The effects of ecstasy on neurotransmitter systems: a review on the findings of molecular imaging studies

Ecstasy is a commonly used psychoactive drug with 3,4-methylenedioxymethamphetamine (MDMA) as the main content. Importantly, it has been suggested that use of MDMA may be neurotoxic particularly for serotonergic (5-hydroxytryptamine (5-HT)) neurons. In the past decades, several molecular imaging studies examined directly in vivo the effects of ecstasy/MDMA on neurotransmitter systems. The objective of the present study is to review the effects of ecstasy/MDMA on neurotransmitter systems as assessed by molecular imaging studies in small animals, non-human primates and humans. A search in PubMed was performed. Eighty-eight articles were found on which inclusion and exclusion criteria were applied. Thirty-three studies met the inclusion criteria; all were focused on the 5-HT or dopamine (DA) system. Importantly, 9 out of 11 of the animal studies that examined the effects of MDMA on 5-HT transporter (SERT) availability showed a significant loss of binding potential. In human studies, this was the case for 14 out of 16 studies, particularly in heavy users. In abstinent users, significant recovery of SERT binding was found over time. Most imaging studies in humans that focused on the DA system did not find any significant effect of ecstasy/MDMA use. Preclinical and clinical molecular imaging studies on the effects of ecstasy/MDMA use/administration on neurotransmitter systems show quite consistent alterations of the 5-HT system. Particularly, in human studies, loss of SERT binding was observed in heavy ecstasy users, which might reflect 5-HT neurotoxicity, although alternative explanations (e.g. down-regulation of the SERT) cannot be exclude

Do Relapses Follow ANCA Rises? A Systematic Review and Meta-Analysis on the Value of Serial ANCA Level Evaluation

Objectives: ANCA-vasculitis (AAV) patients frequently suffer from relapses and risk subsequent organ damage. There is much debate on the value of serial ANCA level evaluation to monitor disease activity. We aimed to evaluate the association between ANCA rises and disease relapses at (I) moment of the rise, (II) within 6 months or (III) within a year from the rise. Methods: 3 databases (MEDLINE, EMBASE, COCHRANE) were searched from 1993 through September 2021. We included studies that reported relapse incidence within 12 months after an ANCA rise measured by antigen-specific immunoassays in peripheral blood of AAV patients in remission. Quality assessment was performed using QUADAS-2. Finally, a meta-analysis was carried out to estimate average OR using a random effects model. Results: Twenty unique studies were included. The methodological quality was limited due to risk of selection bias. An ANCA rise often preceded a disease relapse within 6 months (OR 3.65, 95% CI 1.66–8.03) and less often within 12 months (OR 2.88, 95% CI 1.21–6.88), while it was not indicative of a concurrent relapse (OR 0.13, 95% CI 0.03–0.53). Once a relapse is diagnosed, ANCA is significantly more often present than not (OR 10.80, 95% CI 3.82–30.55). As expected based on clinical, technical and methodological variability between studies, there was substantial heterogeneity across studies in all analyses (I2 = 70–87%). Conclusion: In previously ANCA-positive patients, the ANCA test is often positive upon clinical suspicion of a disease relapse. Patients with a rise in ANCA are at risk of encountering disease relapses in the upcoming 6 or 12 months

Irisin Stimulates Osteoclast Differentiation and Function

Irisin is the cleaved product of the protein FNDC5 expressed in skeletal muscle, and is increased by exercise. Recent work suggests this myokine is a modulator of muscle-bone crosstalk. Irisin has been shown to increase bone formation (Colaiannia, PNAS 2015), prevent disuse-associated bone loss (Colaiannia, Sci Rep 2017), and directly stimulate osteoblasts (Colaiannia, Int J Endo 2014). These results demonstrate an anabolic function, but the full mechanisms of action on each key cell type in bone, and the relative impacts of irisin on bone formation, resorption, and coupled remodeling have yet to be elucidated. Converse to an anabolic role, genetic loss of FNDC5 protects against ovariectomy-induced bone loss by blocking bone resorption and osteocytic osteolysis. Additionally irisin acts directly on the osteocyte via the ?V?5 receptor to increase production of sclerostin and RANKL, key regulators of osteoclast differentiation (Kim, Cell 2018). The present work continues this investigation with the hypothesis that irisin acts directly on the osteoclast itself as well, stimulating differentiation and modulating downstream resorption and signaling functions. To characterize the effects of physiologic elevated concentrations of irisin on osteoclast differentiation in vitro, we cultured primary BMSCs from C57BL/6J (B6) female mice with mCSF and RANKL, with or without 10 ng/mL irisin. Continuous irisin treatment for 7 days led to significantly increased osteoclast numbers and heightened expression of differentiation markers (c-Fos, c-Src, fam10, Itgb3, NfkB, NFATC, RANK, Rela). Irisin-treated osteoclasts demonstrated larger, more nucleated cells, with increased expression of the fusion markers Atp6vod2 and DCstamp. Treatment with neutralizing antibodies against integrin ?V?5 abolished the increase in osteoclast number with irisin, indicating this integrin pair as the functional receptor for osteoclasts, as it has been demonstrated in the osteocyte. Irisin treatment also increased total resorption for osteoclasts on Corning Osteo Assay Surface plates, and heightened expression of bone resorption markers (TRAP5b, ADAMTS5, CLCN7, cathepsinK, MMP2). Irisin-treated osteoclasts also demonstrated increased expression of osteoblast-stimulating markers (CTHRC1, TGFB, WNT10a), indicating secretion of clastokines that may stimulate osteoblast function and promote coupled remodeling. The present work demonstrates that in addition to the osteoblast and osteocyte, irisin acts directly on the osteoclast via the integrin receptor ?V?5 to stimulate differentiation and resorption. These results support the inhibition of bone resorption observed with the genetic deletion of FNDC5. The stimulation of clastokine production further suggests that irisin may dynamically regulate coupled remodeling, as opposed to independently stimulating formation or resorption. However, the net effect of irisin on bone structure appears to vary depending on experimental conditions. Elucidating the cellular mechanisms of irisin and their interaction with the dose and timing of treatment could pave the way for development of this myokine as an anabolic therapy for bone diseases

