Sympathectomy aggravates subchondral bone changes during osteoarthritis progression in mice without affecting cartilage degeneration or synovial inflammation.

OBJECTIVE: Osteoarthritis (OA) pathogenesis involves the interaction of articular cartilage with surrounding tissues, which are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers suggesting a role of the sympathetic nervous system (SNS) during OA progression. We analyzed the effects of sympathectomy (Syx) in a murine OA model. METHODS: Peripheral Syx was generated by 6-hydroxydopamine (6-OHDA) injections in male C57BL/6 mice. OA was induced in wild-type (WT) and Syx mice by destabilization of the medial meniscus (DMM). TH+ fibers and splenic NE were analyzed to evaluate Syx efficiency. OA progression was examined by OARSI and synovitis scores and micro-CT. Expression of TH, α2A- and ß2-adrenergic receptors (AR), and activity of osteoblasts (ALP) and osteoclasts (TRAP) was investigated by stainings. RESULTS: Syx resulted in synovial TH+ fiber elimination and splenic NE decrease. Cartilage degradation and synovitis after DMM were comparably progressive in both WT and Syx mice. Calcified cartilage (CC) and subchondral bone plate (SCBP) thickness and bone volume fraction (BV/TV) increased in Syx mice due to increased ALP and decreased TRAP activities compared to WT 8 weeks after DMMWT and Syx mice developed osteophytes and meniscal ossicles without any differences between the groups. AR numbers decreased in cartilage but increased in synovium and osteophyte regions after DMM in both WT and Syx mice. CONCLUSION: Peripheral dampening of SNS activity aggravated OA-specific cartilage calcification and subchondral bone thickening but did not influence cartilage degradation and synovitis. Therefore, SNS might be an attractive target for the development of novel therapeutic strategies for pathologies of the subchondral bone.

Increased Serum Levels of soluble ST2 as a Predictor of Disease Progression in Systemic Sclerosis.

OBJECTIVE: Interleukin-33 (IL-33) has been investigated as a mediator in the pathogenesis of fibrosis in lung, liver, and heart. There is accumulating evidence for the involvement of the IL-33/IL-33 receptor ST2L signalling pathway in systemic sclerosis (SSc). Little is known about the role of serum sST2 in SSc, which is the subject of the present investigation. METHOD: Serum levels of sST2 were measured in 49 patients with SSc, recruited prospectively between November 2017 and March 2019. Patients were divided into those with progressive and those with stable disease. Receiver operating characteristics (ROC) curve analysis was applied to study sST2 as a marker for identifying patients with progressive disease. We used multivariate logistic regression analysis to evaluate the predictive value of sST2 for progressive disease after adjustment for potential confounding factors. RESULTS: Serum sST2 levels in patients with progressive disease were significantly elevated compared with patients with stable disease (mean ± sem: 50.4 ± 4.7 ng/mL vs 29.2 ± 2.97 ng/mL, p < 0.001). ROC curve analysis identified an sST2 cut-off value of 37.8 ng/mL as optimal for discriminating patients with progressive disease from those with stable disease (sensitivity 80.0%, specificity 79.3%, area under the curve 0.80). After controlling for potential confounding factors (age, gender, C-reactive protein, pro-brain natriuretic peptide, and sum of internal medicine comorbidities), sST2 remained predictive of progressive disease (odds ratio 1.070, 95% confidence interval 1.017-1.126, p < 0.009). CONCLUSION: In the present study, sST2 serum levels were predictive of disease progression in patients with SSc.

Increased extracellular water measured by bioimpedance analysis and increased serum levels of atrial natriuretic peptide in polymyalgia rheumatica patients : Signs of volume overload.

