From feedback loop transitions to biomarkers in the psycho-immune-neuroendocrine network: Detecting the critical transition from health to major depression.

BACKGROUND: Biological pathways underlying major depressive disorder (MDD) can be viewed as systems biology networks. The psycho-immune-neuroendocrine (PINE) network comprises central nervous, immune, endocrine and autonomic systems, integrating biological mechanisms of MDD. Such networks exhibit recurrent motifs with specific functions, including positive and negative feedback loops, and are subject to critical transitions, influenced by feedback loop transitions (FLTs). AIMS: We aim to identify critical feedback loops and their FLTs, as well sentinel network nodes (SNNs), key network nodes that drive FLTs, within the PINE network. Examples of biomarkers are provided which may reflect early warning signs of impending critical transition to MDD. RESULTS: Disruption of homeostatic feedback loops reflects the physiological transition to MDD. Putative FLTs are identified within hypothalamic-pituitary-adrenal (HPA) and sympathetic-parasympathetic axes, the kynurenine pathway, gut function and dysbiosis. CONCLUSIONS: Progression from health to disease is driven by FLTs in the PINE network, which is likely to undergo changes characteristic of system instability. Biomarkers of system instability may effectively predict the critical transition to MDD.

[Dialysis and ultrafiltration therapy in patients with cardio-renal syndrome: recommendations of the working group "heart-kidney" of the German Cardiac Society and the German Society of Nephrology]. / Dialyse- und Ultrafiltrationsverfahren bei kardio-renalem Syndrom. Empfehlung der Arbeitsgemeinschaft "Herz--Niere" der Deutschen Gesellschaft für Kardiologie--Herz- und Kreislaufforschung e.V. und der Deutschen Gesellschaft für Nephrologie e.V.

Renal failure is common in patients with severe heart failure. This complex pathophysiological interaction has been classified as cardio-renal syndrome. In these patients hydropic decompensation is the main cause of hospitalization. In patients with refractory heart failure, characterized by diuretic resistance and congestion due to volume overload, ultrafiltration has to be considered. In acute decompensated heart failure with worsening of renal function, extracorporeal ultrafiltration is the preferred treatment modality. On the other hand, patients suffering from chronic decompensated heart failure, particularly patients with ascites, will profit from the treatment specific advantages of peritoneal ultrafiltration. Prerequisite for an optimized care of patients with cardio-renal syndrome is the close collaboration among intensive care doctors, cardiologists and nephrologists.

Upper Blepharoplasty for Areola Reconstruction.

Blepharoplasty is one of the most common rejuvenating facial plastic surgery procedures. The procedure has been described many times and has very few complications. The tissue removed from the upper eyelid during blepharoplasty can be used as a skin graft for areola reconstruction due to the tissue's similarity to the areola's natural skin. The present study investigated the use of upper blepharoplasty for areola reconstruction. Criteria were patient satisfaction, objective measurements and the assessment of cosmesis by a panel of physicians. All eight patients included in the study were very satisfied with the cosmetic result. Objective measurements and assessment by a panel of physicians using photographs of the reconstructed nipple-areola complex showed very good aesthetic results.

Change of aesthetic and functional outcome over time and their relationship to quality of life after breast conserving therapy.

PURPOSE: We analyzed changes in aesthetic and functional outcome over time after breast conserving therapy. Our special interest resides in the question of whether these aspects gain or loose their influence on quality of life (QoL) with temporal progress. PATIENTS AND METHODS: This prospective single centre cohort study included 138 patients, treated with breast conserving surgery and consecutive radiotherapy. Patients completed two questionnaires one week and one year after surgery: the BCTOS (Breast Cancer Treatment Outcome Scale) to measure Functional, Aesthetic, and Breast Sensitivity Status and the EORTC (European Organisation for Research and Treatment of Cancer) C30-BR23 to assess QoL. We applied correlation and multiple regression analysis as statistical methods. RESULTS: Aesthetic and Functional Status did not change significantly over one year, whereas Breast Sensitivity Status and several QoL subscales showed significant improvement (p < 0.0001). Correlations between BCTOS scales and EORTC subscales remain similar over time. Functional and Aesthetic Status kept a strong impact on global health (Spearman's Rho = -0.28 to -0.45 depending on time of assessment). Increasing age and poorer Functional Status shortly after surgery are predictors of a decline in global health over one year (p < 0.001). CONCLUSION: Functional and aesthetic outcome after breast conserving surgery maintain their impact on QoL over a one year follow-up period and are valuable predictors of QoL.

