the lower respiratory tract.

The entire coding region of the human transforming growth factor beta 1 (TGF-beta 1) precursor cDNA has been stably expressed in a human renal carcinoma cell line. Like platelet TGF-beta 1, the recombinant TGF-beta 1 is secreted in a biologically latent form. Immunoblot analysis and gel-filtration indicate that the recombinant latent TGF-beta 1 is a 100-kDa complex in which active 25-kDa TGF-beta 1 is noncovalently associated with the remaining 75 kDa of the processed precursor. Unlike the platelet latent complex, the recombinant latent complex contains no 135-kDa component. Thus, the processed precursor peptide alone is sufficient to confer latency on active TGF-beta 1, and the 135-kDa platelet component has a different role. The processed precursor is similarly glycosylated in recombinant and platelet complexes, and in both has an exposed heparin binding site that may be involved in targeting of the latent complex. Finally, acid activation of recombinant and platelet complexes is reversible, suggesting that the activation process does not cause major structural modifications in the components of the latent complex.