Monocytes and macrophages in ANCA-associated vasculitis

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) are characterized by inflammation of small-to-medium-sized blood vessels and the presence of autoantibodies against cytoplasmic proteases sited in neutrophils and monocytes. Increasing evidence indicates a substantial role of monocytes and macrophages in the pathogenesis of AAV. Activated monocytes and macrophages contribute to necroinflammation in peripheral vasculitic lesions as well as to central and peripheral mechanisms of autoimmunity. The intermediate monocyte subset (CD14++CD16+) is increased and monocytes show elevated expression of CD14, Toll-like receptor 2/4, MHCII and integrins, likely reflecting activation and increased monocyte extravasation. Monocytes differentiate locally predominantly into alternatively activated (M2) macrophages, which are known for cell-clearance and phagocytosis, but may ultimately lead to fibrosis. Phagocytotic function of macrophages can be impaired by surface expression of cytoplasmic proteases on apoptotic neutrophils and causes release of inflammatory cytokines and immunogenic contents, presumably resulting in a vicious circle of increased neutrophil, T and B cell activation and consequent ANCA production. Considering their crucial role in initiating necroinflammation as well as fibrogenesis, monocytes and macrophages may represent a logic first-line target for new treatment options in AAV

Bronchoscopic Intrapulmonary Recombinant Factor VIIa for Diffuse Alveolar Hemorrhage-induced Acute Respiratory Failure in MPO-ANCA Vasculitis: A Case Report

INTRODUCTION: Diffuse alveolar haemorrhage (DAH) is a potentially life-threatening disease, characterized by diffuse accumulation of red blood cells within the alveoli. It can be caused by a variety of disorders. In case DAH results in severe respiratory failure, veno-venous extracorporeal membrane oxygenation (VV-ECMO) can be required. Since VV-ECMO coincides with the need for anticoagulation therapy, this results in a major clinical challenge in DAH patients with hemoptysis. CASE PRESENTATION: We report a patient case with severe DAH-induced acute respiratory failure and hemoptysis in need for VV-ECMO complicated by life-threatening membrane oxygenator thrombosis. The DAH-induced hemoptysis was successfully treated with local bronchoscopic recombinant factor VIIa (rFVIIa), allowing systemic anticoagulation to prevent further membrane oxygenator thrombosis. Neither systemic clinical side effects nor differences in the serum coagulation markers occurred after applying recombinant factor VIIa (rFVIIa) treatment endobronchially. CONCLUSION: This is, to our knowledge, the first case that reports the use of rFVIIa in a patient with DAH due to vasculitis and in need for VV-ECMO complicated by membrane oxygenator thrombosis

Traditional and disease-related cardiovascular risk factors in ANCA-associated vasculitis: A prospective, two-centre cohort study

Objectives: ANCA-associated vasculitis (AAV) has been associated with increased risk of cardiovascular (CV) events. The aim was to assess traditional and disease-related CV risk determinants in a two-centre prospective cohort of AAV patients. Methods: Patients were recruited from centres in the Netherlands and Canada. A comprehensive CV risk assessment was performed at inclusion. Subjects were followed up yearly for 3–5 years until the first CV event, death or end of follow-up. Cox proportional hazards analyses were performed to relate baseline characteristics to the first CV event. Results: A total of 144 patients were included (mean age 62 years, female sex 44%, median Framingham risk score 14.3%). Insulin resistance was present in 73% of patients tested at inclusion, independent of concurrent prednisone therapy. After a median follow-up of 2.90 years, 16 patients (11%) experienced a CV event (14 non-fatal and 2 fatal). The incidence of CV events was 5.45 per 100 patient-years. Age, Framingham risk score, HbA1c level, Diabetes Mellitus (DM), and previous CV event were significantly associated with CV events. Other factors, such as sex, impaired renal function, dyslipidemia, hypertension, smoking history and microalbuminuria, or disease-specific variables, like ANCA serotype or disease activity, were not significantly related to CV events in univariable or age-adjusted cox regression analysis. Conclusions: Determinants of an increased CV risk were identified. Disease-related factors and treatments can further modify individual risk factors, such as for steroids causing chronic insulin resistance and DM. Treatment of risk factors is essential to optimize long-term outcomes in AAV patients

Irisin directly stimulates osteoclastogenesis and bone resorption

The myokine irisin facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In the current study we investigated whether irisin also directly regulates osteoclasts

Macrophages in Lupus Nephritis: Exploring a potential new therapeutic avenue

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that occurs in about half of patients. LN is characterized by glomerular deposition of immune complexes, leading to subendothelial, mesangial and subepithelial electron dense deposits, triggering immune cell infiltration and glomerular as well as tubulointerstitial injury. Monocytes and macrophages are abundantly present in inflammatory lesions, both in glomeruli and the tubulointerstitium. Here we discuss how monocytes and macrophages are involved in this process and how monocytes and macrophages may represent specific therapeutic targets to control LN

Dual targeting of salt inducible kinases and csf1r uncouples bone formation and bone resorption

Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05–099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05–099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05–099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05–099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05–099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity