Background The continuous development of biological disease modifying antirheumatic drugs (bDMARDs) in recent years has significantly improved the treatment options for patients suffering from rheumatoid arthritis. Selecting the most effective biologic remains a challenge, since therapy-response is highly individual depending on the patient history, laboratory values and demographics. Objectives The aim of this study was to investigate, if non-responders can be detected before therapy start using machine learning models and explainable artificial intelligence to provide a probability of non-response and to identify the most impactful contributing factors to the model output. Methods Data from the Austrian Registry for bDMARDs and tsDMARDs in Rheumatic Diseases – BIOREG were obtained. BIOREG provides a real-world data set, which covers rheumatology hospitals and practices throughout Austria. According to EULAR-guidelines the observation time window for treatment response is 6 months and the prediction time horizon was set at 6 months as well. Different machine learning models were trained for Abatacept (ABA), Adalimumab (ADA), Certolizumab (CERT), Etanercept (ETA) and Tocilizumab (TOC) to predict the risk of non-response per treat to target (ttt)-course. Nested cross-validation and hyperparameter tuning (iteration over fixed parameter grid) were applied. To evaluate the prognostic quality per model the area under the receiver operating characteristic (AUROC) was collected and the model with the highest score was selected for further evaluation. By applying the Explainable AI method SHAP (SHapley Additive exPlanations; a game-theoretic approach to evaluate variable importance) to each final model, the most contributing factors and direction of impact were evaluated. Results Data from 1397 patients, 2004 (baseline) visits and 22 variables (19 after cleaning) with at least 100 ttt-courses per drug were included in the study. The best models per biologic achieved an AUROC-score of: CERT: 0.76 (95% CI, 0.67–0.86). TOC: 0.72 (95% CI, 0.69–0.79), ABA: 0.71 (95% CI, 0.65–0.77), ADA: 0.67 (95% CI, 0.62–0.76), ETA: 0.68 (95% CI, 0.53–0.85). The explainable AI interpreted visual analytic scores (VAS) as most important variables for ABA, ETA and TOC. High scores were associated with high risk of non-response for these drugs. For ADA, co-therapy with glucocorticoids was the most important and risk-increasing factor. For CERT, the dosage of the prescribed drug was ranked as the most influential variable; high dosages were associated with lower risk of non-response. Interestingly, some variables displayed opposite impacts in different drugs: Male gender was interpreted as risk-increasing for ABA and risk-decreasing for ETA. Moreover, negative rheumatoid-factor was interpreted as risk-decreasing for ABA/ETA, but risk-increasing for ADA/CERT. Conclusion The results of our study show that non-responders of biological drugs can be detected with moderate to even good prognostic quality before starting a ttt-course, comparable to similar research with different prediction time horizons [1]. The opposite impact of some variables in different bDMARDs as well as the difference in variable importance per bDMARD indicate, that selecting the right drug is highly dependent on the individual patient characteristic. Machine Learning could be of additional support for rheumatologists and patients by providing not only a prediction of ineffectiveness per drug, but also an explanation for the prediction. Reference [1]Koo, B.S., Eun, S., Shin, K. et al. Machine learning model for identifying important clinical features for predicting remission in patients with rheumatoid arthritis treated with biologics. Arthritis Res Ther 23, 178 (2021). https://doi.org/10.1186/s13075-021-02567-y Acknowledgements: NIL. Disclosure of Interests Dubravka Ukalovic Employee of: Siemens Healthineers. Siemens Healthineers is a medical technology company (NOT a pharmaceutical company), Burkhard Leeb Speakers bureau: AbbVie, Roche, MSD, Pfizer, Actiopharm, Boehringer-Ingelheim, Kwizda, Celgene, Sandoz, Grünenthal, Eli-Lilly, Consultant of: AbbVie, Amgen, Roche, MSD, Pfizer, Celgene, Grünenthal, Kwizda, Eli-Lilly, Novartis, Sandoz, Grant/research support from: TRB, Roche, Bernhard Rintelen Speakers bureau: BMS, Eli-Lilly, Pfizer, TRB-Chemedica, UCB, Wyeth, Consultant of: Abbott, Abbvie, Amgen, Gileat, Novartis, Pfizer, Roche, TRB-Chemedica, UCB, Wyeth, Grant/research support from: Abbott, Aesca, Amgen, Centocor, Eli-Lilly, Servier, UCB, Gabriela Eichbauer-Sturm Speakers bureau: AbbVie, Astro-Pharma, Grünenthal, Jansen, Eli-Lilly, Menarini, MSD, Novartis, Pfizer, Roche, TRB, UCB, Fresenius Kabi, Peter Spellitz: None declared, Rudolf Puchner Speakers bureau: AbbVie, BMS, Janssen, Kwizda, MSD, Pfizer, Celgene, Grünenthal, Eli-Lilly, Consultant of: AbbVie, Amgen, Pfizer, Celgene, Grünenthal, Eli-Lilly, Manfred Herold: None declared, Miriam Stetter: None declared, Vera Ferincz: None declared, Johannes Resch-Passini: None declared, Marcus Zimmermann-Rittereiser Employee of: Siemens Healthineers. Siemens Healthineers is a medical technology company (NOT a pharmaceutical company), Ruth Fritsch-Stork Speakers bureau: AbbVie, Astra Zeneca, Astropharm, Novartis.