BACKGROUND: Water retention is a typical feature of acute inflammatory episodes, chiefly implemented by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. This is an important compensatory mechanism counteracting expected water loss, e.g., due to sweating. Both the SNS and HPA axis are activated in polymyalgia rheumatica (PMR). As retention mechanisms may similarly apply in this disease, we hypothesized increased water retention in PMR. METHODS: Using bioimpedance analysis body composition was investigated in 64 healthy controls and 32 treatment-naive PMR patients. All PMR patients satisfied the 2012 EULAR/ACR classification criteria for PMR. 32 PMR patients were tested before and after 7 days of glucocorticoid-based therapy. Serum levels of pro-atrial natriuretic peptide (proANP) were investigated in all PMR patients and 15 healthy controls. RESULTS: Extracellular water (ECW) was markedly higher in PMR patients than in controls (mean ± SD: 49.1 ± 6.0% versus 36.3 ± 2.5% of total body water, p < 0.001). Patients with PMR demonstrated significantly higher serum levels of proANP compared to controls. Even before glucocorticoid treatment was initiated, systolic and diastolic blood pressure were higher in PMR patients compared to controls. Extracellular water levels did not change in PMR patients upon 7 days of intensified treatment. CONCLUSION: This study demonstrated increased extracellular water and elevated serum levels of proANP as signs of fluid overload in patients with PMR. Volume changes are imprinted as long-lasting mechanisms as water distribution is not affected by short-term anti-inflammatory therapy.

[Research consortium Neuroimmunology and pain in the research network musculoskeletal diseases]. / Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa) im Forschungsnetz Muskuloskelettale Erkrankungen.

BACKGROUND: The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis. MATERIAL AND METHODS: The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients. RESULTS: Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases. DISCUSSION: Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.

Quantification of coronary low-attenuation plaque volume for long-term prediction of cardiac events and reclassification of patients.

BACKGROUND: To investigate the incremental prognostic value of low-attenuation plaque volume (LAPV) from coronary CT angiography datasets. METHODS: Quantification of LAPV was performed using dedicated software equipped with an adaptive plaque tissue algorithm in 1577 patients with suspected CAD. A combination of death and acute coronary syndrome was defined as primary endpoint. To assess the incremental prognostic value of LAPV, parameters were added to a baseline model including clinical risk and obstructive coronary artery disease (CAD), a baseline model including clinical risk and calcium scoring (CACS) and a baseline model including clinical risk and segment involvement score (SIS). RESULTS: Patients were followed for 5.5 years either by telephone contact, mail or clinical visits. The primary endpoint occurred in 30 patients. Quantified LAPV provided incremental prognostic information beyond clinical risk and obstructive CAD (c-index 0.701 vs. 0.767, p < .001), clinical risk and CACS (c-index 0.722 vs. 0.771, p < .01) and clinical risk and SIS (c-index 0.735 vs. 0.771, p < .01. A combined approach using quantified LAPV and clinical risk significantly improved the stratification of patients into different risk categories compared to clinical risk alone (categorical net reclassification index 0.69 with 95% CI 0.27 and 0.96, p < .001). The combined approach classified 846 (53.6%) patients as low risk (annual event rate 0.04%), 439 (27.8%) patients as intermediate risk (annual event rate 0.5%) and 292 (18.5%) patients as high risk (annual event rate 0.99%). CONCLUSION: Quantification of LAPV provides incremental prognostic information beyond established CT risk patterns and permits improved stratification of patients into different risk categories.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Systemic metabolic signaling in acute and chronic gastrointestinal inflammation of inflammatory bowel diseases.

Acute and chronic intestinal inflammation stimulates innate and adaptive immune systems, thereby increasing energy demand of activated immune cells. Energy regulation by systemically released mediators is of critical importance for homeostasis. We wanted to find out how systemic metabolic mediators are affected during intestinal inflammation. A total of 123 patients suffering from Crohn's disease (CD), 76 patients with ulcerative colitis (UC), and 21 healthy controls were recruited. Patients receiving systemic steroids or therapy regimens including biologicals (anti-TNF) were excluded from the study. Serum levels of IL-6, CRP, insulin, glucose, free fatty acid, and RBP-4 were measured by ELISA and RIA. Intestinal inflammation was accompanied by elevated systemic inflammatory para-meters such as IL-6 and CRP in UC and CD and, concomitantly, with elevated insulin levels and increased insulin/glucose ratio in patients with UC. This indicates insulin resistance in liver, muscle, and fat. In addition, intestinal inflammation was associated with elevated levels of circulating free fatty acids in UC and CD, indicating an activation of the organism's appeal for energy-rich substrates (energy appeal reaction). RBP-4 serum levels were also high in acute and chronic intestinal inflammation in UC and CD, which can support insulin resistance. The organism's "energy appeal reaction" in response to acute and chronic inflammation provides free energy in the circulation, which is needed by inflammatory cells. A major mechanism of the redirection program is insulin resistance. New therapeutic strategies might be developed in the future, directly impacting on the storage and utilization of energy-rich fuels.