[Prevention of thromboembolism in patients with atrial fibrillation]. / Vorhofflimmern bewirkt Thrombenbildung. Effektive Antikoagulation reduziert das Schlaganfallrisiko.

Provided that account is taken of the criteria discussed in the present article, there is no doubt about the therapeutic benefits of effective anticoagulation in patients with chronic atrial fibrillation. Indeed, it is to be expected that the previously valid therapeutic guidelines are more likely to be expanded to reduce feared thromboembolic complications to a minimum, as is exemplified by the recommendation that the application of anticoagulation treatment with vitamin K antagonists should be continued over the longer term, that is, after the restoration of sinus rhythm. Furthermore, there is hope that effective drugs with a calculable (level of) safety and simplicity of administration may soon become available.

Suppressors of cytokine signaling proteins in human preterm placental tissues.

Decreased suppressors of cytokine signaling (SOCS) activity in human gestational tissues may play a part in the onset/progression of term labor. Since SOCS proteins negatively regulate cytokine-mediated inflammatory processes, we hypothesized that SOCS proteins are elevated in gestational tissues from spontaneous preterm deliveries with intrauterine infection. SOCS1, -2 and -3 mRNAs and proteins were detectable by RT-PCR and immunoblotting respectively, in preterm amnion, choriodecidua and placenta, irrespective of infection status. Immunoperoxidase staining localized SOCS1, -2 and -3 to all cell types of the gestational membranes, with infiltrating leukocytes reacting strongly in infected tissues. In villous placenta, SOCS was immunolocalized to the syncytiotrophoblast with marked staining of round mesenchymal cells, possibly Hofbauer cells. Nuclear SOCS staining was seen in amnion, chorion and placental syncytiotrophoblasts. SOCS proteins were, in general, significantly more abundant in placenta compared with amnion or choriodecidua. Placental SOCS1 and interleukin-1beta concentrations were positively correlated (r(2)=0.47; P<0.05). However, no changes in SOCS levels in any tissues were observed with intrauterine infection. The relatively large amounts of SOCS proteins in the placenta may reflect a placenta-specific immunoprotective response to minimize the elaboration and effects of cytokines with potential to harm the placenta and fetus. Lack of labor-associated changes in SOCS levels suggests that the regulation of SOCS expression in preterm gestational tissues differs from those at term, perhaps reflecting roles in regulating placental somatotropic responses.

Cytokines, prostaglandins and parturition--a review.

The elaboration of cytokines, chemokines and immunomodulatory proteins in the placenta and gestational membranes has been extensively investigated in the context of both normal and abnormal pregnancy and delivery. Patterns of expression of cytokines in the foetal membranes and decidua suggest that inflammatory activation occurs modestly with term labour, but much more robustly in preterm delivery, particularly in the presence of intrauterine infection. Enhanced chemokine expression, particularly evident in deliveries with an infected amniotic cavity, is presumably responsible for recruiting infiltrating leukocytes into the membranes thereby amplifying the inflammatory process and hastening membrane rupture and delivery. Anti-inflammatory cytokines suppress inflammatory reactions in the placenta, but under some circumstances may act in a pro-inflammatory fashion in the membranes. Intracellular signalling by cytokines is modulated by proteins such as SOCS (Silencer Of Cytokine Signalling)-1, -2 and -3. Changes in the abundance of these proteins occur with term labour, implicating them as modulators of cytokine actions around the time of parturition. Prostaglandins, released by the membranes in response to stretch and the actions of pro-inflammatory cytokines, act not only upon the myometrium and cervix, but may also exert paracrine/autocrine effects on cell viability and matrix protein integrity. The localization and regulation of prostanoid isomerases, responsible for converting PGH(2) (derived from prostaglandin H synthase-1 and -2) to bioactive prostanoids, are being studied in these tissues, particularly in the context of cytokine interactions. Although the gestational tissues are known to be sources of PGD(2), PGJ(2) and its derivatives, the regulation of production of these prostaglandins has yet to be studied in any detail and their actions, which may include apoptosis and suppression of inflammation, remain poorly defined. A more complete understanding of these aspects of cytokine-prostaglandin interactions in pregnancy and parturition will, no doubt, unfold as current studies come to fruition.