Background In this multi-centre, randomised, placebo-controlled pilot trial, we investigated the clinical and haemodynamic effects of the endothelin-receptor blocker Bosentan in patients with heart failure, preserved ejection fraction and pulmonary hypertension (PH-HFpEF).Materials and Methods Eligible patients received either 12 weeks of Bosentan therapy, or a placebo drug. Patients were thereafter followed for a further period of 12 weeks without the study medication. At three points during the study (study Commencement, Week 12 and Week 24), a six-minute walk test (6MWT), echocardiographic and laboratory assessments were performed, as well as a quality of life survey. Right heart catheterisation (RHC) was undertaken at commencement only. The study was aborted early, after an interim analysis favoured the placebo.Results Six-minute walk distance (6MWD) did not change in the Bosentan group (309.7 +/- 96.3m (Commencement), 317.0 +/- 126.1m (Week 12), 307.0 +/- 84.4m (Week 24); p = 0.86), but almost reached statistical significance in the placebo group from 328.8 +/- 79.6m, to 361.6 +/- 98.2m and 384.0 +/- 74.9m (Week 24); p = 0.075. In the placebo group, estimated systolic pulmonary artery pressure (measured via echocardiography) significantly decreased (from 62.3 +/- 16.7 mmHg [Commencement], 45.3 +/- 13.9 mmHg [Week 12], to 44.6 +/- 14.5 mmHg [Week 24]; p = 0.014) as did right atrial pressure (13.1 +/- 5.3 [Commencement], 10.0 +/- 3.8 [Week 12], to 9.4 +/- 3.2 [Week 24]; p = 0.046).Conclusion Despite this study's limited sample size and premature cessation, it nevertheless suggests that endothelin receptor blockade in patients with PH-HFpEF may have no beneficial effects and could even be detrimental in comparison to a placebo.

Background: As the ongoing discussions about the effects of COX-2 inhibition and its cardiovascular risk are not limited to the selective COX-2 inhibitors, but refer to therapy with NSAIDs in general, a group of Austrian rheumatologists decided to update their recommendations for NSAID therapy elaborated 2005/2006.Methods: 16 Austrian rheumatologists agreed to revise the 2005/2006 consensus statement concerning NSAID therapy applying an e-mail Delphi procedure. At the beginning each participant had to send 10 statements to the editorial office. Either rewording of or using the unchanged 2005/2006 statements was allowed as well as formulating new statements. The preliminary statements of the first round were collected and similar statements were merged to one single statement by the central editor. In a second round the participants had to choose the 10 most preferred out of all statements. Sentences achieving 60% agreement were accepted, while recommendations with 0 to 2 nominations in one Delphi round were discarded. The procedure was stopped when ultimately 10 recommendations were identified. The statements were discussed and finalised during the Rheumatological Winter Conference in Seefeld 2009. In a last e-mail run the participants 'agreement with the single recommendations were evaluated using a 10-point Likert-scale from "I do not agree at all" to "I completely agree".Results: In four Delphi-rounds 10 statements concerning NSAID therapy were identified by expert opinion. Eight of these are reworded statements of the consensus 2005/2006, two new recommendations were included. General agreement with the ten recommendations was 90.6% (from 73.8-98.8%). The attendance rate for each Delphi round was 68.75% on average.Conclusion: While the 2005/2006 recommendations on NSAID use were primarily focussed on gastrointestinal or renal toxicity of NSAIDs, the updated recommendations much more deal with cardiovascular toxicity of the whole group of NSAIDs. Topical use of NSAIDs and alternatives such as analgetics, glucocorticoids, antidepressants and some antiepileptic drugs in pain treatment in contrast to 2005/2006 are now part of the recommendations.