Electrodermal hyporeactivity as a trait marker for suicidal propensity in uni- and bipolar depression.

BACKGROUND: A meta-analysis of studies investigating electrodermal activity in depressed patients, suggested that electrodermal hyporeactivity is sensitive and specific for suicide. AIMS: To confirm this finding and to study electrodermal hyporeactivity relative to type and severity of depression, trait anxiety, its stability and independence of depressive state. METHOD: Depressed inpatients (n = 783) were tested for habituation of electrodermal responses and clinically assessed using the Beck Depression Inventory (BDI) and the STAI-Trait scale for trait anxiety. RESULTS: The high sensitivity and raw specificity of electrodermal hyporeactivity for suicide were confirmed. Its prevalence was highest in bipolar disorders and was independent of severity of depression, trait anxiety, gender and age. Hyporeactivity was stable, while reactivity changed into hyporeactivity in a later depressive episode. CONCLUSIONS: The findings support the hypothesis that electrodermal hyporeactivity is a trait marker for suicidal propensity in depression.

Urine of patients with acute kidney transplant rejection show high normetanephrine and decreased 2-hydroxyestrogens concentrations.

BACKGROUND: A shift from anti- to proinflammatory steroid hormones has been observed in chronic inflammation. We tested the hypothesis that this shift occurs also in kidney transplant rejection together with a rise of urinary catecholamine degradation product concentrations as a consequence of locally produced cytokines, thus further promoting rejection. METHODS: We examined 8 patients with an early rejection episode in the protocol biopsy ∼2 weeks, 9 with biopsy-proven rejection at 2-3 months, and 18 without rejection, both at 2 weeks and 3 months after transplantation. Metanephrine, normetanephrine, and 2- and 16-hydroxyestrogens concentrations were measured by EIA. RESULTS: The median urinary concentrations of normetanephrine, but not metanephrine, were significantly higher in acute kidney transplant rejection in the first 2 weeks after transplantation (P < .05). During acute kidney transplant rejection at 2-3 months, but not in the first 2 weeks, after transplantation, 2-, but not 16-hydroxyestrogens, concentrations were significantly decreased (P < .05). CONCLUSIONS: We demonstrated that the downstream product of noradrenaline conversion normetanephrine was elevated in kidney transplant rejection in the first weeks after transplantation. This change may promote rejection together with an important proinflammatory and mitogenic steroid hormone shift, which becomes increasingly relevant over time.

Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: impact of exogenous neuropeptide Y.

BACKGROUND & AIMS: Splanchnic vasodilation is an essential disturbance in portal hypertension. Increased systemic sympathetic nerve activity is well known, but potential corresponding vascular desensitization is incompletely characterized. Release of splanchnic sympathetic neurotransmitters noradrenaline (NA) and co-transmitter neuropeptide Y (NPY) remains to be elucidated. Finally, the effects of exogenous NPY on these mechanisms are unexplored. METHODS: Portal vein ligated cirrhotic, and control rats were used for in vitro perfusion of mesenteric arteries. Depletion of vascular pressure response was induced by repetitive electric sympathetic perivascular nerve stimulation (PNS) and performed in the absence and presence of exogenous NPY. Additionally, PNS-induced release of NA and NPY was measured. RESULTS: Mesenteric PNS-induced pressure response was lower in portal hypertension. Depletion of the pressure response to PNS, representing the degree of desensitization, was enhanced in portal hypertension. NA release was elevated, whereas NPY release was attenuated in cirrhosis. Administration of exogenous NPY led to marked recovery from desensitization and vasoconstrictive improvement in cirrhotic rats, being associated with more pronounced decrease of NA release. CONCLUSIONS: Pronounced depletion of splanchnic arterial pressure-response to repetitive sympathetic nerve stimulation in cirrhosis is partly attributable to altered NA release as well as to deficient NPY release. External NPY restores vascular contractility and attenuates pathologically elevated NA release in the portal hypertensive mesenteric vasculature, revealing post-, and prejunctional effects at the vascular smooth muscle motor endplate; therefore outlining encouraging therapeutic strategies.

Loss of sensory and noradrenergic innervation in benign colorectal adenomatous polyps--a putative role of semaphorins 3F and 3A.