Hypoxia inhibits activin A production by term villous trophoblast in vitro.

Elevated activin A and inhibin A levels have been associated with pre-eclampsia, a pregnancy-related disorder associated with placental hypoxaemia. We investigated the effect of in vitro hypoxia on the production of inhibin A, activin A and its binding protein follistatin in term villous placental explants (n=4-7) and trophoblast monolayer cultures (n=4). Explants and trophoblasts were incubated for 24-72 h under either normoxic (21 per cent O(2)) or hypoxic (2 per cent O(2)) conditions. Production of activin A, inhibin A, and follistatin was determined by specific ELISA. After 48 h of hypoxia, villous explants exhibited a significant reduction in activin A production rates to 53.2 +/- 8.9 per cent (mean +/- SEM, P<0.05) of normoxic controls which was sustained after 72 h in culture (46.8 +/- 5.9 per cent), whereas production by trophoblast monolayers was not affected by hypoxia. Follistatin production was decreased to 53.7 +/- 9.2 per cent of control (P<0.05) after 48 h of hypoxia. Inhibin A production remained unaltered in both culture systems. Our data demonstrate for the first time that hypoxia lowers term placental activin A and follistatin production in vitro. These findings do not support the notion that elevated circulating activin A levels in pre-eclampsia originate from the placenta as a result of placental hypoxia. Other as yet unknown maternal/placental factors may contribute to elevated activin A production in women with severe pre-eclampsia.

Efficacy and specificity of non-steroidal anti-inflammatory drugs for the inhibition of cytokine-stimulated prostaglandin E(2) secretion by amnion-derived WISH cells.

Prostaglandin H synthase-2 (PGHS-II) specific inhibitors have been proposed as a potential treatment in the prevention of preterm birth. We examined the efficacy of PGHS inhibitors on basal and cytokine-stimulated prostaglandin (PG) production by the amnion-like WISH cell line. WISH cells were treated with interleukin (IL)-1 beta and tumour necrosis factor (TNF)-alpha in the presence or absence of indomethacin, etodolac, 5,5-dimethy-3-(3-fluorophenyl)-4-(4-methlysulphonyl) phenyl-2 (5H)-furanone (DFU) or nimesulide (1.6-1000 nM) for 16 h. PG production was then measured using radioimmunoassay. Nimesulide and DFU were the most selective non-steroidal anti-inflammatory drugs (NSAIDs) of IL-beta-stimulated PG production in these studies with an a IC(50)(basal)/IC(50)(stimulated) ratio of, respectively, 142.2 and 113.8, followed by etodolac (25.3) and indomethacin (2.2). Similar results were obtained when cells were stimulated with TNF-alpha. The results of this study suggest that PGHS-II-selective NSAIDs may be effective in the prevention of cytokine-driven amnion PG production associated with preterm labour.

[Atherosclerotic renal artery stenosis]. / Die atherosklerotische Nierenarterienstenose. Screening nur bei konkretem Verdacht.

Only patients with the typical symptoms of a stenosis of the renal artery should be submitted to a screening examination. In elderly patients with suspected atherosclerotic stenosis of the renal artery, color-coded duplex ultrasonography is the diagnostic method of choice. If visualization proves to be poor, and in particular when accessory renal arteries are present, magnetic resonance angiography may be considered. If there is significant stenosis of the renal artery, and if a positive effect on renal function or blood pressure control is to be expected, percutaneous transluminal angioplasty with implantation of a stent is the treatment of first choice. In the case of patients with additional aortic pathology, operative revascularization must be considered.

Hypoxia attenuates PGE(2)but increases prostacyclin and thromboxane production in human term villous trophoblast.