Methotrexate (MTX) is commonly used in rheumatological disorders and is the first-line treatment in rheumatoid arthritis. To improve MTX therapy and standardise treatment, recommendations were established on a national basis. An Austrian expert panel retrieved 13 questions by a Delphi process including topics such as workup, monitoring, safety, dosing, pregnancy, surgery as well as pulmonary toxicity, infection and vaccination under MTX treatment. A systematic literature review was performed for each question categorising according to the Oxford level of evidence. On the basis of the evidence 20 Austrian experts discussed the results and formulated recommendations. Finally, internal approval was assessed as well as external validity; the latter was done by an anonymous questionnaire asking practising rheumatologists for their agreement with the recommendations and their practical value. The article summarises the 13 recommendations with the relevant evidence. Additionally we show internal and external agreement with the elaborated recommendations as well as a comparison of the Austrian, German and Multinational 3e recommendations for the use of methotrexate in rheumatic disorders in every day clinical practice.

OBJECTIVE:A prospective study was performed to assess the usefulness of contrast-enhanced color Doppler ultrasound (CDUS) in the evaluation of intraarticular vascularization of finger joints in patients with rheumatoid arthritis (RA).METHODS:We investigated 198 finger joints in 46 patients with RA, and 80 finger joints in 10 healthy volunteers. Joints with varying levels of clinical activity of inflammation were classified as being active, moderately active, or inactive. CDUS was performed with a high-frequency multi-D linear array transducer. A microbubble-based ultrasound (US) contrast agent (Levovist; Schering, Berlin, Germany) was intravenously infused. Doppler findings were rated on the basis of both unenhanced and contrast-enhanced CDUS images.RESULTS:Healthy joints showed no intraarticular vascularization on either unenhanced or contrast-enhanced CDUS. Unenhanced CDUS detected intraarticular vascularization in 7 (8%) of 83 inactive joints, in 31 (52%) of 60 moderately active joints, and in 32 (58%) of 55 active joints. Contrast-enhanced CDUS detected intraarticular vascularization in 41 (49%) of 83 joints with inactive RA, in 59 (98%) of 60 joints with moderately active RA, and in all 55 joints with active RA. Detection of intraarticular vascularization was improved by administration of the microbubble-based US contrast agent (P < 0.001). Contrast-enhanced CDUS demonstrated differences in intraarticular vascularization between joints with inactive RA and those with active RA (P < 0.001), between joints with inactive RA and those with moderately active RA (P < 0.001), and between joints with moderately active RA and those with active RA (P < 0.001).CONCLUSION:The use of a microbubble-based US contrast agent significantly improved the detection of intraarticular vascularization in the finger joints of patients with RA. This technique seems to be a useful adjunct in the assessment of disease activity.