BACKGROUND: Nerve fibers can exert trophic/anti-trophic effects on epithelial cells. Substance P (SP) is a pro-proliferative neuropeptide, whereas sympathetic noradrenaline is anti-proliferative at high concentrations. METHODS: Density of noradrenergic and sensory nerve fibers and presence of nerve repellent factors specific for noradrenergic (semaphorin 3F) and sensory nerve fibers (semaphorin 3A) were investigated in colorectal adenomas. KEY RESULTS: The pedunculus was innervated by noradrenergic fibers, whereas the mucosa was sparsely innervated. The control submucosa compared with control mucosa demonstrated increased density of noradrenergic fibers. Control tissue was much better innervated than the polyp. This was accompanied by strong expression of semaphorin 3F in epithelial cells. Density of sensory SP+ nerve fibers was higher in control colon mucosa compared with polyp mucosa, and SP+ cell clusters and semaphorin 3A-positive cells appeared in the intercrypt space in polyps, but not in control tissue. CONCLUSIONS & INFERENCES: This study demonstrated a marked loss of noradrenergic and sensory nerve fibers in polyp mucosa, which was associated with a strong increase of semaphorin 3F and 3A. Up-regulation of the sympathetic repellent semaphorin 3F in the polyps possibly triggers sympathetic repulsion and polyp growth due to the loss of anti-proliferative noradrenaline and presence of SP from local SP+ cells.

Regulation of glucocorticoids by the central nervous system.

The central nervous biological CLOCK system (highly conserved and sophisticated molecular 'clock'), under the influence of light/dark alterations, 'creates' the internal circadian rhythms. The organisms 'feel' these rhythmic external changes to synchronise their physical activities, including energy metabolism, sleep, and immune function. A number of immunological functions are dependent on influence of sleep on circadian rhythms, including the type and magnitude of immune responses following antigenic challenge. Loss of sleep, in turn, prevents these immunosupportive actions and alters the production of glucocorticoids during the night. Major life events lead to an intense release of stress response system mediators (mainly norepinephrine and cortisol), whereas in minor life events, only short-lived surges of these neurotransmitters and hormones are expected. The immune system reactivity follows circadian rhythms imposed by the CLOCK and sleep synchronisation, and is particularly altered in presence of chronic stress. As a consequence of the altered CNS-endocrine control, low-dose long-term glucocorticoid therapy in chronic rheumatic diseases is today considered as a 'hormonal replacement therapy' to supplement the peripheral insufficiency of endogenous glucocorticoids in modulating the immune/inflammatory reaction.

Prednisone chronotherapy.

Glucocorticoids (GCs) are widely used in clinical medicine because of their anti-inflammatory and immunosuppressive effects. However, these agents have a considerable potential for adverse effects, especially if used in high doses. The currently most advanced approach to improve the risk-benefit ratio of GCs is low-dose prednisone chronotherapy with modified release (MR) prednisone timing drug release to chronobiological rhythms. In RA, the circadian rhythms of pain, stiffness and functional disability show maximum symptoms in the early morning hours, which is preceded by elevated levels of pro-inflammatory cytokines, in particular interleukin 6. It was hypothesised that preventing the nocturnal rise of pro-inflammatory cytokines by GC therapy is more effective than treating established symptoms in the morning. As waking in the night for tablet intake is impracticable, modified release (MR) prednisone was developed, which releases prednisone approximately four hours after ingestion (i.e. at approximately 2 am if taken at 10 pm bedtime). Data from two large-scale trials in rheumatoid arthritis (RA) (CAPRA-1 and 2) document that MR prednisone has greater efficacy for long-term, low-dose glucocorticoid treatment in patients with RA, with a significant reduction in morning joint stiffness, in addition to all known therapeutic effects with conventional prednisone and a similar safety profile without additional suppression of hypothalamic-pituitary-adrenal (HPA) axis. For patients with RA on low to medium doses of prednisone, especially those who continue to experience a long duration of morning stiffness, MR prednisone appears a valuable additional treatment option.

Alterations of the hypothalamic-pituitary-adrenal axis in systemic immune diseases - a role for misguided energy regulation.