Prostanoids have been proposed to play a major role in the regulation of uteroplacental blood flow. We examined the effect of hypoxia on the production of prostaglandin E(2)(PGE(2)) thromboxane B(2)(TXB(2)), and prostacyclin (measured as 6-keto-PGF(1alpha)) by human term trophoblast cells and villous placental explants. Explants (n=8) and purified trophoblast cells (n=5) were incubated for 24-72 h under either normoxic (21 per cent O(2)) or hypoxic (2 per cent O(2)) conditions. In trophoblast monolayer cultures, hypoxia attentuated PGE(2)production rates to 52+/-9.4 per cent (mean+/-sem, P< 0.05) but recovered to control rates within 48 h. In villous explants, PGE(2)production was significantly decreased after 48 and 72 h of hypoxia versus the normoxic control, accompanied by increased production of 6-keto-PGF(1alpha)to 173.9+/-26.7 per cent after 48 h. TXB(2)production was increased to 172.3+/-25.9 per cent and 653.2+/-135.7 per cent (P< 0.05) control after 48 and 72 h of hypoxia, respectively. These results were confirmed in villous explants (n=3) cultured in the presence of exogenous 10 microm arachidonic acid. Hypoxia had no significant effect on TXB(2)and 6-keto-PGF(1alpha)in trophoblast cells. In summary, our findings suggest that hypoxia could be responsible for abnormal profiles of prostanoid production commonly observed in women with pre-eclampsia. These results indicate a putative link between hypoxia and compromised placental perfusion.

Differential regulation in human amnion epithelial and fibroblast cells of prostaglandin E(2) production and prostaglandin H synthase-2 mRNA expression by dexamethasone but not tumour necrosis factor-alpha.

Previous studies have identified both pro-inflammatory cytokines and glucocorticoids as positive regulators of amnion prostaglandin (PG) biosynthesis. The stimulatory effects of dexamethasone (Dex), a glucocorticoid agonist, on prostaglandin endoperoxide H synthase (PGHS)-2 mRNA expression and PG biosynthesis in amnion have been attributed to an atypical response by the mesenchymal cells of the amnion. The objective of this study was to confirm previous findings concerning cell type-dependant Dex-induced upregulation of PGHS-2 mRNA expression and PG production using separated amnion cell populations, in comparison with the effects of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha). Amnion cells from placentae delivered at term by caesarian section were isolated by tryptic digestion and epithelial cells were then separated from mesenchymal cells by differential absorption onto plastic. After 24-72 h, the two cell populations were passaged and sub-cultured. Cells were treated with Dex (10(-9)-10(-6) m) or TNF-alpha (0.1-50 ng/ml) or media alone. Thereafter, PGE(2)production was determined and PGHS-2 mRNA content analysed by a competitive quantitative RT-PCR method established and validated for this study. PGE(2)production in fibroblast-enriched cultures was increased to 310+/-41 per cent (mean+/-sem, n=4 wells per treatment point) of control in the presence of 10(-8) m Dex. Conversely, PGE(2)production in Dex-treated amnion epithelial cells was decreased to 67+/-24 per cent of control. Altered PGE(2)biosynthesis was accompanied by the upregulation of PGHS-2 mRNA in amnion fibroblasts but not in epithelial cells. TNF-alpha increased PG output and PGHS-2 expression independent of cell type. Glucocorticoids therefore appear to have opposing effects on PG biosynthesis in the two major cellular components of the human amnion.

Platelet-leukocyte aggregates during hemodialysis: effect of membrane type.