The aim of this study was to assess any variation in positive, negative and total affect recorded longitudinally; to compare the results with those from prior transverse or hybrid population studies, based on the same or a different method of mood rating; and to test for any association of mood with cardiovascular, hormonal and geophysical variables monitored concomitantly. The study approach was as follows. A clinically healthy 34-year-old man filled out the positive and negative affective scale (PANAS) questionnaire five times a day for 86 days. Systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) were also measured automatically at 30-minute intervals with an ambulatory monitor from May 19 to June 29, 2000, while different endpoints of heart rate variability (HRV) were also determined at 5-minute intervals from beat-to-beat electrocardiogram (ECG) monitoring for 42 days between May 3 and June 14, 2000, with only short interruptions while the subject took a shower and changed ECG tapes. Saliva samples were collected at the times of mood ratings for one month for later determination of melatonin and cortisol concentrations. Intervals of 24 hours of the record of each variable displaced in increments of 24 hours were analyzed by chronobiologic serial section at a trial period of 24 hours to assess the circadian characteristics as they changed from one day to another. Estimates of the midline-estimating statistic of rhythm (MESOR) and circadian amplitude and acrophase obtained on consecutive days were correlated among variables to assess any associations. The findings were as follows. Overall, a circadian rhythm was demonstrated for all variables. A positive association was noteworthy between the circadian amplitude of negative affect and the MESOR of both SBP (r= 0.363; P= 0.029) and DBP (r= 0.389; P= 0.019), suggesting that BP is raised in the presence of large swings in negative affect. Needing further validation was a weak association between the MESOR of negative affect and the circadian amplitude of SBP (r= − 0.272; P = 0.108), suggesting a lowering of the circadian SBP amplitude in the presence of a strong negative affect. Of further interest was the lack of a statistically significant relation between positive and negative affect, not only in terms of the MESOR but also in terms of the circadian amplitude.

The immune system interacts with the hypothalamo-pituitary-adrenal axis via so-called glucocorticoid increasing factors, which are produced by the immune system during immune reactions, causing an elevation of systemic glucocorticoid levels that contribute to preservation of the immune reactions specificities. Previous results from our laboratory had already shown an altered immuno-neuroendocrine dialogue via the hypothalamo-pituitary-adrenal axis in autoimmune disease-prone chicken and mouse strains. In the present study, we further investigated the altered glucocorticoid response via the hypothalamo-pituitary-adrenal axis in murine lupus. We established the circadian rhythms of corticosterone, dehydroepiandrosterone-sulfate, adrenocorticotropic hormone and melatonin, as well as the time response curves after injection of interleukin-1 of the first three parameters in normal SWISS and lupus-prone MRL/MP-fas(Ipr) mice. The results show that lupus-prone MRL/ MP-fas(Ipr) mice do not react appropriately to changes of the light/dark cycle, circadian melatonin rhythms seem to uncouple from the light/dark cycle, and plasma corticosterone levels are elevated during the resting phase. Diurnal changes of dehydroepiandrosterone-sulfate and adrenocorticotropic hormone were normal compared to healthy controls. These data indicate that MRL/ MP-fas(Ipr) mice not only show an altered glucocorticoid response mediated via the hypothalamo pituitary adrenal axis to IL-1, but are also affected by disturbances of corticosterone and melatonin circadian rhythms. Our findings may have implications for intrathymic T cell development and the emergence of autoimmune disease.

The present study was performed to investigate the effects of exhaustive long lasting exercise at moderate altitude on the time course of serum immunomodulatory peptides, vascular endothelial growth factor (VEGF) and serum erythropoietin (EPO). Thirteen well trained runners participated at the Swiss Alpine Marathon of Davos (distance 67 km, altitude difference 2300 m). Interleukin-6 was significantly elevated in the first 2h after the run. In contrast, tumor necrosis factor-α and both soluble tumor necrosis factor-a receptors I and II were increased after exercise termination and showed sustained serum concentrations the following days. Neopterin, a serum marker for the activation of the cellular immune system, was increased until day two after the run. Immediately after the run VEGF was significantly elevated and further increased 2.4-fold until day five post exercise (p = 0.005). EPO was also increased after exercise but reached its maximum 2 h after the run (2-fold increase; p = 0.004) and decreased thereafter. The main findings of our study are that prolonged strenuous exercise at moderate altitude induced a significant long lasting increase in serum VEGF and EPO which was accompanied by an activation of the immune system.

Platelet count is regularly low in patients after multiple trauma, mainly due to blood loss and dilution. Thrombopoietin (TPO) is the main regulator of the circulating platelet mass. Under several clinical conditions an inverse correlation between TPO and the circulating platelet mass was reported. Since platelets bind and internalize TPO, a platelet-dependent regulation of TPO was suggested. Thus, acute blood loss should be accompanied by elevated TPO. We measured serum TPO, platelets, interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in 17 multiple traumatized victims. Blood was collected within 12 h after trauma as well as in the morning of days 2, 4, 6 and 9 after admission at the intensive care unit. Platelet count was low at admission and remained low until day 4. Thereafter platelets increased until day 9. TPO nearly doubled within the first 2 d, reaching its maximum on day 6. IL-6 was initially very high and steadily decreased until day 9. VEGF increased 3-fold during the 9 d. Statistically significant correlations of TPO were found with platelets and IL-6, but not with VEGF. In multiple traumatized patients low platelet count is followed by a rapid increase in serum TPO. This fits into the concept of a feedback regulation between circulating TPO and platelet mass.

Interleukin-8 (IL-8) is a potent neutrophil chemotaxin, which can also be produced by endothelial cells to facilitate leukocyte emigration. The aim of this study was to determine the effects of the anti-inflammatory drug thalidomide (THD) on chemotaxin release from endothelial cells. Human umbilical vein endothelial cells (HUVEC) were stimulated with tumor necrosis factor alpha (TNFalpha) or endotoxin (LPS) in the presence or absence of various concentrations of THD. Endothelium-derived interleukin-8 (eIL-8) in supernatants was measured using an enzyme-linked immunosorbent assay (ELISA) and biological activity of the harvested eIL-8 was tested in Boyden chamber chemotaxis assays on PMNL. THD itself had no effect on eIL-8 release. Upon stimulation with TNFalpha or LPS, HUVEC produced increased amounts of eIL-8 and THD affected this process in a bidirectional manner, with augmentation of TNFalpha- and inhibition of LPS-effects. Functionality of eIL-8 was confirmed in chemotaxis experiments and by inhibition of chemotactic effects of supernatants with anti-human IL-8 monoclonal antibodies. Results explain and emphasize immunomodulatory properties of THD in cytokine- and endotoxin-induced inflammation and regulation of transendothelial migration.

OBJECTIVETo define the respiratory burst activity of neutrophils, the total anti-oxidative status of plasma, and the parameters of systemic inflammation in patients with ankylosing spondylitis (AS) before and after a combined radon-hyperthermia treatment in the thermal tunnels of Böckstein-Bad Gastein in Austria.METHODSIn 20 patients with AS the effects of a total of 15 hours of radon-hyperthermia-treatment spread over a period of three weeks were studied. The respiratory burst activity of neutrophils was measured fluorometrically using dichlorofluorescein diacetate, the total anti-oxidant status was measured using azinodiethyl-benzthiazoline-sulphonate, and inflammation parameters were determined by routine laboratory assays.RESULTSBefore treatment, the basal neutrophil respiratory burst in patients (n = 20) was 409 +/- 62 fluorescence arbitrary units (AU; mean +/- SEM) and 359 +/- 37 AU in controls (n = 9; p > 0.5); the stimulated respiratory burst (fMet-Leu-Phe, 10(-6) M) was 1,027 +/- 133 AU in patients and 1,152 +/- 218 AU in controls (p > 0.5). After treatment, the basal neutrophil respiratory burst in patients (n = 19) was 137 +/- 16 and in controls it was 174 +/- 35 AU (n = 8; p > 0.1); the stimulated respiratory burst was 670 +/- 66 and 1,305 +/- 82 AU, in patients and controls respectively (p < 0.001). No effects of treatment on the total anti-oxidant status of the plasma or on the parameters of inflammation were detected.CONCLUSIONCombined radon-hyperthermia treatment reduces the respiratory burst activity of the blood circulating neutrophils in patients with AS. If respiratory burst activity from the neutrophils plays a role in the pathophysiology of ankylosing spondylitis, the observed reduction may be related to the beneficial effects of radon-hyperthermia treatment.

In the present study, we investigated the effects of the anti-inflammatory drug pentoxifylline (PTX) on activation of endothelial cells for enhanced adhesion and transmigration of neutrophils by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and granulocyte colony-stimulating factor (G-CSF). To evaluate the mechanism by which PTX exerts its effect, human umbilical vein endothelial cells (HUVEC) were pretreated with theophylline, 2′-O-dibutyryl-3′, 5′-cyclic adenosine monophosphate (db cAMP), and 3-isobutyl-1-methylxanthine, respectively, prior to stimulation. Pretreatment of HUVEC with PTX significantly antagonized TNF-, IL-1-, and G-CSF-activated transmigration of neutrophils. Additive stimulatory effects of PTX were seen with LPS. With the exception of theophylline, all other test cAMP-raising agents stimulated transmigration in similar fashion to PTX. Upon stimulation with TNF or LPS, HUVEC produced IL-8 and PTX affected this process in opposing fashions, with inhibition of the effects of TNF and augmentation of those of LPS. These results demonstrate that PTX differentially affects mediator-induced activation of HUVEC. The present IL-8 dependent and cAMP-regulated augmentation of LPS-induced stimulation of transmigration is the first description of an additive effect of PTX with a pro-inflammatory agent.

The aims of this investigation were to measure corticotropin-releasing hormone (CRH), corticotropin (ACTH) and cortisol before, during and after delivery searching for an endocrine intercorrelation of the hypothalamic-pituitary-adrenal (HPA) axis and to correlate these findings with obstetrical variables.Blood was sampled from 50 women with singleton pregnancies at term without uterine contractions, during delivery (after full cervical dilatation) and on the 4th postnatal day. Hormones were measured by radioimmunoassay (RIA). The correlation between obstetric variables, sociodemographic and endocrine data were evaluated using the Spearman rank coefficient. Group comparisons for continuous variables were calculated using the Mann-Whitney U test and Kruskal-Wallis test.Maternal plasma ACTH and cortisol increased significantly during labor, declining toward the 4th postnatal day (p < 0.001) and showing a significant intercorrelation (p < 0.01). Compared to women without uterine contractions CRH rose during labor (p < 0.05) and decreased rapidly to the 4th postnatal day (p < 0.001). No correlations between CRH and ACTH or cortisol were observed. None of the obstetrical variables (parity, newborn's weight, duration of delivery) revealed any significant correlation with ACTH. Analgetic medication (pethidine hydrochloride) was not able to influence the endocrine response to labor stress.Stressful experience during childbirth has an impact on endocrine response. However, this is not fully evident along the HPA axis in a simple biological model with monocausal dependencies. This 'biological stress model' is not sensitive enough to detect different childbirth conditions and the hormones in the maternal compartment have partially fetal (placental) origin.

The mode of action of intravenous immunoglobulins (IVIG) in autoimmune and immunoregulatory disorders is still poorly understood. In vitro, direct effects of IVIG on cytokine release and on cytokine receptors have been described, as well as naturally occurring, neutralizing anti‐cytokine antibodies. The aim of our study was to investigate whether the enrichment in IgM and IgA would have any impact on the in vitro immunomodilatory capacity of IVIG. The preparation tested (Pentaglobin) contains 76% IgG and 12% IgM and IgA, respectively. We could demonstrate a significant inhibition of alloantigen‐induced proliferation in the mixed lymphocyte reaction (MLR) even at a Pentaglobin concentration of 1·0 mg/ml. About 10‐fold higher concentrations of standard 7S IVIG containing only trace amounts of IgM and IgA were necessary to achieve equivalent suppression of the alloimmune response. Similarly, phytohaemagglutinin (PHA)‐induced lymphocyte proliferation was more effectively inhibited by Pentaglobin than by standard 7S IVIG. Cytokine analyses in culture supernatants of MLR provide evidence that Pentaglobin not only modulates interleukin‐2 (IL‐2), which has already been observed with standard 7S IVIG, but, moreover, modulates interferon‐γ production with a subsequent impact on monocyte‐derived tumour necrosis factor‐α and IL‐6 release. Based on these results we conclude that in vitro the IgM‐ and IgA‐enriched Pentaglobin has a more potent immunomodulatory capacity than conventionally used standard 7S IVIG.BMT, bone marrow transplantation, GVHD, graft‐versus‐host diseaseIFN, interferonIL, interleukinIVIG, intravenous immunoglobulinMLRmixed lymphocyte reactionPHA, phytohaemagglutininTNF, tumour necrosis factor.