The investigation of the hypothalamicpituitary-adrenal (HPA) axis in chronic inflammation has demonstrated: 1) an anti-inflammatory influence of the HPA axis; 2) low serum levels of adrenal androgen; 3) equivocal results with respect to levels of adrenocorticotropic hormone and cortisol; 4) inadequately low secretion of adrenal hormones in relation to inflammation (the disproportion principle); 5) modulating role of TNF and IL-6 on the HPA axis; 6) disturbed cooperativity of HPA axis and sympathetic nervous system (uncoupling); 7) observable glucocorticoid resistance; 8) the circadian rhythmicity explains morning symptoms; 9) new medications based on malfunction of the HPA axis (e.g. adapted to the circadian rhythm of hormones and cytokines); and 10) the newly described role of the HPA axis in the context of misguided energy regulation in chronic inflammatory diseases. This review discusses items 1-6 and 10, while the other items are presented elsewhere in this Supplement. Evidence is presented that the basis for many alterations is in an adaptive program positively selected for short-lived inflammatory responses (energy appeal reaction), which becomes a disease-inherent pathogenetic factor, if it continues too long, that can drive systemic disease sequelae of chronic inflammatory diseases such as the metabolic syndrome.

Failure of oral DHEA treatment to increase local salivary androgen outputs of female patients with Sjögren's syndrome.

OBJECTIVES: Sjögren's syndrome (SS) is a female-dominant autoimmune disease characterized by androgen depletion and defective dehydroepiandrosterone (DHEA) processing enzymatic machinery in the salivary glands. We hypothesized that, because of these local failures, DHEA replacement therapy would be unable to improve the local androgen deficiency in SS salivary glands. METHODS: DHEA-deficient female SS patients (n = 12) were treated with placebo for 4 months followed by DHEA 50 mg q.d. for 4 months. Serum and saliva, collected in the morning before the trial and after both periods, were analysed for pro-hormones, androgens, and androgen metabolite using an enzyme-linked immunosorbent assay (ELISA). RESULTS: DHEA treatment increased serum DHEA-sulfate from 1.3 ± 0.1 to 6.4 ± 1.3 µM (p = 0.005), DHEA from 16.5 ± 2.8 to 34.8 ± 8.2 nM (p = 0.012), androstenedione from 3.1 ± 0.3 to 17.2 ± 1.9 nM (p = 0.002), free testosterone from 2.2 ± 0.1 to 7.7 ± 1.1 pM (p = 0.002), DHT from 275.5 ± 24.4 to 834.6 ± 122.8 pM (p = 0.002) and 3-α-diol-G from 3.8 ± 0.6 to 13.6 ± 2.0 nM (p = 0.001). However, only salivary DHEA and DHT outputs increased significantly and 25% of the patients showed no increases, except for DHEA itself. Outputs of active androgens (T, DHT) and 3-α-diol-G metabolite correlated with salivation. CONCLUSIONS: The local androgen deficiency in SS salivary glands is not only caused by low serum DHEA(-S) because restoration of systemic androgen levels by DHEA treatment did not correct local androgen depletion. This could be explained by low or no capacity of DHEA-substituted patients to convert the pro-steroid to active androgen metabolites. Such intracrine failures affect women in particular, who must produce their salivary T and DHT locally from DHEA.

[Neuroendocrine immunology: new pathogenetic aspects and clinical application]. / Neuroendokrinimmunologie: Neue Aspekte zur Pathogenese und Klinischen Anwendung.

After two decades of enormous improvements in anti-inflammatory therapy with biologics long-standing disease sequelae in chronic inflammatory diseases (CID) can be recognized, such as fatigue, anorexia/malnutrition, cachectic obesity, insulin resistance, dyslipidemia, changes of steroid hormone axes (e. g. loss of androgens), increased sympathetic nervous tone/decreased parasympathetic nervous tone, inflammation-related anemia and osteopenia. This article demonstrates for the first time in the German language a new theory to explain the pathophysiology of these disease sequelae. It includes concepts from evolutionary medicine and neuroendocrine regulation of energy allocation. The core statement is: the networks of energy regulation and energy allocation have been evolutionarily positively selected for transient inflammatory episodes (not for CIDs due to the negative selection pressure) but long-standing use of these adaptive programs for CID support systemic disease sequelae. These considerations might help to deviate focus from pure anti-inflammatory treatment to adequate diagnosis and therapy of systemic disease sequelae.