Hemodialysis is associated with the formation of platelet-leukocyte aggregates. Whether this phenomenon is hemodialysis (HD) membrane dependent is unclear. To evaluate this process, we examined respectively platelet activation (anti-CD41, anti-CD62, and antifibrinogen monoclonal antibodies [MoAb] binding), leukocyte activation (CD11b expression), and the appearance of platelet specific antigens on leukocytes as an index of platelet-leukocyte aggregation during HD using 3 different membrane materials, Cuprophan, Hemophan, and polysulfone. Flow cytometric techniques and specific MoAb were used. All parameters were assayed 5 min after initiation of HD to avoid the confounding variable of leukopenia and resultant cell subpopulation analysis. Platelet activation (anti-CD62 and antifibrinogen binding) occurred only with Cuprophan. All 3 membranes induced equivalent increases in CD11b expression on neutrophils and similarly increased the binding of anti-CD41 to neutrophils, reflecting an increment in the formation of platelet neutrophil aggregates. However, only Cuprophan induced an increase in anti-CD62 binding to neutrophils, suggesting that the aggregated platelets linked to neutrophils were activated. Increased anti-CD41 binding by monocytes was similarly observed with all 3 membranes. However, only polysulfone induced an increase in CD11b expression and fibrinogen binding to monocytes. We conclude that while the formation of platelet leukocyte aggregates appears to be a universal phenomenon in HD occurring with a variety of membrane types, subtypes of this phenomenon consisting of activated platelets and fibrinogen binding may be membrane dependent. This phenomenon may serve as a new biocompatibility parameter and may shed light on some of the biologic consequences of hemodialysis.

Expansion of CD14+CD16+ monocytes in critically ill cardiac surgery patients.

We have asked whether critically ill cardiac valve surgery patients identified by a high APACHE II score exhibit an increase in the number of proinflammatory CD14+CD16+ monocytes. A group of 12 patients was studied over a period of 5 days post cardiac valve surgery for changes in blood monocyte populations. Patients were selected on day 1 post surgery to either be in good clinical condition (APACHE II Score of < or = 14; N = 9) or to be critically ill (APACHE II score of > or = 24; N = 3). The < or = 14 patients had an uneventful course and could leave the ICU after 2-3 days. Among the > or = 24 patients two showed a decrease of the score to < or = 14 within the 5 days of observation and they could leave the ICU thereafter. One > or = 24 patient (patient #2) had a persistently high score and finally died on day 28. Analysis of blood monocytes on day 1 post surgery revealed that the < or = 14 patients had normal values of CD14+CD16+ monocytes (44 +/- 9/microliter). By contrast the > or = 24 patients had increased values of these cells with 243 +/- 106 cells per microliter on day 1. The numbers of CD14+CD16+ monocytes returned to the control range over the 5 days of observation in 2 of the > or = 24 patients concomitant with the improvement of the APACHE II score. CD14+CD16+ monocytes remained, however, at a high level in patient #2, the patient with persistently high APACHE II score.

Down-regulation of surface monocyte lipopolysaccharide-receptor CD14 in patients on cardiopulmonary bypass undergoing aorta-coronary bypass operation.

OBJECTIVES: Major operative trauma like aorta-coronary bypass operation may lead to postoperative immunodisturbance, putting the patient at an increased risk for infection and sepsis. The monocyte/macrophage system and the endotoxin receptor CD14 are important in the early recognition and elimination of invading bacteria. The aim of this study was to analyze changes in membrane-associated CD14 and soluble CD14 during and after cardiac involving cardiopulmonary bypass. METHODS: We studied numbers of leukocytes, monocytes, and monocyte subpopulations, expression of monocyte membrane-associated CD14 and plasma levels of soluble CD14 in 10 patients (63 +/- 8 years of age), who underwent elective cardiopulmonary bypass. RESULTS: Cardiopulmonary bypass induced marked postoperative monocytosis, which was maximal 20 hours after the operation (485 +/- 242 cells/microl before, 1080 +/- 264 cells/microl 20 hours after surgery). Expression of membrane-associated CD14 on classical CD14++ monocytes decreased significantly by 40%, reaching a nadir 20 hours after surgery (p < 0.05). At the time of maximal membrane-associated CD14 suppression, the levels of soluble CD14 measured by enzyme-linked immunosorbent assay were clearly increased (3.2 +/- 1.0 microg/ml before versus 5.6 +/- 1.0 microg/ml 20 hours after, p < 0.001). No significant change of the percentage of small (alpha) and large (beta) forms of soluble CD14 was found. CONCLUSIONS: Cardiopulmonary bypass leads to reduced membrane-associated CD14 expression on peripheral blood monocytes and increased levels of soluble CD14 through shedding or secretion of membrane-associated CD14 from the cell surface. These findings indicate that bypass is associated with significant monocyte activation.