A cross-sectional study regarding endocrine and cytokine parameters in human follicular fluid (FF) as compared to serum values following hormonal stimulation for in-vitro fertilization was conducted. The patients (n = 32) were treated sequentially with the luteinizing hormone-releasing hormone (LHRH) agonist buserelin followed by a combination of buserelin plus highly purified follicle stimulating hormone and finally human chorionic gonadotrophin, in order to induce ovulation. The FF content of pro-inflammatory (IL-1, IL-6), and anti-inflammatory (IL-1ra, IL-10) cytokines, of the immune response-related soluble interleukin-2 receptor (sIL-2R), as well as the mitogens vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) were determined. Routine evaluation included peripheral blood cell counts, morphological data of the ovary and ova, ovarian steroids, prolactin concentrations and thyroid function parameters [free thyroxine (fT4), thyroglobulin]. The concentrations of IL-6, IL1-ra, siL-2R, VEGF and bFGF in the FF compartment were higher than in serum in the majority of cases. Regression analysis showed a significant association between the serum and FF concentrations of fT4 (P = 0.04; y = 0.37 + 0.34x) and IL-6 (P = 0.002; y = 0.78 + 0.5x). Multiple regression analysis revealed that progesterone played a role in determining VEGF concentrations in the FF (P = 0.07; y = 0.37 + 0.86x). Thyroglobulin concentrations within the FF were extremely low whereas fT4 concentrations in the FF were similar to those in serum. Patients with a previously diagnosed hypothyroidism tended to have lower serum oestradiol and higher serum progesterone when compared to euthyroids. We conclude that the human FF represents a functional compartment that integrates endocrine, immunological, and mitogenic signalling that is unique for each ovarian follicle. The close association between progesterone and VEGF within the FF suggests a close association of this mitogen to gonadotrophin stimulation, confirming the ovary as a production site of VEGF.

Objectives: The release of monocyte chemoattractant protein-1 (MCP-I) in the vessel wall may lend to accumulation of monocytes in the subendothelial space. The role of neutrophils (PMNL) in the initiation of this process is unknown. We tested whether PMNL are able to induce the production and release of MCP-1 in endothelial cells. Methods: PMNL were allowed to interact with human umbilical vein endothelial cell (HUVEC) monolayers in culture. Culture media were collected and assessed for chemotactic activity on mononuclear leukocytes (MNC) or purified monocytes in a modified Boyden chamber assay. Additionally, MCP-I levels in supernatants were quantified by ELISA. Results: Media from unstimulated HUVEC culture supernatants induced a slight increase (1.2-fold) of MNC and purified monocyte chemotaxis, which was significantly augmented by addition of PMNL for 1 h (1.4-fold; P < 0,05). The increase in chemotaxis was time- and dose-dependent and could be blocked by an anti-MCP-1 monoclonal antibody. Media obtained after coculture of PMNL and HUVEC for 1-5 h contained increased amounts of MCP-1 as measured by ELISA; addition of cycloheximide abolished this response. Conclusions: Interaction of PMNL with endothelium induces the release of functionally active MCP-I suggesting, that in the vascular wall, PMNL may play a role in the recruitment of MNC. (C) 1998 Elsevier Science B.V. All rights reserved.

Measurements of α-fetoprotein (AFP) detect hepatocellular carcinoma (HCC) with low levels of sensitivity and specificity, and therefore are not recommended for use in liver cancer surveillance. However, AFP levels might accurately detect HCC in subgroups of patients. We performed a retrospective case-control study to identify features of patients with cirrhosis in whom levels of AFP correlated with HCC.We collected data from patients with cirrhosis, with (n = 452) or without (n = 676) HCC, diagnosed at Parkland Hospital in Dallas, Texas, from January 2005 through June 2012. We determined sensitivities and specificities with which different levels of AFP identified those with HCC; multivariate logistic regression was used to associate accurate identification of HCC with patient features (age, sex, race/ethnicity, alcohol intake, smoking, etiology of cirrhosis, presence of decompensation, and laboratory test results). We assessed the overall accuracy of these factors in detecting HCC using receiver operator characteristic curve analysis and the Delong method. We calculated levels of AFP that detect HCC with the highest levels of sensitivity and specificity in subgroups using receiver operator characteristic analysis.The most common etiologies of cirrhosis were hepatitis C virus (HCV) infection (60%) and alcohol induced (22%). Nearly 11% of patients were human immunodeficiency virus (HIV)-positive. Levels of AFP greater than 20 ng/mL detected HCC with 70.1% sensitivity and 89.8% specificity. This AFP level identified patients with HCC with a c-statistic of 0.87 (95% confidence interval, 0.85–0.89); it was significantly more accurate in HCV-negative patients than in HCV-positive patients (c-statistic, 0.89 vs 0.83; P = .007). AFP levels of 59 ng/mL or greater most accurately detected HCC in patients with HCV-associated cirrhosis; levels of AFP of 11 ng/mL or greater accurately identified HCC in HCV-negative patients. The level of AFP identified early stage HCC with a c-statistic of 0.62 (95% confidence interval, 0.58–0.66), and had a significantly higher level of accuracy for HIV-positive patients than for HIV-negative patients (c-statistic, 0.81 vs 0.59; P < .001).Based on a retrospective analysis of data from patients with cirrhosis, with or without HCC, AFP level most accurately detects HCC in patients without HCV infection. It detects HCC with a high level of accuracy in patients with cirrhosis and HIV infection.

PURPOSE The clinical impact of endogenous cytokines supplied with deterministic properties in the generation of either T helper (Th)1 -type or Th2-type immune response was investigated in patients with ovarian cancer. Whereas interleukin (IL)- 12 initiates the differentiation of naive Th0 cells toward Th1 phenotype, IL-4 and IL-10 mediate the development of Th2-type immunity. PATIENTS AND METHODS Cytokines were determined before treatment by means of enzyme-linked immunosorbent assay (ELISA) in ascites fluid and serum of 76 patients with ovarian cancer. Cytokine levels were compared with each other and with standard clinicopathologic parameters. A stepwise logistic regression was calculated to rule out interdependence in the associations of the various variables. Survival analyses were performed with the Kaplan-Meier method and differences in survival were examined according to Mantel and Breslow. Cox proportional hazards analysis was used to identify independent prognostic factors. RESULTS Whereas IL-10 and IL-12 were detectable in all ascites-fluid samples, IL-4 was measurable in only 43% of the specimens. With the exception of neopterin, macrophage colony-stimulating factor (M-CSF), and IL-4, determined cytokine levels were significantly elevated in ascites fluid compared with serum (P < .01). In univariate analyses, high ascitic-fluid concentrations of either neopterin, tumor necrosis factor-alpha (TNF-alpha), or IL-12 were associated with poor disease-free (P < .005) and overall (P < .01) survival. Multivariate Cox regression analysis showed ascitic-fluid IL-12 levels to be the only immunologic variable that retained independent prognostic significance (P < .03 for disease-free and P < .01 for overall survival), together with residual disease, Fédération Internationale de Gynécologie et d'Obstétrique (FIGO)-stage, and patient age. CONCLUSION In ovarian cancer, high ascitic-fluid IL-12 levels, which may indicate a local Th1-generated immune response, are associated with disease progression.

To determine whether iron chelation modulates nitric oxide (NO) formation and cell-mediated immune effector function in children with cerebral malaria, serum concentrations were measured of the stable end products of NO, nitrite and nitrate (NO2-/NO3-), interleukin (IL)-4, -6, and -10, and neopterin in 39 Zambian children enrolled in a placebo-controlled trial of desferrioxamine B and quinine therapy. Mean concentrations of NO2-/NO3- increased significantly over 3 days in children receiving desferrioxamine plus quinine but not in those given placebo and quinine. Neopterin levels declined significantly with placebo but not with desferrioxamine. IL-4 levels increased progressively in the placebo group and ultimately decreased in the desferrioxamine group, but the trends were not statistically significant. IL-6 and IL-10 levels were elevated initially and decreased significantly in both groups over 3 days. These data are consistent with the hypothesis that iron chelation therapy in children with cerebral malaria strengthens Th1-mediated immune effector function involving increased production of NO.